transforming-growth-factor-beta and Atrophy

Fibrotic diseases are a significant global burden for which there are limited treatment options. The effector cells of fibrosis are activated fibroblasts called myofibroblasts, a highly contractile cell type characterized by the appearance of α-smooth muscle actin stress fibers. The underlying mechanism behind myofibroblast differentiation and persistence has been under much investigation and is known to involve a complex signaling network involving transforming growth factor-β, endothelin-1, angiotensin II, CCN2 (connective tissue growth factor), and platelet-derived growth factor. This review addresses the contribution of these signaling molecules to cardiac fibrosis.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Anti-Inflammatory Agents; Arrhythmias, Cardiac; Atrophy; Cicatrix; Connective Tissue Growth Factor; Endothelin Receptor Antagonists; Endothelin-1; Fibrosis; Humans; Hypoxia; Models, Cardiovascular; Molecular Targeted Therapy; Myocardium; Myofibroblasts; Platelet-Derived Growth Factor; Pyridones; Rats; Signal Transduction; Transforming Growth Factor beta

Chronic allograft nephropathy is the major cause of kidney allograft loss, and recent advances in immunosuppression therapy do not alter the picture. Interstitial fibrosis and tubular atrophy is an early event that starts early after engraftment and even could be found in recipients with good allograft function. Serum creatinine and estimated glomerular filtration rate have limited clinical roles in estimating the histopathological changes and graft fibrosis. Recent progress in microRNA research has created a great promise to identify new diagnostic biomarkers and therapeutic targets in renal fibrosis.

Topics: Allografts; Atrophy; Biomarkers; Epithelial-Mesenchymal Transition; Extracellular Matrix; Fibrosis; Graft Rejection; Humans; Kidney; Kidney Transplantation; Kidney Tubules; MicroRNAs; Nephritis, Interstitial; Transforming Growth Factor beta

Hypertensive nephrosclerosis is the second most common cause of end-stage renal disease, however morphologic evidence on the subject is poorly understood. A perennial and vexing problem in understanding kidney hypertension is that correlations between hypertension and vascular and glomerular lesions are only moderate, in part because all of these lesions are present to a greater or lesser degree in the normotensive, aging kidney, with racial differences in severity further compounding the problem. This review looks at newer data on this topic.. Recent data suggest that there are two different processes leading to glomerulosclerosis, and the combination of the two begins to explain why global correlations between hypertension and morphologic lesions are destined to remain poor. Arterial stiffening with increased pulse pressure down as far as the afferent arteriolar level likely plays an important role in the progression of glomerular lesions. Loss of renal autoregulation with glomerular hypertrophy, hyperfiltration, and focal segmental glomerulosclerosis is now recognized to contribute significantly to nephrosclerosis, particularly in the black population. Ischemic glomerulosclerosis, however, may ultimately be the most important lesion, with consequent hypoxia in the parenchyma beyond, leading to tubular atrophy and interstitial fibrosis.. Hypertensive nephrosclerosis should be seen as a process with two principal modes of glomerular sclerosis, ischemic and hypertrophic, with consequent focal segmental glomerulosclerosis, contributing variably to renal failure according to race and level of hypertension.

Topics: Animals; Atrophy; Blood Pressure; Cell Hypoxia; Disease Models, Animal; Elasticity; Fibrosis; Glomerular Filtration Rate; Homeostasis; Humans; Hypertension; Hypertrophy; Inflammation Mediators; Ischemia; Kidney Glomerulus; Nephrosclerosis; Renal Artery; Renal Circulation; Transforming Growth Factor beta

The dramatic improvements in short-term graft survival and acute rejection rates could only have been dreamed of 20 years ago. Late graft loss following kidney transplantation is now the critical issue of this decade. Frequently, graft loss is associated with the development of tubular atrophy and interstitial fibrosis within the kidney (i.e. chronic allograft nephropathy; CAN). Major treatment strategies in this disorder are non-specific and the focus of intervention has been on limiting injurious events. Following graft injury is a fibrogenesis phase featuring both proliferative and infiltrative responses mediated by chemokines, cytokines and growth factors. In particular, TGFbeta has been strongly implicated in the pathogenesis of chronic injury and epithelial-mesenchymal transformation (EMT) may be part of this process. The cascade of events results in matrix accumulation, due to either increased production and/or reduced degradation of matrix. Recent investigations into the pathogenesis of tissue fibrosis have suggested a number of new strategies to ameliorate matrix synthesis. While the majority of therapies have focused on TGFbeta, this may not be an ideal maneuver in transplant settings and alternative targets identified in other fibrotic diseases will be discussed. Attacking graft fibrosis should be a new focus in organ transplantation.

Topics: Animals; Atrophy; Chemokines; Cytokines; Fibrosis; Graft Rejection; Growth Substances; Humans; Kidney Diseases; Kidney Transplantation; Transforming Growth Factor beta; Transplantation, Homologous

Topics: Atrophy; Fibrosis; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Kidney Failure, Chronic; Kidney Tubules; Nephritis, Interstitial; Platelet-Derived Growth Factor; Transforming Growth Factor beta

Topics: Animals; Atrophy; Bone Marrow Transplantation; Disease Models, Animal; Edema; Graft vs Host Disease; Interleukin-2; Lymphocyte Activation; Mice; Mice, Inbred Strains; Radiation Chimera; Scleroderma, Systemic; Sclerosis; Spleen; T-Lymphocytes; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

To compare the effect of recombinant human bone morphogenetic protein-2 (rhBMP-2) in an absorbable collagen sponge carrier (ACS) with autogenous bone graft for augmentation of the edentulous atrophic anterior maxilla.. Twenty-four subjects were enrolled in a randomized, controlled, parallel-group, open-label clinical trial. Subjects either received rhBMP-2/ACS (1.5 mg/ml) or particulated autogenous bone harvested from the mandibular retromolar region. A titanium-mesh was used to provide space and wound stability. A guide was used to standardize clinical recordings using an analogue caliper. Alveolar ridge width was also assessed using cone-beam computed tomography.. rhBMP-2/ACS yielded significantly greater radiographic horizontal bone gain compared with autogenous bone graft at immediate subcrestal levels (1.5 ± 0.7 versus 0.5 ± 0.9 mm; p = 0.01); non-significant differences were observed at mid- (2.9 ± 0.8 versus 2.9 ± 0.9 mm; p = 0.98) and apical (1.7 ± 0.9 versus 1.8 ± 1.1 mm; p = 0.85) crestal levels. No significant differences in clinical horizontal bone gain were observed at 6 months between rhBMP-2/ACS and autogenous bone graft (3.2 ± 0.9 mm versus 3.7 ± 1.4 mm; p = 0.31). Sixty-two implants were placed after 6 month of healing with no significant differences between groups for number of implants, implant size, primary stability and survival.. rhBMP-2/ACS appears a realistic alternative for augmentation of the edentulous atrophic anterior maxilla.

Topics: Absorbable Implants; Adult; Alveolar Process; Alveolar Ridge Augmentation; Atrophy; Autografts; Biocompatible Materials; Bone Morphogenetic Protein 2; Bone Transplantation; Collagen; Cone-Beam Computed Tomography; Dental Implantation, Endosseous; Dental Implants; Drug Carriers; Female; Follow-Up Studies; Humans; Jaw, Edentulous, Partially; Male; Maxilla; Middle Aged; Osteogenesis; Recombinant Proteins; Surgical Mesh; Titanium; Transforming Growth Factor beta

Growth/differentiation factor 8 (GDF8), or myostatin, negatively regulates muscle mass. GDF8 is held in a latent state through interactions with its N-terminal prodomain, much like TGF-β. Using a combination of small-angle X-ray scattering and mutagenesis, we characterized the interactions of GDF8 with its prodomain. Our results show that the prodomain:GDF8 complex can exist in a fully latent state and an activated or "triggered" state where the prodomain remains in complex with the mature domain. However, these states are not reversible, indicating the latent GDF8 is "spring-loaded." Structural analysis shows that the prodomain:GDF8 complex adopts an "open" configuration, distinct from the latency state of TGF-β and more similar to the open state of Activin A and BMP9 (nonlatent complexes). We determined that GDF8 maintains similar features for latency, including the alpha-1 helix and fastener elements, and identified a series of mutations in the prodomain of GDF8 that alleviate latency, including I56E, which does not require activation by the protease Tolloid. In vivo, active GDF8 variants were potent negative regulators of muscle mass, compared with WT GDF8. Collectively, these results help characterize the latency and activation mechanisms of GDF8.

Topics: Activins; Animals; Atrophy; Cell Differentiation; Dependovirus; Growth Differentiation Factor 2; Growth Differentiation Factors; HEK293 Cells; Humans; Hydrogen-Ion Concentration; Ligands; Male; Mice; Mice, Inbred C57BL; Mutagenesis; Mutation; Myostatin; Protein Domains; Scattering, Small Angle; Signal Transduction; Transforming Growth Factor beta

Cases of severely atrophic edentulous maxilla require reconstruction techniques employing bone grafts to promote adequate bone dimension for the successful placement of dental implants for prosthetic rehabilitation that reestablishes the patient's function and aesthetics. This study aims to present a severely atrophic edentulous maxilla reconstruction with the off-label use of recombinant human bone morphogenetic protein type 2 (rhBMP-2) associated with lyophilized particulate bovine bone xenograft for the prosthetic rehabilitation with osseointegrable dental implants. The paper describes a case of severely atrophic edentulous maxilla in a 42-year-old woman referred to the dental school with complaint of failure in adaptating to the dentures. The patient reported 27 years of maxilla edentulism and consecutive treatment failures, so the proposed therapy was the reconstruction of the maxilla with an association of rhBMP-2 and lyophilized bovine bone xenograft for increasing bone volume and further prosthetic rehabilitation with osseointegrated dental implants. The present report illustrates a case of atrophic edentulous maxilla in which the off-label use of rhBMP-2 was successful and the patient's prosthetic rehabilitation could be concluded. The 8 dental implants received prosthetic functional load during 1 year of follow-up with no complications. Based on the case presented, the association between rhBMP-2 and a bovine bone xenograft could be considered a viable option for the reconstruction of atrophic edentulous maxilla. After a year of functional prosthetic load follow-up, the patient is asymptomatic and satisfactorily adaptated to the prosthesis, which restored her functional and aesthetic demands.

