transforming-growth-factor-beta and Rupture

The incidence of acute and chronic conditions of the tendo Achillis appear to be increasing. Causation is multifactorial but the role of inherited genetic elements and the influence of environmental factors altering gene expression are increasingly being recognised. Certain individuals' tendons carry specific variations of genetic sequence that may make them more susceptible to injury. Alterations in the structure or relative amounts of the components of tendon and fine control of activity within the extracellular matrix affect the response of the tendon to loading with failure in certain cases. This review summarises present knowledge of the influence of genetic patterns on the pathology of the tendo Achillis, with a focus on the possible biological mechanisms by which genetic factors are involved in the aetiology of tendon pathology. Finally, we assess potential future developments with both the opportunities and risks that they may carry.

Topics: ABO Blood-Group System; Achilles Tendon; Apoptosis; Cartilage Oligomeric Matrix Protein; Collagen Type V; Epigenesis, Genetic; Extracellular Matrix Proteins; Fibrillar Collagens; Genetic Markers; Glycoproteins; Humans; Inflammation; Matrilin Proteins; Matrix Metalloproteinases; Rupture; Tenascin; Tendinopathy; Tendon Injuries; Transforming Growth Factor beta

Arthroscopic reconstruction is a standard surgical procedure in cases of symptomatic knee instability due to rupture of the anterior cruciate ligament. Bone-tendon-bone and hamstring tendon grafts are both in use for anterior cruciate ligament reconstruction. There are no significant differences between the two types of graft in relation to function scores, but there is a difference in anteroposterior stability when measured on the KT-2000 arthrometer: knee joints after reconstruction with bone-tendon-bone autografts are more stable than those reconstructed with hamstring tendon autografts.. To improve knee stability after anterior cruciate ligament reconstruction with a hamstring graft and use of platelet-derived growth factors.. Platelet-leukocyte gel was produced from platelet-leukocyte-rich plasma prepared from a unit of whole blood in an autologous platelet separator. The gel was applied locally, after hamstring graft placement. Fifty patients were included in the study: 25 in the platelet gel group, 25 in a control group. We evaluated anteroposterior knee stability with the KT-2000 arthrometer before surgery and at 3 and 6 months after surgery.. Patients treated with the gel demonstrated significantly better anteroposterior knee stability than patients in the control group. The calculated improvements in knee stability at 6 months were 1.3 +/- 1.8 mm in the control group and 3.1 +/- 2.5 mm in the platelet gel group (P = 0.011).. Platelet-leukocyte gel, applied locally, can improve knee stability in surgery for reconstruction of the anterior cruciate ligament.

Topics: Administration, Topical; Adult; Anterior Cruciate Ligament; Anterior Cruciate Ligament Injuries; Arthrometry, Articular; Arthroscopy; Connective Tissue Growth Factor; Epidermal Growth Factor; Female; Fibroblast Growth Factor 2; Growth Substances; Humans; Joint Instability; Knee Injuries; Male; Middle Aged; Platelet-Derived Growth Factor; Plateletpheresis; Rupture; Tendon Transfer; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Young Adult

Achilles tendon reconstruction surgery is the primary clinical method for repairing acute Achilles tendon ruptures. However, the efficacy of the postoperative healing process and the recovery of physiological function are inadequate. This study examines the healing mechanism of ruptured rat Achilles tendons seamed with heparin-loaded core-shell fiber sutures fabricated via near-field electrospinning. High-heparin-concentration sutures (PPH3.0) perform better than the low-heparin-concentration sutures and commercial sutures (CSs). The PPH3.0 suture recruits fewer inflammatory cells and shows good histocompatibility in peritoneal implantation experiments. Staining of the Achilles tendon rupture repair zone demonstrates that a high heparin concentration in sutures reduces immune-inflammatory responses. Immunohistochemical analysis reveals that the transforming growth factor-β staining scores of the PPH3.0 sutures are not significantly different from those of the corresponding control group but are significantly different from those of the CSs and non-heparin-loaded-suture groups. According to vascular endothelial growth factor (VEGF) analysis, the concentration of VEGF in the group treated with the PPH3.0 suture increases by 37.5% compared with that in its control group. No significant difference in tension strength is observed between the PPH3.0 group and healthy Achilles tendons. These findings illustrate that this novel method effectively treats Achilles tendon rupture and promotes healing and regeneration.