Topics: Adult; Animals; Atrophy; Bone Morphogenetic Protein 2; Bone Transplantation; Cattle; Dental Implantation, Endosseous; Dental Prosthesis, Implant-Supported; Esthetics, Dental; Female; Freeze Drying; Humans; Jaw, Edentulous, Partially; Maxilla; Recombinant Proteins; Transforming Growth Factor beta

Substantial evidence exists demonstrating the individual effectiveness of both rhBMP-2 and -7 in the treatment of nonunions, data comparing the clinical effectiveness of adjunct rhBMP-2 and -7 remains scarce. Therefore, we examined our large single-center case series to compare the clinical effectiveness of both rhBMP-2 and -7 in non-union therapy aiming to answer: - Does a certain type of BMP have an advantageous effect on radiological outcome of applied lower limb non-union therapy? - Does application of a certain type of BMP have an advantageous effect on radiological outcome of infected lower limb nonunions? - Are there any additional risk factors associated with inferior outcome in context with an adjunct BMP treatment?. Both BMPs have the same effect on the radiological outcome of surgically treated lower limb nonunions.. Single-center retrospective database analysis of a case series of patients with lower limb long bone nonunions receiving either a one- or two-stage (Masquelet-) procedure based on the "diamond concept" with application of rhBMP-2 or -7. The "diamond concept" summarizes core factors that need to be present to achieve bone healing. In particular, these factors relate to the optimization of the mechanical (stability) and biological environment (sufficient osteogenic and angiogenic cells, osteoconductive scaffolds and growth factors). All medical data from patients that received surgical treatment between 01/01/2010 and 31/12/2016 were assessed. In total, 356 patients were treated with BMPs and 156 patients 18 years or older with non-union of their tibia or femur having a follow-up of at least 1 year were included. Consolidation in context with type of rhBMP was compared and the influence of relevant risk factors assessed.. Consolidation rate was significantly higher in patients treated with rhBMP-2 (rhBMP-2: 42/46 (91%) vs. rhBMP-7: 64/110 (58%); p<0.001). In particular, application of rhBMP-2 increased the likelihood of consolidation for tibial nonunions (OR 32.744; 95%CI: 2.909-368.544; p=0.005) and when used in two-stage therapy (OR 12.095; 95% CI: 2.744-53.314; p=0.001). Furthermore, regression modeling revealed a higher correlation between application of rhBMP-2 and osseous consolidation in infected nonunions (OR 61.062; 95% CI: 2.208-1688.475; p=0.015) than in aseptic nonunions (OR 4.787; 95% CI: 1.321-17.351; p=0.017). Risk factors negatively influencing the outcome of non-union treatment in context with rhBMPs were identified as active smoking (OR 0.357; 95% CI: 0.138-0.927; p=0.024), atrophic nonunion (OR 0.23; 95% CI: 0.061-0.869; p=0.030), higher BMI (OR 0.919; 95% CI: 0.846-0.998; p=0.046) and a larger defect size (OR 0.877; 95% CI: 0.784-0.98; p=0.021).. Patients who received rhBMP-2 for the treatment of tibial nonunions and as part of the two-stage treatment had a significantly higher rate of healing compared to patients treated with rhBMP-7 regardless of infection.. III, retrospective case-control study.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Atrophy; Body Mass Index; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 7; Bone Transplantation; Chemotherapy, Adjuvant; Female; Femoral Fractures; Femur; Fracture Fixation, Internal; Fracture Healing; Fractures, Ununited; Humans; Male; Middle Aged; Radiography; Recombinant Proteins; Retrospective Studies; Risk Factors; Smoking; Tibia; Tibial Fractures; Transforming Growth Factor beta; Treatment Failure; Young Adult

Mesenchymal Stem Cells (MSCs) have been identified in prostate cancer, raising the critical question of their physical and temporal source. Therefore, MSCs were quantified and characterized in benign and malignant prostate tissue representing different disease states and a wide range of age groups from fetal development through adult death using analytical and functional methodologies. In contrast to lineage-restricted Mesenchymal Progenitor Cells (MPCs) found in normal prostate tissue, MSCs with tri-lineage differentiation potential (adipogenesis, osteogenesis, and chondrogenesis) are identified in prostate tissue from a subset of men with prostate cancer, consistent with an influx of more stem-like progenitors (i.e. MSCs) from the bone marrow. Additionally, prostate tissue from a subset of these patients is highly enriched in MSCs, suggesting their enumeration may have prognostic value for identifying men with aggressive disease. This influx is an ongoing process continuing throughout disease progression as documented by the presence of MSCs in metastatic lesions from multiple organ sites harvested at the time of death in metastatic castration-resistant prostate cancer (mCRPC) patients. This infiltration of MSCs from systemic circulation provides the rationale for their use as a cell-based vector to deliver therapeutic agents.

Topics: Aged; Aged, 80 and over; Atrophy; Biomarkers; Cell Transformation, Neoplastic; Cells, Cultured; Cellular Microenvironment; Humans; Immunophenotyping; Male; Mesenchymal Stem Cells; Middle Aged; Muscle, Smooth; Neoplasm Grading; Organogenesis; Paracrine Communication; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, Androgen; Transforming Growth Factor beta

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which upper and lower motoneurons degenerate leading to muscle wasting, paralysis and eventually death from respiratory failure. Several studies indicate that skeletal muscle contributes to disease progression; however the molecular mechanisms remain elusive. Fibrosis is a common feature in skeletal muscle under chronic damage conditions such as those caused by muscular dystrophies or denervation. However, the exact mechanisms of fibrosis induction and the cellular bases of this pathological response are unknown. We show that extracellular matrix (ECM) components are augmented in skeletal muscles of symptomatic hSOD1G93A mice, a widely used murine model of ALS. These mice also show increased TGF-β1 mRNA levels, total Smad3 protein levels and p-Smad3 positive nuclei. Furthermore, platelet-derived growth factor receptor-α (PDGFRα), Tcf4 and α-smooth muscle actin (α-SMA) levels are augmented in the skeletal muscle of symptomatic hSOD1G93A mice. Additionally, the fibro/adipogenic progenitors (FAPs), which are the main producers of ECM constituents, are also increased in these pathogenic conditions. Therefore, FAPs and ECM components are more abundant in symptomatic stages of the disease than in pre-symptomatic stages. We present evidence that fibrosis observed in skeletal muscle of symptomatic hSOD1G93A mice is accompanied with an induction of TGF-β signaling, and also that FAPs might be involved in triggering a fibrotic response. Co-localization of p-Smad3 positive cells together with PDGFRα was observed in the interstitial cells of skeletal muscles from symptomatic hSOD1G93A mice. Finally, the targeting of pro-fibrotic factors such as TGF-β, CTGF/CCN2 and platelet-derived growth factor (PDGF) signaling pathway might be a suitable therapeutic approach to improve muscle function in several degenerative diseases.

Topics: Adipogenesis; Amyotrophic Lateral Sclerosis; Animals; Atrophy; Biomarkers; Extracellular Matrix; Fibrosis; Humans; Male; Mice; Mice, Transgenic; Muscle, Skeletal; Phenotype; Signal Transduction; Stem Cells; Superoxide Dismutase-1; Transforming Growth Factor beta

In an effort to develop novel treatments for communicating hydrocephalus, we have shown previously that the transforming growth factor-β antagonist, decorin, inhibits subarachnoid fibrosis mediated ventriculomegaly; however decorin's ability to prevent cerebral cytopathology in communicating hydrocephalus has not been fully examined. Furthermore, the capacity for diffusion tensor imaging to act as a proxy measure of cerebral pathology in multiple sclerosis and spinal cord injury has recently been demonstrated. However, the use of diffusion tensor imaging to investigate cytopathological changes in communicating hydrocephalus is yet to occur. Hence, this study aimed to determine whether decorin treatment influences alterations in diffusion tensor imaging parameters and cytopathology in experimental communicating hydrocephalus. Moreover, the study also explored whether diffusion tensor imaging parameters correlate with cellular pathology in communicating hydrocephalus.. Accordingly, communicating hydrocephalus was induced by injecting kaolin into the basal cisterns in 3-week old rats followed immediately by 14 days of continuous intraventricular delivery of either human recombinant decorin (n = 5) or vehicle (n = 6). Four rats remained as intact controls and a further four rats served as kaolin only controls. At 14-days post-kaolin, just prior to sacrifice, routine magnetic resonance imaging and magnetic resonance diffusion tensor imaging was conducted and the mean diffusivity, fractional anisotropy, radial and axial diffusivity of seven cerebral regions were assessed by voxel-based analysis in the corpus callosum, periventricular white matter, caudal internal capsule, CA1 hippocampus, and outer and inner parietal cortex. Myelin integrity, gliosis and aquaporin-4 levels were evaluated by post-mortem immunohistochemistry in the CA3 hippocampus and in the caudal brain of the same cerebral structures analysed by diffusion tensor imaging.. Decorin significantly decreased myelin damage in the caudal internal capsule and prevented caudal periventricular white matter oedema and astrogliosis. Furthermore, decorin treatment prevented the increase in caudal periventricular white matter mean diffusivity (p = 0.032) as well as caudal corpus callosum axial diffusivity (p = 0.004) and radial diffusivity (p = 0.034). Furthermore, diffusion tensor imaging parameters correlated primarily with periventricular white matter astrocyte and aquaporin-4 levels.. Overall, these findings suggest that decorin has the therapeutic potential to reduce white matter cytopathology in hydrocephalus. Moreover, diffusion tensor imaging is a useful tool to provide surrogate measures of periventricular white matter pathology in communicating hydrocephalus.

Topics: Animals; Aquaporin 4; Atrophy; Brain; Child; Decorin; Diffusion Magnetic Resonance Imaging; Diffusion Tensor Imaging; Disease Models, Animal; Glial Fibrillary Acidic Protein; Humans; Hydrocephalus; Immunohistochemistry; Kaolin; Myelin Sheath; Neuroprotective Agents; Random Allocation; Rats, Sprague-Dawley; Recombinant Proteins; Transforming Growth Factor beta; White Matter

It is widely believed that endometrial atrophy in postmenopausal women is due to an age-related reduction in estrogen level. But the role of high circulating follicle-stimulating hormone (FSH) in postmenopausal syndrome is not clear. Here, we explored the role of high circulating FSH in physiological endometrial atrophy. We found that FSH exacerbated post-OVX endometrial atrophy in mice, and this effect was ameliorated by lowering FSH with Gonadotrophin-releasing hormone agonist (GnRHa). In vitro, FSH inhibited endometrial proliferation and promoted the apoptosis of primary cultured endometrial cells in a dose-dependent manner. In addition, upregulation of caspase3, caspase8, caspase9, autophagy-related proteins (ATG3, ATG5, ATG7, ATG12 and LC3) and downregulation of c-Jun were also observed in endometrial adenocytes. Furthermore, smad2 and smad3 showed a time-dependent activation in endometrial cells which can be partly inhibited by blocking the transforming growth factor beta receptor II (TβRII). In conclusion, FSH regulated endometrial atrophy by affecting the proliferation, autophagy and apoptosis of endometrial cells partly through activation of the transforming growth factor beta (TGFβ) pathway.

Topics: Age Factors; Animals; Atrophy; Disease Models, Animal; Endometrium; Female; Follicle Stimulating Hormone; Humans; Mice; Signal Transduction; Transforming Growth Factor beta

The molecular mechanisms underlying the muscle atrophy of intensive care unit-acquired weakness (ICUAW) are poorly understood. We hypothesised that increased circulating and muscle growth and differentiation factor-15 (GDF-15) causes atrophy in ICUAW by changing expression of key microRNAs.. To investigate GDF-15 and microRNA expression in patients with ICUAW and to elucidate possible mechanisms by which they cause muscle atrophy in vivo and in vitro.. In an observational study, 20 patients with ICUAW and seven elective surgical patients (controls) underwent rectus femoris muscle biopsy and blood sampling. mRNA and microRNA expression of target genes were examined in muscle specimens and GDF-15 protein concentration quantified in plasma. The effects of GDF-15 on C2C12 myotubes in vitro were examined.. Compared with controls, GDF-15 protein was elevated in plasma (median 7239 vs 2454 pg/mL, p=0.001) and GDF-15 mRNA in the muscle (median twofold increase p=0.006) of patients with ICUAW. The expression of microRNAs involved in muscle homeostasis was significantly lower in the muscle of patients with ICUAW. GDF-15 treatment of C2C12 myotubes significantly elevated expression of muscle atrophy-related genes and down-regulated the expression of muscle microRNAs. miR-181a suppressed transforming growth factor-β (TGF-β) responses in C2C12 cells, suggesting increased sensitivity to TGF-β in ICUAW muscle. Consistent with this suggestion, nuclear phospho-small mothers against decapentaplegic (SMAD) 2/3 was increased in ICUAW muscle.. GDF-15 may increase sensitivity to TGF-β signalling by suppressing the expression of muscle microRNAs, thereby promoting muscle atrophy in ICUAW. This study identifies both GDF-15 and associated microRNA as potential therapeutic targets.

Topics: Aged; Atrophy; Cells, Cultured; Critical Care; Cysteine-Rich Protein 61; Down-Regulation; Female; Growth Differentiation Factor 15; Humans; Male; MicroRNAs; Middle Aged; Muscle Fibers, Skeletal; Muscle Weakness; Quadriceps Muscle; RNA, Messenger; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta; Up-Regulation

The loss of multiple teeth or trauma to the anterior maxilla often results in a deficient ridge width for prosthetic tooth rehabilitation. This study evaluated the use of titanium mesh and recombinant human bone morphogenetic protein 2 (rhBMP-2) for the repair of major bone defects in the alveolar bone. Five patients were enrolled in the study; these patients required implant replacements for two contiguous missing teeth in the anterior maxilla, which lacked sufficient bone. Residual ridges were augmented with rhBMP-2 and titanium mesh to direct the geometry of the newly formed bone. Seven months later, a bone biopsy specimen was removed from the implantation site before osteotomy and insertion of dental implants. Cone beam computed tomography (CBCT) scans were obtained preoperatively, postoperatively (baseline), and 48 months after implantation to evaluate implant healing. All dental implants were placed in the grafted sites without the need for further bone augmentation. The most frequent adverse effects were facial oedema and oral erythema. Biopsy specimens were used to evaluate bone quality. CBCT scans provided a prediction of alveolar restoration and long-term success. The combination of rhBMP-2 and titanium mesh provided effective augmentation of the atrophic anterior maxilla prior to implant placement.

Topics: Alveolar Ridge Augmentation; Atrophy; Biopsy; Bone Morphogenetic Protein 2; Cone-Beam Computed Tomography; Dental Implantation, Endosseous; Dental Implants; Female; Humans; Jaw, Edentulous, Partially; Male; Maxilla; Middle Aged; Osteotomy; Prospective Studies; Recombinant Proteins; Surgical Flaps; Surgical Mesh; Titanium; Transforming Growth Factor beta; Treatment Outcome

A 71-year-old patient was successfully rehabilitated by means of a 3D model-derived, hydroxyapatite-coated titanium subperiosteal mandibular implant. The implant was specifically designed to allow bone augmentation. The deficient bone was simultaneously grafted with mineralized bone allograft and recombinant bone morphogenetic protein -2 (rhBMP-2). The 32-month postoperative cone beam computerized tomography follow-up showed vertical bone augmentation beneath the implant frame.

Topics: Aged; Allografts; Alveolar Bone Loss; Alveolar Ridge Augmentation; Atrophy; Bone Morphogenetic Protein 2; Bone Transplantation; Coated Materials, Biocompatible; Cone-Beam Computed Tomography; Dental Implantation, Subperiosteal; Dental Implants; Dental Materials; Dental Prosthesis Design; Durapatite; Female; Follow-Up Studies; Humans; Mandible; Recombinant Proteins; Titanium; Transforming Growth Factor beta

Transforming growth factor-β (TGF-β) overproduction and activation of the TGF-β pathway are associated with the development of brain injury following germinal matrix hemorrhage (GMH) in premature infants. We examined the effects of GMH on the level of TGF-β1 in a novel rat collagenase-induced GMH model and determined the effect of inhibition of the TGF receptor I.. In total, 92 seven-day old (P7) rats were used. Time-dependent effects of GMH on the level of TGF-β1 and TGF receptor I were evaluated by Western blot. A TGF receptor I inhibitor (SD208) was administered daily for 3 days, starting either 1 hour or 3 days after GMH induction. The effects of GMH and SD208 on the TGF-β pathway were evaluated by Western blot at day 3. The effects of GMH and SD208 on cognitive and motor function were also assessed. The effects of TGF receptor I inhibition by SD208 on GMH-induced brain injury and underlying molecular pathways were investigated by Western blot, immunofluorescence, and morphology studies 24 days after GMH.. GMH induced significant delay in development, caused impairment in both cognitive and motor functions, and resulted in brain atrophy in rat subjects. GMH also caused deposition of both vitronectin (an extracellular matrix protein) and glial fibrillary acidic protein in perilesion areas, associated with development of hydrocephalus. SD208 ameliorated GMH-induced developmental delay, improved cognitive and motor functions, and attenuated body weight loss. SD208 also decreased vitronectin and glial fibrillary acidic protein deposition and decreased GMH-induced brain injury.. Increased level of TGF-β1 and activation of the TGF-β pathway associate with the development of brain injury after GMH. SD208 inhibits GMH-induced activation of the TGF-β pathway and leads to an improved developmental profile, partial recovery of cognitive and motor functions, and attenuation of GMH-induced brain atrophy and hydrocephalus.

Topics: Adult; Animals; Atrophy; Blotting, Western; Brain Injuries; Cerebral Ventricles; Extracellular Matrix Proteins; Female; Glial Fibrillary Acidic Protein; Humans; Hydrocephalus; Immunohistochemistry; Intracranial Hemorrhages; Nervous System Diseases; Neurologic Examination; Pregnancy; Pteridines; Rats; Rats, Sprague-Dawley; Signal Transduction; Survival; Transforming Growth Factor beta; Vitronectin; Weight Loss

To investigate the effect of lymph circulation blockage on the alteration of renal epithelial cell phenotype and the tubular integrity, as well as the underlying mechanisms.. Wistar rats received left renal lymph ligation and right renal nephrectomy (KL group) or right renal nephrectomy without lymph ligation (KN group) and then were killed on day 14, day 28 and day 56. The urine, blood and kidney tissue were collected for the analysis of protein and gene expressions and morphological changes.. The urine albumin and serum creatinine (Cr) in KL group were significantly increased compared with KN group. Masson and PAS staining indicated the epithelial cell degeneration, necrosis, sublethal loss and atrophy in KL rats, but not in KN group. Interestingly, from the atrophic tubules, some epithelial cells exhibited polarity changes with hypertrophy contrasting to the normal epithelial morphology of KN group throughout the experiment. By EM, ligated kidneys showed irregularly wrinkled basement membranes and epithelial cell swelling. Some intertubular areas of the KL kidney were expanded with fibrotic matrix and fibroblast-like cells. In line with these morphological changes, the fibroblast cell markers of FSP1 and α-SMA were markedly increased in contrast to the remarkable reduction in epithelial cell marker E-cadherin and tight junction protein ZO-1. Moreover, the TGF-β1/Smad2/3 signaling pathway was significantly activated in KL rats in contrast to a robust downregulation of BMP7/Smad5 signaling.. Disturbance of renal lymphatic circulation resulted in the epithelial cell phenotypic alteration and impaired tubular integrity possibly via distinct regulation of TGFβ1/Smads and BMP7/Smad5 signaling pathway.

Topics: Actins; Albuminuria; Animals; Atrophy; Bone Morphogenetic Protein 7; Cadherins; Calcium-Binding Proteins; Creatinine; Epithelial Cells; Epithelial-Mesenchymal Transition; Kidney Tubules; Ligation; Lymphatic Vessels; Necrosis; Nephrectomy; Phenotype; Rats, Wistar; RNA, Messenger; Signal Transduction; Smad2 Protein; Smad3 Protein; Smad5 Protein; Transforming Growth Factor beta; Zonula Occludens-1 Protein

Although the two-kidney, one-clip (2K1C) model is widely used as a model of human renovascular hypertension, mechanisms leading to the development of fibrosis and atrophy in the cuffed kidney and compensatory hyperplasia in the contralateral kidney have not been defined. Based on the well-established role of the transforming growth factor (TGF)-β signaling pathway in renal fibrosis, we tested the hypothesis that abrogation of TGF-β/Smad3 signaling would prevent fibrosis in the cuffed kidney. Renal artery stenosis (RAS) was established in mice with a targeted disruption of exon 2 of the Smad3 gene (Smad3 KO) and wild-type (WT) controls by placement of a polytetrafluoroethylene cuff on the right renal artery. Serial pulse-wave Doppler ultrasound assessments verified that blood flow through the cuffed renal artery was decreased to a similar extent in Smad3 KO and WT mice. Two weeks after surgery, systolic blood pressure and plasma renin activity were significantly elevated in both the Smad3 KO and WT mice. The cuffed kidney of WT mice developed renal atrophy (50% reduction in weight after 6 wk, P < 0.0001), which was associated with the development of interstitial fibrosis, tubular atrophy, and interstitial inflammation. Remarkably, despite a similar reduction of renal blood flow, the cuffed kidney of the Smad3 KO mice showed minimal atrophy (9% reduction in weight, P = not significant), with no significant histopathological alterations (interstitial fibrosis, tubular atrophy, and interstitial inflammation). We conclude that abrogation of TGF-β/Smad3 signaling confers protection against the development of fibrosis and atrophy in RAS.

Topics: Animals; Atrophy; Collagen; Constriction, Pathologic; Fibrosis; Hypertension, Renovascular; Immunohistochemistry; Kidney; Kidney Function Tests; Mice; Mutation; Real-Time Polymerase Chain Reaction; Renal Artery Obstruction; Renal Circulation; Renin; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

We have investigated the gross, microscopic and molecular effects of carnitine deficiency in the neonatal gut using a mouse model with a loss-of-function mutation in the OCTN2 (SLC22A5) carnitine transporter. The tissue carnitine content of neonatal homozygous (OCTN2(-/-)) mouse small intestine was markedly reduced; the intestine displayed signs of stunted villous growth, early signs of inflammation, lymphocytic and macrophage infiltration and villous structure breakdown. Mitochondrial β-oxidation was active throughout the GI tract in wild type newborn mice as seen by expression of 6 key enzymes involved in β-oxidation of fatty acids and genes for these 6 enzymes were up-regulated in OCTN2(-/-) mice. There was increased apoptosis in gut samples from OCTN2(-/-) mice. OCTN2(-/-) mice developed a severe immune phenotype, where the thymus, spleen and lymph nodes became atrophied secondary to increased apoptosis. Carnitine deficiency led to increased expression of CD45-B220(+) lymphocytes with increased production of basal and anti-CD3-stimulated pro-inflammatory cytokines in immune cells. Real-time PCR array analysis in OCTN2(-/-) mouse gut epithelium demonstrated down-regulation of TGF-β/BMP pathway genes. We conclude that carnitine plays a major role in neonatal OCTN2(-/-) mouse gut development and differentiation, and that severe carnitine deficiency leads to increased apoptosis of enterocytes, villous atrophy, inflammation and gut injury.

Topics: Animals; Apoptosis; Atrophy; Bone Morphogenetic Proteins; Carnitine; Cytokines; Down-Regulation; Enterocytes; Female; Gastrointestinal Tract; Gene Deletion; Lymph Nodes; Lymphocytes; Mice; Mitochondria; Organic Cation Transport Proteins; Oxidation-Reduction; Phenotype; Solute Carrier Family 22 Member 5; Spleen; Thymus Gland; Transforming Growth Factor beta

This study aimed to investigate torque deficit and activation of protein synthesis and/or protein degradation signaling pathways during the early and recovery phase after high- and low-velocity eccentric contractions (ECs). Male Wistar rats (n = 36) were randomly divided into fast angular velocity ECs group (FAST; 180 degrees/s; n = 12), slow ECs group (SLOW; 30 degrees/s; n = 12), and control group (control; n = 12). ECs comprised four sets of five forced dorsiflexions combined with electrical stimulation of the plantar flexors. Isometric tetanic torque was measured before and after ECs. Tissue contents of Akt(P) (P, phosphorylated), mammalian target of rapamycin (mTOR)(P), 70-kDa ribosomal protein S6 kinase (P70S6k), P70S6k(P), forkhead transcription factor 1 of the O class (FOXO1), FOXO1(P), FOXO3, FOXO3(P), myostatin, and activin receptor type IIB (ActRIIB) were measured. The isometric tetanic torque after ECs was significantly lower in FAST than in SLOW (days 1, 3, and 5, P < 0.05; day 2, P < 0.01). The ratio of P70S6k(P) against total P70S6k on days 2 and 7 was significantly higher in SLOW than in the control. The ratio of FOXO1 against total FOXO1, the ratio of FOXO3a against total FOXO3a, and myostatin on days 2 and 7 were significantly higher in FAST than in the control, while that of ActRIIB on day 7 was significantly lower in SLOW than in the other two groups. These results suggest that EC intensity plays a key role in impairment of muscular function and activation of protein synthesis and/or protein degradation signaling pathways.

Topics: Activin Receptors, Type II; Animals; Atrophy; Biomechanical Phenomena; Blotting, Western; Body Weight; Forkhead Box Protein O3; Forkhead Transcription Factors; Hypertrophy; Isometric Contraction; Joints; Male; Muscle Contraction; Muscle Proteins; Muscle, Skeletal; Myostatin; Nerve Tissue Proteins; Organ Size; Rats; Rats, Wistar; Signal Transduction; Transforming Growth Factor beta

The prevailing notion is that ischemia reperfusion injury of the small bowel induces transient changes that resolve within a few days post-occurrence. However, chronic injury has been described following a single ischemia reperfusion in the kidney. We proceeded to ascertain if a similar outcome is also witnessed in the small bowel.. ACI rats (n=32) underwent 1, 2 or 3 episodes of ischemia reperfusion by clamping the superior mesenteric artery for 45 minutes at 7-day intervals. Control groups included sham-operated (n=6) or non-operated (n=5) rats. Morphology was examined at day ninety post-ischemia reperfusion and immunostaining was used to evaluate macrophage infiltration, microvascular distribution, and apoptosis. RT-PCR was used to evaluate expression of Inter-Cellular Adhesion Molecule-1 (ICAM-1), transforming growth factor-beta (TGF-beta), Insulin Growth Factor-I (IGF-1), and Insulin Growth Factor-I Receptor (IGF-R). Intestinal function was evaluated by D-xylose performed 24 hours and 4, 8, and 12 weeks after reperfusion.. Chronic morphologic changes were observed with degeneration of crypts, endothelial damage, matrix degeneration, and heightened lymphocyte degeneration within the Payer's patches. Major structural changes were characterized by villous atrophy from partial to total. The grade of histological injuries was significantly increased (P<0.001) after multiple ischemia reperfusion episodes. A higher number of apoptotic cells (P<0.001) and a prominent macrophage infiltration (P<0.05) was also witnessed. Altered expression of ICAM-1, TGF-beta, and IGF-1 was observed. At 24 hours after ischemia reperfusion D-xylose absorption was diminished, returning to baseline values within 4 weeks and becoming abnormal again at 8 and 12 weeks (P<0.05).. Unlike the prevailing conviction, these data demonstrate that transient ischemia reperfusion repeated injuries of the small bowel result in chronic intestinal damage.

Topics: Animals; Apoptosis; Atrophy; Immunohistochemistry; Insulin-Like Growth Factor I; Intercellular Adhesion Molecule-1; Intestinal Absorption; Intestinal Mucosa; Intestine, Small; Male; Rats; Rats, Inbred ACI; Receptor, IGF Type 1; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Transforming Growth Factor beta

This study was conducted to evaluate the long term effect of castration on the prostate gland proliferation, extracellular matrix remodeling and angiogenesis. Prostate gland proliferation was assessed by immunolocalization of proliferating cell nuclear antigen (PCNA). The expression level of vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-beta) and metaloprotenase-13 (MMP-13) by the prostate gland were assessed by immunohistochemistry and quantitative real-time PCR. The expression of the above mentioned parameters by the prostate gland of mature intact dogs were compared to that of castrated dogs six months post-castration. The results showed that castration induced a remarkable atrophy of the prostate gland which was associated with a highly significant decrease in the PCNA proliferation index. Although TGF-beta protein was immunolocalized to the epithelial and stroma cells of the prostate gland from both intact and castrated dogs, castration induced a significant up-regulation of TGF-beta mRNA expression. VEGF mRNA expression and its encoded protein immunolocalization were decreased significantly by the prostate gland from castrated dogs as compared to that of intact dogs. Castration, on the other hand, resulted in no significant change in MMP-13 mRNA expression despite an effect on its cellular immunolocalization which appeared to be localized to the epithelial and stromal cells of the prostate gland from castrated dogs as compared to epithelial cells of the prostate gland from intact dogs. These results indicated that castration-induced prostate gland regression continued to exert a potent suppressive effect on prostate gland proliferation which might be mediated by the elevated level of TGF-beta. Moreover, the low expression level of VEGF might reflect a reduced blood flow demand by the regressed and growth-dormant prostate after castration.

Topics: Animals; Atrophy; Cell Division; Dogs; Epithelial Cells; Extracellular Matrix; Gene Expression; Male; Matrix Metalloproteinase 13; Neovascularization, Physiologic; Orchiectomy; Prostate; Stromal Cells; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Advanced diabetic nephropathy (DN) is difficult to address experimentally in mice because available models of DN lack global glomerulosclerosis and major tubulointerstitial pathology. Accelerating the development of DN in mice would be desirable for feasible experimental validation of potential targets that mediate the progression to late stage DN.. 6 week old male db/db mice underwent uninephrectomy and the development of nephropathy was compared to wild-type mice and sham-operated db/db mice.. Uninephrectomy at young age was associated with increased albuminuria and severe glomerulosclerosis in 37% of glomeruli at 24 weeks of age as compared to sham-operated db/db mice (8%). Uninephrectomy also increased the number of glomerular macrophages in db/db mice. The uninephrectomy-related acceleration of glomerular damage was associated with significant tubulointerstitial injury as indicated by an increase in indices of tubular cell damage, tubular dilatation, and expansion of interstitial volume. Uninephrectomy markedly increased the renal mRNA expression of Mcp-1/Ccl2, Tgf-beta, and collagen I.. Early uninephrectomy can accelerate the development of advanced DN in db/db mice which may be instrumental in the design of interventional studies that intend to focus on the molecular pathology of the progression to late stage DN.

Topics: Animals; Atrophy; Biomarkers; Chemokine CCL2; Collagen Type I; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Gene Expression; Kidney Glomerulus; Kidney Tubules; Male; Mice; Mice, Inbred C57BL; Nephrectomy; Nephritis, Interstitial; RNA, Messenger; Transforming Growth Factor beta

Myostatin, a transforming growth factor-beta (TGF-beta) super-family member, has been well characterized as a negative regulator of muscle growth and development. Myostatin has been implicated in several forms of muscle wasting including the severe cachexia observed as a result of conditions such as AIDS and liver cirrhosis. Here we show that Myostatin induces cachexia by a mechanism independent of NF-kappaB. Myostatin treatment resulted in a reduction in both myotube number and size in vitro, as well as a loss in body mass in vivo. Furthermore, the expression of the myogenic genes myoD and pax3 was reduced, while NF-kappaB (the p65 subunit) localization and expression remained unchanged. In addition, promoter analysis has confirmed Myostatin inhibition of myoD and pax3. An increase in the expression of genes involved in ubiquitin-mediated proteolysis is observed during many forms of muscle wasting. Hence we analyzed the effect of Myostatin treatment on proteolytic gene expression. The ubiquitin associated genes atrogin-1, MuRF-1, and E214k were upregulated following Myostatin treatment. We analyzed how Myostatin may be signaling to induce cachexia. Myostatin signaling reversed the IGF-1/PI3K/AKT hypertrophy pathway by inhibiting AKT phosphorylation thereby increasing the levels of active FoxO1, allowing for increased expression of atrophy-related genes. Therefore, our results suggest that Myostatin induces cachexia through an NF-kappaB-independent mechanism. Furthermore, increased Myostatin levels appear to antagonize hypertrophy signaling through regulation of the AKT-FoxO1 pathway.

Topics: Animals; Atrophy; Cachexia; Cell Size; Cells, Cultured; CHO Cells; Cricetinae; Cricetulus; Forkhead Box Protein O1; Forkhead Transcription Factors; Gene Expression Regulation; Mice; Mice, Nude; Microarray Analysis; Models, Biological; Muscle Development; Muscle Fibers, Skeletal; Muscle Proteins; Myostatin; NF-kappa B; Protein Processing, Post-Translational; RNA, Messenger; SKP Cullin F-Box Protein Ligases; Transforming Growth Factor beta; Ubiquitin; Ubiquitin-Protein Ligases

Inflammation induces premature maturation of the fetal lung but the signals causing this effect remain unclear. We determined if nitric oxide (NO) synthesis, evoked by Escherichia coli lipopolysaccharide (LPS, 2 microg ml-1), participated in this process. Fetal rat lung airway surface complexity rose 2.5-fold over 96h in response to LPS and was associated with increased iNOS protein expression and activity. iNOS inhibition by N6-(1-iminoethyl)-L-lysine-2HCl (L-NIL) abolished this and induced airway atrophy similar to untreated explants. Surfactant protein-C (SP-C) expression was also induced by LPS and abolished by L-NIL. As TGFbeta suppresses iNOS activity, we determined if feedback regulation modulated NO-dependent maturation. LPS induced TGFbeta1 release and SMAD4 nuclear translocation 96 h after treatment. Treatment of explants with a blocking antibody against TGFbeta1 sustained NO production and airway morphogenesis whereas recombinant TGFbeta1 antagonized these effects. Feedback regulation of NO synthesis by TGFbeta may, thus, modulate airway branching and maturation of the fetal lung.

Topics: Animals; Atrophy; Cell Line, Tumor; Cells, Cultured; Endotoxins; Escherichia coli; Humans; Lipopolysaccharides; Lung; Nitric Oxide; Rats; Rats, Sprague-Dawley; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1

Receptors of the P2X7 type have been demonstrated in granulocytes, monocytes/macrophages, B and T lymphocytes, and have been involved in several cellular mechanisms including those related to inflammation and immunological response. This study attempted to investigate the role of these receptors on the inflammatory and fibrogenic response in the kidneys of unilateral ureteral obstruction (UUO), by using P2X7 knockout mice (-/-). C57Bl6 mice were submitted to left UUO and killed after 7 and 14 days. Histopathology using hematoxylin-eosin, periodic-acid Schiff and Sirius-red staining, immunohistochemistry for macrophages, myofibroblasts, transforming growth factor-beta (TGF-beta)1 and P2X7, and immunofluorescence for apoptotic cells (terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick-end labeling) were performed. Protocols were as follows: (1) control; (2) sham; (3) control P2X7 (-/-); (4) sham P2X7 (-/-); (5) UUO wild type (WT); (6) UUO P2X7 (-/-). Myofibroblasts and Sirius-red staining were significantly lower in UUO P2X7 (-/-) mice at days 7 and 14, compared to UUO WT. Kidneys from UUO P2X7 (-/-) mice showed reduced number of inflammatory cells at day 14 but not at day 7, compared to UUO WT. TGF-beta1 was less in UUO P2X7 (-/-) mice at days 7 and 14 when compared to UUO WT. Macrophage infiltration and tubular apoptosis were lower in UUO P2X7 (-/-) at day 14 but not at day 7, compared to UUO WT. P2X7 was expressed only in tubular epithelial cells at day 7 of UUO WT mice. These findings constitute the first evidence that P2X7 receptors are implicated in macrophage infiltration, collagen deposition and apoptosis in response to ureteral obstruction in mice.

Topics: Actins; Animals; Antigens, Differentiation; Apoptosis; Atrophy; Collagen; Fibroblasts; Fibrosis; Gene Expression Regulation; Inflammation; Kidney Tubules; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Purinergic P2; Receptors, Purinergic P2X7; Transforming Growth Factor beta; Ureteral Obstruction

Recent studies have demonstrated that synthetic protease inhibitors could ameliorate the progression of pancreatic fibrosis in some animal models. Since oral administration of protease inhibitors increases the plasma cholecystokinin (CCK) levels and causes hypertrophy of the pancreas in rats, there is a possibility that the protease inhibitor inhibits fibrosis in the pancreas via endogenous CCK release. We examined the effects of camostat, a synthetic protease inhibitor, on histopathologic changes in Otsuka Long-Evans Tokushima Fatty (OLETF) rat that has genetically no expression of CCK-1 receptor and displays inflammation and degeneration of the pancreas.. Three groups of OLETF rats received a camostat-rich diet (200 mg/100 g normal diet) from 12 to 28 weeks of age or from 12 or 28 weeks of age to the age of 72 weeks, while the fourth group received standard rat diet.. Pancreatic wet weight and pancreatic contents of protein, DNA, amylase, lipase, and trypsin in camostat-treated rats were significantly higher than those in the untreated control rats. Immunohistochemical studies of the pancreas showed that expressions of interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, and alpha-smooth muscle actin in camostat-treated rats were greatly suppressed compared with those in the untreated control rats. Atrophy and fibrosis in the pancreas observed in the untreated control rats were not found in camostat-fed rats.. The results of the present study suggest that camostat greatly inhibits pancreatic inflammation and prevents and reverses fibrosis and atrophy of the pancreas in the genetically obese and CCK-1 receptor-deficient OLETF rats.

Topics: Actins; Amylases; Animals; Atrophy; Eating; Esters; Fibrosis; Gabexate; Guanidines; Interleukin-6; Lipase; Male; Obesity; Organ Size; Pancreas; Pancreatitis, Chronic; Protease Inhibitors; Rats; Rats, Inbred OLETF; Receptor, Cholecystokinin A; Transforming Growth Factor beta; Trypsin; Tumor Necrosis Factor-alpha

The SAMP1/Sku mouse is a substrain of the SAMP1 (senescence-accelerated-mouse prone 1) which exhibits renal mononuclear cell infiltration from a younger age. We hypothesized that this renal characteristic is related to the incidence of tubulointerstitial nephritis (TIN). The purpose of the present study was to evaluate the applicability of the SAMP1/Sku mouse as a murine model for TIN. TIN was experimentally induced by unilateral ureteral obstruction (UUO). The SAMP1/Sku and control ICR of both sexes received either a sham or UUO operation and were sacrificed 7 days after the operation. The kidneys of the mice were observed histopathologically, immunohistochemically and semiquantitatively. UUO kidneys showed mononuclear cell infiltration, tubular atrophy and interstitial fibrosis. In males, semiquantitative scores of mononuclear cell infiltration, tubular atrophy, and F4/80, alpha-smooth muscle actin (alpha-SMA) and transforming growth factor (TGF)-beta1 reactions were significantly higher in SAMP1/Sku than in ICR. Likewise, in females, tubular atrophy and F4/80 reaction scores were significantly higher in SAMP1/Sku than in ICR. In conclusion, induction of TIN damage by UUO was more serious in SAMP1/Sku mice than in ICR. Therefore, we propose that SAMP1/Sku mice, especially male SAMP1/Sku, have congenital risk factors for the development of TIN.

Topics: Actins; Animals; Antigens, Differentiation; Atrophy; Disease Models, Animal; Female; Fibrosis; Immunohistochemistry; Kidney; Male; Mice; Mice, Inbred Strains; Necrosis; Nephritis, Interstitial; Risk Factors; Transforming Growth Factor beta; Ureteral Obstruction

Severe periosteal and soft tissue disruption at the time of fracture may result in the formation of an atrophic nonunion. We have developed a reproducible atrophic nonunion in an animal model. The purpose of this study was to evaluate whether the immediate application of recombinant human BMP-7 to the fracture site could rescue the healing process in this nonunion model. A total of 56 three month old Fisher 344 rats were utilized. A 1.25 mm diameter K-wire was inserted into the femur in a retrograde fashion, and a mid-diaphyseal closed transverse fracture was created using a standard three point bending device. To create a nonunion, the fracture site was exposed and 2 mm of the periosteum was cauterized on each side of the fracture. The fracture site was immediately treated with either the application of rhBMP-7 50 microg in 25 microl of rat tail tendon collagen buffer (BMP-7 group), or with 25 microl of rat tail tendon collagen buffer only (Control group). Fracture healing was evaluated with serial radiographs every two weeks for an eight weeks period. Specimens at four and eight weeks were subjected to biomechanical and histological evaluation. None of the Control group healed throughout the eight weeks experimental duration. At four weeks 63% of the BMP-7 group had healed, and all had healed by six weeks. This investigation showed pronounced differences between the BMP-7 group and the Control group both histologically and biomechanically. In conclusion, we have demonstrated that the immediate application of BMP-7 may rescue the fracture healing process and prevent the development of nonunion following severe periosteal disruption.

Topics: Animals; Atrophy; Biomechanical Phenomena; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Dose-Response Relationship, Drug; Fracture Healing; Fractures, Bone; Humans; Male; Rats; Rats, Inbred F344; Recombinant Proteins; Transforming Growth Factor beta

Myostatin inhibits myogenesis. Therefore, we sought to determine if mice lacking the myostatin gene [Mstn(-/-)] would lose less muscle mass than wild-type mice during 7 days of hindlimb suspension (HS). Male Mstn(-/-) and wild-type (C57) mice were subjected to HS or served as ground-based controls (n = 6/group). Wild-type mice lost 8% of body mass and approximately 13% of wet mass from biceps femoris, quadriceps femoris, and soleus, whereas the mass of extensor digitorum longus (EDL) was unchanged after HS. Unexpectedly, Mstn(-/-) mice lost more body (13%, P < 0.05) and quadriceps femoris (17%, P < 0.05) mass than wild-type mice and lost 33% of EDL mass (P < 0.01) after HS. Protein expression of myostatin in biceps femoris and quadriceps femoris was not altered, whereas expression of MyoD, Myf-5, and myogenin increased in wild-type mice and tended to decrease in muscles of Mstn(-/-) mice. These data suggest that HS induced myogenesis in wild-type mice to counter atrophy, whereas myogenesis was not induced in Mstn(-/-) mice, thereby resulting in a greater loss of muscle mass.

Topics: Animals; Atrophy; Biomarkers; Blotting, Western; Body Weight; DNA-Binding Proteins; Hindlimb Suspension; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Proteins; Muscle, Skeletal; MyoD Protein; Myogenic Regulatory Factor 5; Myogenin; Myostatin; Organ Size; Trans-Activators; Transforming Growth Factor beta

In interstitial fibrosis, monocytes and myofibroblasts have been directly implicated in scarring, apoptosis, and tissue necrosis. While much has been done to explore the role of these cell types individually in fibrosis, the interactive dependency of monocytes and myofibroblasts has been only marginally explored.. Alport mice were treated or not with a soluble receptor inhibitor for transforming growth factor-beta 1 (TGF-beta 1), which was previously shown to inhibit the accumulation of myofibroblasts, but not monocytes, in the tubulointerstitium. Kidneys were examined for fibrosis using several matrix markers, TGF-beta 1 mRNA expression by in situ hybridization, apoptosis using the terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end labeling (TUNEL) assay, expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPS) by dual immunofluorescence microscopy, MMP activity by gelatin and in situ zymography, MMP mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR), and basement membrane degradation by dual immunofluorescence confocal microscopy and electron microscopy.. Treated mice showed a markedly reduced accumulation of matrix proteins. Tissue monocytes express TGF-beta 1 mRNA, and TGF-beta 1 is required for myofibroblast accumulation. The number of apoptotic cells was not influenced by TGF-beta 1 inhibition. Monocytes express MMP-2, MMP-9, TIMP-2, and TIMP-3. MMP activity and mRNA expression is equally up regulated in treated and untreated Alport mice. Tubular basement membranes (TBM) around clusters of monocytes are notably degraded. TGF-beta 1 inhibition does not extend the life of Alport mice.. These studies demonstrate that monocytes may influence myofibroblast accumulation via TGF-beta1, and that monocytes, and not myofibroblasts, are associated with tubular atrophy in Alport mice. Elevated MMP expression and activity is associated with TBM destruction near monocytes clusters, suggesting an anoikis mechanism may contribute to apoptosis in this model.

Topics: Animals; Apoptosis; Atrophy; B-Lymphocytes; Fibroblasts; Fibrosis; Kidney; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Monocytes; Nephritis, Hereditary; RNA, Messenger; T-Lymphocytes; Tissue Inhibitor of Metalloproteinases; Transforming Growth Factor beta; Transforming Growth Factor beta1

Thrombospondin-1 is a major activator of transforming growth factor-beta1 (TGF-beta1), and a peptide derived from the latency-associated peptide, Leu-Ser-Lys-Leu (LSKL), inhibits the activation of TGF-beta1. In this study, the effects of LSKL on the hepatocyte damage and fibrogenesis in dimethylnitrosamine (DMN)-induced rat liver fibrosis were examined.. Animals were given an intraperitoneal (i.p.) injection of DMN or saline three times per week for 4 weeks, and treated with LSKL, a control peptide, or saline i.p. daily.. Liver atrophy caused by DMN-injection was significantly inhibited in the DMN+LSKL group. The degrees of necrosis/degeneration and fibrosis scores were significantly lower in the DMN+LSKL group than in the control groups. The hydroxyproline content was significantly higher in the control groups than in the DMN+LSKL group. The amount of active TGF-beta1 was less in the DMN+LSKL group than in the control groups, and the active/total TGF-beta1 ratio in the DMN+LSKL group was suppressed in the control groups. Phosphorylation of Smad 2 in the liver was significantly decreased in the DMN+LSKL group.. The LSKL peptide prevented the progression of hepatic damage and fibrosis through the inhibition of TGF-beta1 activation and its signal transduction in vivo.

Topics: Animals; Atrophy; Dimethylnitrosamine; Disease Progression; DNA-Binding Proteins; Hydroxyproline; Liver; Liver Cirrhosis; Male; Necrosis; Peptides; Phosphorylation; Rats; Rats, Sprague-Dawley; Smad2 Protein; Trans-Activators; Transforming Growth Factor beta; Transforming Growth Factor beta1

Tubulointerstitial pathology with the accumulation of extracellular matrix are pathological hallmarks of diabetic nephropathy that are directly related to declining renal function. Tranilast (N-[3,4-dimethoxycinnamoyl]anthranilic acid), an inhibitor of transforming growth factor-beta (TGF-beta), used to treat hypertrophic scars has recently been shown in pilot studies to exert a beneficial effect in advanced diabetic nephropathy in humans. However, its effects on diabetic renal pathology are unknown.. Studies were conducted using a transgenic model, the diabetic (mRen-2)27 rat, which develops many of the structural and functional characteristics of human diabetic nephropathy when diabetes is induced with streptozotocin (STZ). An experimental design was chosen to mimic, in part, the clinical context with drug therapy (tranilast 400 mg/kg/ day) initiated in established disease (8 weeks after STZ) and in the presence of persistent hyperglycaemia and hypertension.. At 16 weeks, diabetes was associated with progressive albuminuria, tubulointerstitial fibrosis and tubular atrophy. Without affecting blood pressure or blood glucose, tranilast treatment was associated with a 83% reduction in tubulointerstitial fibrosis (p < 0.001), a 58% reduction in tubular atrophy (p < 0.01) and near normalization of albuminuria (p < 0.05) in diabetic Ren-2 rats. In vitro studies in primary cultures of human renal cortical fibroblasts demonstrated a reduction in TGF-beta-induced hydroxyproline incorporation and fibronectin synthesis with tranilast 100 microM.. Tranilast, when administered during the course of experimental diabetic nephropathy, attenuates tubulointerstitial pathology and albuminuria. These findings are consistent with the antagonist effects of tranilast on TGF-beta actions in the diabetic kidney.

Topics: Albuminuria; Animals; Animals, Genetically Modified; Anti-Inflammatory Agents, Non-Steroidal; Atrophy; Blotting, Western; Cells, Cultured; Collagen Type IV; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Female; Fibroblasts; Fibronectins; Fibrosis; Humans; Immunohistochemistry; Kidney; Mice; ortho-Aminobenzoates; Proline; Random Allocation; Rats; Rats, Sprague-Dawley; Renin; Time Factors; Transforming Growth Factor beta; Tritium

The response to the liver damage caused by portacaval shunt (PCS) is characterized by low-grade hyperplasia and atrophy. To clarify mechanisms of this dissociation, we correlated the expression of 'hepatotrophic factors' and the antihepatotrophic and proapoptotic peptide, transforming growth factor (TGF)-beta, with the pathologic changes caused by PCS in rats.. PCS was created by side-to-side anastomosis between the portal vein and inferior vena cava, with ligation of the hilar portal vein. Hepatic growth mediators were measured to 2 months.. The decrease in the liver/body weight ratio during the first 7 days which stabilized by day 15, corresponded to parenchymal cell apoptosis and increases in hepatic TGF-beta concentration that peaked at 1.4 x baseline at 15 days before returning to control levels by day 30. Variable increases in the concentrations of growth promoters (hepatocyte growth factor, TGF-alpha and augmenter of liver regeneration) also occurred during the period of hepatocellular apoptosis.. The development of hepatic atrophy was associated with changes in TGF-beta concentration, and occurred despite increased expression of multiple putative growth promoters. The findings suggest that apoptosis set in motion by TGF-beta constrains the amount of hepatocyte proliferation independently from control of liver volume.

Topics: Animals; Apoptosis; Atrophy; Cell Division; Gene Expression; Growth Substances; Hepatic Artery; Liver; Liver Diseases; Male; Organ Size; Portacaval Shunt, Surgical; Rats; Rats, Inbred Lew; RNA, Messenger; Transforming Growth Factor alpha; Transforming Growth Factor beta

Tubular atrophy is a major feature of most renal diseases and is closely associated with loss of renal function. The present study sought to investigate tubular epithelial cell apoptosis in experimental diabetic nephropathy and to explore the role of pro-apoptotic [transforming growth factor-beta (TGF-beta) and anti-apoptotic growth factors [epidermal growth factor (EGF)]. The effects of renoprotective therapy with blockade of the renin-angiotensin system (RAS) also were examined.. Six-week-old female Ren-2 rats were injected with streptozotocin (STZ) and maintained diabetic for 12 weeks. Further groups of diabetic rats were treated with the angiotensin-converting enzyme (ACE) inhibitor, perindopril, or the angiotensin II type 1 (AT1) receptor antagonist, valsartan, for 12 weeks.. Widespread apoptosis, identified immunohistochemically by single stranded DNA and TUNEL, was noted in the tubules of diabetic Ren-2 rats. These changes were associated with a 50% decrease in EGF expression and a twofold increase in TGF-beta1 mRNA. Treatment of diabetic Ren-2 rats with either valsartan (20 mg/kg/day) or perindopril (6 mg/kg/day) reduced apoptosis to control levels in association with supranormal levels of EGF mRNA (P < 0.01) and a reduction in TGF-beta1 gene expression (P < 0.05) to that of control rats.. Tubular apoptosis is a prominent feature of diabetic Ren-2 rats that is attenuated by blockade of the RAS in association with modulation of pro- and anti-apoptotic growth factor expression.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Antihypertensive Agents; Apoptosis; Atrophy; Autoradiography; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Epidermal Growth Factor; Female; Fibrosis; Gene Expression; In Situ Hybridization; In Situ Nick-End Labeling; Kidney Tubules; Nephritis, Interstitial; Perindopril; Rats; Renin-Angiotensin System; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta; Valine; Valsartan

Interleukin (IL)-10, a potent anti-inflammatory cytokine, limits the severity of acute pancreatitis and downregulates transforming growth factor (TGF)-beta release by inflammatory cells on stimulation. Proinflammatory mediators, reactive oxygen species, and TGF-beta can activate pancreatic stellate cells and their synthesis of collagen I and III. This study evaluates the role of endogenous IL-10 in the modulation of the regeneration phase following acute pancreatitis and in the development of pancreatic fibrosis. IL-10 knockout (KO) mice and their C57BL/6 controls were submitted to repeated courses (3/wk, during 6 wk, followed by 1 wk of recovery) of cerulein-induced acute pancreatitis. TGF-beta(1) release was measured on plasma, and its pancreatic expression was assessed by quantitative RT-PCR and immunohistochemistry. Intrapancreatic IL-10 gene expression was assessed by semiquantitative RT-PCR, and intrapancreatic collagen content was assessed by picrosirius staining. Activated stellate cells were detected by immunohistochemistry. S phase intrapancreatic cells were marked using tritiated thymidine labeling. After repeated acute pancreatitis, IL-10 KO mice had more severe histological lesions and fibrosis (intrapancreatic collagen content) than controls. TGF-beta(1) plasma levels, intrapancreatic transcription, and expression by ductal and interstitial cells, as well as the number of activated stellate cells, were significantly higher. IL-10 KO mice disclosed significantly fewer acinar cells in S phase, whereas the opposite was observed for pseudotubular cells. Endogenous IL-10 controls the regeneration phase and limits the severity of fibrosis and glandular atrophy induced by repeated episodes of acute pancreatitis in mice.

Topics: Acute Disease; Animals; Atrophy; Cell Division; Chronic Disease; Collagen; Down-Regulation; Fibrosis; Gene Expression; Interleukin-10; Mice; Mice, Inbred C57BL; Mice, Knockout; Pancreas; Pancreatitis; Recurrence; Regeneration; Transcription, Genetic; Transforming Growth Factor beta; Transforming Growth Factor beta1

During chemo- and radiation therapy, the balance between epithelial cell proliferation, differentiation, and cell death at the villus tip is disrupted by premature death of dividing epithelial cells. This will subsequently lead to the onset of mucosal barrier injury in the whole gastrointestinal tract. Up till now there is no validated method to treat side effects occurring due to therapy. An approach to manage this side effect might be to reversibly arrest growth of epithelial stem cells during therapy using Transforming Growth Factor-beta2. A Transforming Growth Factor-beta2 enriched fraction prepared from bovine milk was shown to protect small intestinal epithelial cells against cell cycle specific chemotherapeutic agents by arresting the cells in G1-phase. Secondly, in a rat model for induced small intestinal damage, oral supplementation of rats exposed to methotrexate with the Transforming Growth Factor-beta2 enriched fraction significantly reduced the chemotherapy-associated weight loss and ileal villus atrophy by reducing cell proliferation in the normal stem cell population. Thus oral supplementation with a bovine milk fraction enriched for Transforming Growth Factor-beta2 attenuated the side effects of chemotherapy in the small intestine in rats.

Topics: Administration, Oral; Animals; Antimetabolites, Antineoplastic; Atrophy; Cell Cycle; Cell Death; Disease Models, Animal; Epithelial Cells; Female; Immunosuppressive Agents; Intestine, Small; Methotrexate; Rats; Transforming Growth Factor beta; Transforming Growth Factor beta2; Weight Loss

The roles that thymus cytokines might play in regulating thymic atrophy are not known. Reversing thymic atrophy is important for immune reconstitution in adults. We have studied cytokine mRNA steady-state levels in 45 normal human (aged 3 days to 78 years) and 34 myasthenia gravis thymuses (aged 4 to 75 years) during aging, and correlated cytokine mRNA levels with thymic signal joint (sj) TCR delta excision circle (TREC) levels, a molecular marker for active thymopoiesis. LIF, oncostatin M (OSM), IL-6, M-CSF, and stem cell factor (SCF) mRNA were elevated in normal and myasthenia gravis-aged thymuses, and correlated with decreased levels of thymopoiesis, as determined by either decreased keratin-positive thymic epithelial space or decreased thymic sjTRECs. IL-7 is a key cytokine required during the early stages of thymocyte development. Interestingly, IL-7 mRNA expression did not fall with aging in either normal or myasthenia gravis thymuses. In vivo administration of LIF, OSM, IL-6, or SCF, but not M-CSF, i.p. to mice over 3 days induced thymic atrophy with loss of CD4+, CD8+ cortical thymocytes. Taken together, these data suggest a role for thymic cytokines in the process of thymic atrophy.

Topics: Adolescent; Adult; Aged; Aging; Animals; Atrophy; Child; Child, Preschool; Epithelial Cells; Extracellular Space; Female; Gene Expression Regulation; Gene Rearrangement, delta-Chain T-Cell Antigen Receptor; Growth Inhibitors; Humans; Infant; Infant, Newborn; Injections, Intraperitoneal; Interleukin-6; Leukemia Inhibitory Factor; Lymphokines; Macrophage Colony-Stimulating Factor; Mice; Mice, Inbred BALB C; Middle Aged; Myasthenia Gravis; Oncostatin M; Peptides; RNA, Messenger; Stem Cell Factor; Thymus Gland; Transforming Growth Factor beta

Unilateral ureteral obstruction (UUO) is a model of renal injury characterized by progressive tubulointerstitial fibrosis and renal damage, while relatively sparing the glomerulus and not producing hypertension or abnormalities in lipid metabolism. Tubulointerstitial fibrosis is a major component of several kidney diseases associated with the progression to end-stage renal failure. Here we report that when a critical renal developmental morphogen, osteogenic protein-1 (OP-1; 100 or 300 microg/kg body wt), is administered at the time of UUO and every other day thereafter, interstitial inflammation and fibrogenesis are prevented, leading to preservation of renal function during the first 5 days after obstruction. Compared with angiotensin-converting enzyme inhibition with enalapril treatment, OP-1 was more effective in preventing tubulointerstitial fibrosis and in preserving renal function. The mechanism of OP-1- induced renal protection was associated with prevention of tubular atrophy, an effect not shared with enalapril, and was related to preservation of tubular epithelial integrity. OP-1 blocked the stimulation of epithelial cell apoptosis produced by UUO, which promoted maintenance of tubular epithelial integrity. OP-1 preserved renal blood flow (RBF) during UUO, but enalapril also stimulated RBF. Thus OP-1 treatment inhibited tubular epithelial disruption stimulated by the renal injury of UUO, preventing tubular atrophy and diminishing the activation of tubulointerstitial inflammation and fibrosis and preserving renal function.

Topics: Actins; Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Atrophy; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Cell Size; Collagen; Enalapril; Epithelial Cells; Fibrosis; Immunohistochemistry; Inflammation; Kidney; Macrophages; Rats; Rats, Sprague-Dawley; Renal Circulation; Transforming Growth Factor beta; Ureteral Obstruction

Unilateral ureteral obstruction (UUO) is characterized by progressive renal atrophy, renal interstitial fibrosis, an increase in renal transforming growth factor-beta (TGF-beta), and renal tubular apoptosis. The present study was undertaken to determine the effect of a monoclonal antibody to TGF-beta (1D11) in UUO.. Mechanical stretch was applied to tubular epithelial cells (NRK-52E) by a computer-assisted system. Three doses of 1D11 (either 0.5, 2, or 4 mg/rat) were administered to rats one day prior to UUO and every two days thereafter, and kidneys were harvested at day 13. Fibrosis was assessed by measuring tissue hydroxyproline and mRNA for collagen and fibronectin. Apoptosis was assessed with the terminal deoxy transferase uridine triphosphate nick end-labeling assay. TGF-beta levels were determined by bioassay. Western blot and immunostaining were used to identify proliferating cell nuclear antigen (PCNA), p53, bcl-2, and inducible nitric oxide synthase (iNOS).. Stretch significantly induced apoptosis in NRK-52E cells, which was accompanied by an increased release of TGF-beta; 1D11 (10 microg/mL) totally inhibited stretch-induced apoptosis. Control obstructed kidney contained 20-fold higher TGF-beta as compared with its unobstructed kidney; 1D11 neutralized tissue TGF-beta of the obstructed kidney. Control obstructed kidney exhibited significantly more fibrosis and tubular apoptosis than its unobstructed counterpart, which was blunted by 1D11. In contrast, 1D11 significantly increased tubular proliferation. p53 immunostaining was localized to renal tubular nuclei of control obstructed kidney and was diminished by 1D11. In contrast, bcl-2 was up-regulated in the 1D11-treated obstructed kidney. Total NOS activity and iNOS activity of the obstructed kidney were increased by 1D11 treatment.. The present study strongly suggests that an antibody to TGF-beta is a promising agent to prevent renal tubular fibrosis and apoptosis in UUO.

Topics: Animals; Antibodies, Monoclonal; Apoptosis; Atrophy; Blotting, Western; Cell Line; Citrulline; Fibrosis; Gene Expression Regulation, Enzymologic; In Situ Nick-End Labeling; Kidney Tubules; Nephritis, Interstitial; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Stress, Mechanical; Transforming Growth Factor beta; Tumor Suppressor Protein p53; Ureteral Obstruction

Latent transforming growth factor-beta 1 (TGF-beta 1) and its binding protein-1 (LTBP-1) are components of the extracellular matrix microfibrils of cultured human fibroblasts. Using immunohistochemistry we have studied the localization of TGF-beta 1 and LTBP-1 and compared their distribution with that of elastic fibres in the interstitial connective tissue matrix of the human dermis. Prominent LTBP-1 specific fibrillar staining co-localized with the elastic fibres in normal human skin. Co-distribution was also observed in a number of pathological states of the elastic fibres such as solar elastosis, solar keratosis and pseudoxanthoma elasticum. TGF-beta 1 had a staining pattern similar to that of LTBP-1 in solar elastosis and solar keratosis. No staining for LTBP-1 or TGF-beta 1 was found in dermis devoid of elastic fibres, as in anetoderma. LTBP-1 is released from the extracellular matrix of cultured human fibroblasts, epithelial and endothelial cells by proteases. Analogously, the immunoreactivity for LTBP-1 and TGF-beta 1 were also lost from the skin sections by elastase, and by trypsin, a protease pretreatment commonly used in immunohistochemistry. These results indicate that LTBP-1 is a component of the elastin-associated microfibrils of the interstitial connective tissue matrix of human skin. Furthermore, the small latent form of TGF-beta 1 is likely to associate with the extracellular matrix of human dermis via LTBP-1. The release of latent TGF-beta 1 from the matrix, as a consequence of proteolytic cleavage of LTBP-1, is a plausible extracellular mechanism for the regulation of TGF-beta 1 activation.

Topics: Adolescent; Adult; Aged; Atrophy; Biomarkers; Carrier Proteins; Child; Child, Preschool; Elastic Tissue; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Latent TGF-beta Binding Proteins; Middle Aged; Nevus; Photosensitivity Disorders; Pseudoxanthoma Elasticum; Skin; Skin Diseases; Skin Neoplasms; Transforming Growth Factor beta

To evaluate the ability of hyaluronic acid (HA), with and without transforming growth factor beta (1GF-beta), to stabilize the catabolic processes associated with atrophy of articular cartilage.. 20 adult, skeletally normal, hound-type dogs.. Dogs (20 to 30 kg) were randomly assigned to 1 of 5 groups. One group served as untreated controls. Bivalve casts were placed on the left hind limbs of the remaining 16 dogs to limit weightbearing and motion of the limb for 92 days. One group served as the cast control. Beginning on day 56, 3 groups received aseptic intra-articular injections in the left stifles of either 5 mg of HA or 5 mg of HA containing either 20 or 50 micrograms of TGF-beta. Intraarticular injections were repeated at 4-day intervals until the end of the study. Or day 92, stifles were harvested at necroscropy. Medial femoral condyle were histologically processed, and the articular cartilage was stained for the presence of proteoglycans, stromelysin, tumor necrosis facto (TNF) alpha, and TNF receptors (p55 and p75).. Decreased metachromasia was evident in the cartilage matrix of all cast groups, with the smallest decrease in the HA-treated group. Stromelysin was immunolocalized in articular cartilage of the cast (left) limbs of cast control and both HA/TGF-beta-treated groups. TNF-alpha was localized in articular cartilage of all cast (left) and right limbs, except those of the HA-treated group. Receptors for TNF were observed in both limbs of untreated control and cast control groups and cast limbs of HA/TGF-3-treated groups. The receptors were not localized in the right limbs of the HA with or without TGF-beta-treated groups. TGF-beta did not decrease stromelysin or TNF-alpha or receptors at the doses used.. HA may mediate a chondrostabilizing influence on articular cartilage by down-regulating TNF-alpha importantly. HA appeared to exert its inhibitory influence on TNF-alpha, as well as stromelysin and TNF receptors, on a systemic basis.. Results provide insight into the mode of action of HA as a therapeutic agent for arthritis and its stabilizing influence on cartilage metabolism.

Topics: Animals; Antibodies; Atrophy; Cartilage, Articular; Dogs; Enzyme-Linked Immunosorbent Assay; Female; Hindlimb; Hyaluronic Acid; Immobilization; Immunohistochemistry; Male; Matrix Metalloproteinase 3; Receptors, Tumor Necrosis Factor; Stifle; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Changes in the testicular peritubular lamina propria in rats treated for 1-11 weeks with intra-scrotal injections of epinephrine were studied by quantitative immunohistochemical methods. In control testes, BrdU-labelled nuclei (proliferating cells) were observed only in spermatogonia and some primary spermatocytes, whereas testes from epinephrine-treated rats showed BrdU labelling in some of the spermatogonia and in peritubular cells. Immunostaining for transforming growth factor beta 1 (TGF-beta 1) was present in germ cells, Sertoli cells and Leydig cells; vimentin immunostaining was found mainly in Sertoli cells; desmin immunostaining was found in the peritubular cells, and immunostaining for type IV collagen, laminin and fibronectin was found in the extracellular matrix of the lamina propria. The volume densities of seminiferous tubules (including seminiferous epithelium, lamina propria and tubular lumen) that immunostained for TGF-beta 1, vimentin, laminin, desmin or fibronectin were calculated. All of these parameters increased significantly in testes from epinephrine-treated animals during the course of the experiment, except for desmin immunostaining which showed no significant change in volume density. Since total seminiferous tubule volume decreased markedly in the testes of treated rats during the experiment, the transformation of relative values for immunostaining into absolute volumes per testis revealed a significant increase in TGF-beta 1 immunostaining, no significant change in vimentin immunostaining, and a significant decrease in desmin immunostaining during the time of the study. The absolute volume occupied by laminin and fibronectin immunostaining decreased from the 3rd to the 8th weeks of treatment, and increased from the 8th to the 11th weeks. These changes, associated with germ cell depletion and tubular fibrosis, suggest that tubular ischaemic atrophy caused by epinephrine alters the peritubular myoid cells, which change immunophenotype and increase their secretion of the extracellular matrix components producing tubular fibrosis. The mechanism of this alteration may involve direct effects on the peritubular cells or the changes may be secondary to germ cell and/or Sertoli cell lesions.

Topics: Animals; Atrophy; Bromodeoxyuridine; Cell Division; Collagen; Desmin; Epinephrine; Extracellular Matrix; Fibronectins; Immunohistochemistry; Laminin; Leydig Cells; Male; Rats; Rats, Wistar; Reference Values; Scrotum; Seminiferous Tubules; Sertoli Cells; Spermatogonia; Spermatozoa; Testis; Transforming Growth Factor beta