Topics: Achilles Tendon; Animals; Electrochemical Techniques; Gene Expression; Guided Tissue Regeneration; Heparin; Humans; Male; Nanofibers; Rats; Rats, Sprague-Dawley; Rupture; Suture Techniques; Sutures; Tendon Injuries; Tensile Strength; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Wound Healing

Transglutaminase 2 (TG2) is important for the deposition and stability of the extracellular matrix via effects on cross-linking of matrix proteins and transforming growth factor beta (TGFbeta) activity. The purpose of this study was to investigate the effect of TG2 deficiency on the composi- tion of atherosclerotic plaques.. Apolipoprotein E (ApoE)(-/-) mice were crossbred with TG2(-/-) mice to obtain ApoE(-/-)TG2(-/-) mice. ApoE(-/-) and ApoE(-/-)TG2(-/-) mice were fed a Western-type diet for 16 or 30 weeks to determine the effect of TG2 deficiency on early and advanced atherosclerosis, respectively.. Atherosclerotic plaques of ApoE(-/-)TG2(-/-) mice showed decreased cross-linking of matrix proteins, as well as decreased nuclear staining for phospho-Smad2/-Smad3, indicative of decreased TGFbeta activity. Compared to ApoE(-/-) mice, plaque area was decreased by 45 and 48% in ApoE(-/-)TG2(-/-) mice after 16 and 30 weeks, respectively. Sirius red staining showed a significant decrease in collagen content in early and advanced atherosclerotic plaques of ApoE(-/-)TG2(-/-) mice. Furthermore, there was a significant increase in macrophages in advanced atherosclerotic plaques of ApoE(-/-)TG2(-/-) mice.. TG2 deficiency resulted in a decreased collagen content and increased inflammation, which are features of a more unstable plaque.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Collagen; Disease Models, Animal; Disease Progression; Extracellular Matrix Proteins; Female; Fibrosis; GTP-Binding Proteins; Inflammation; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Glutamine gamma Glutamyltransferase 2; Rupture; Time Factors; Transforming Growth Factor beta; Transglutaminases

Bone marrow cells possess multipotentiality and have been used for several treatments. We hypothesized that bone marrow cells might differentiate into regenerated tendon and that several cytokines within bone marrow cells might accelerate tendon healing. Therefore, we treated Achilles tendon ruptures in a rat model with transplantation of whole bone marrow cells.. Nine F344/Nslc (Fisher) rats were the source of bone marrow cells and mesenchymal stem cells as well as normal Achilles tendons. Eighty-seven Fisher rats were used for the experiments. The rats were divided into three groups: the BMC group (bone marrow cells injected around the tendon), the MSC group (mesenchymal stem cells injected around the tendon), and the non-treated control group (incision only). Outcome measures included mechanical testing, collagen immunohistochemistry, histological analysis, and reverse transcription-polymerase chain reaction to detect expression of transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF).. The ultimate failure load in the BMC group was significantly greater than that in the non-treated or the MSC group at seven days after incision (3.8 N vs. 0.9 N or 2.1 N, p < 0.016) and at fourteen days after incision (10.2 N vs. 6.1 N or 8.2 N, p < 0.016). The ultimate failure load in the BMC group at twenty-eight days after incision (33.8 N) was the same as that of normal tendon (34.8 N). The BMC group demonstrated stronger staining for type-III collagen at seven days after incision and stronger staining for type-I collagen at twenty-eight days than did the MSC group. Expression of TGF-β and VEGF in the BMC group was significantly increased compared with that in the other groups at four days after incision (TGF-β: 1.6 vs. 1.3 or 0.6, p < 0.01; VEGF: 1.7 vs. 1.1 or 0.9, p < 0.01).. Transplantation of whole bone marrow cells may be a better and more readily available treatment for Achilles tendon rupture than cultured mesenchymal stem cells.

Topics: Achilles Tendon; Analysis of Variance; Animals; Biomechanical Phenomena; Bone Marrow Transplantation; Collagen Type III; Immunohistochemistry; Male; Mesenchymal Stem Cell Transplantation; Range of Motion, Articular; Rats; Rats, Inbred F344; Reverse Transcriptase Polymerase Chain Reaction; Rupture; Tendon Injuries; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Wound Healing

The aim of this experimental study was to investigate the effect of mycophenolate mofetil (MMF) during the three phases of colonic anastomosis healing and specifically to check the effect of MMF on the expression of transforming growth factor-beta1 (TGF-beta1), one of the most important growth factors contributing to mechanical stability of colonic anastomosis.. Sixty male Wistar rats underwent colonic resection and end-to-end anastomosis. The animals were divided into two groups, a study group given MMF 40 mg/kg, intraduodenally and a control group given vehicle. The rats were sacrificed at 3, 7, and 14 days (10 animals in each group). The anastomoses were tested by measuring bursting pressure and hydroxyproline content. Histological examination and immunohistochemical expression of TGF-beta1 also were assessed.. The mean bursting pressure in the study group was significantly lower on day 3 and 7, but there was no statistical significance on day 14. The mean hydroxyproline content was lower in the study group on days 3, 7, and 14. Histology showed decreased number of macrophages and fibroblasts on days 3 and 7 but no difference on day 14. The expression of TGF-beta1 was significantly reduced in the study group, with the difference being more pronounced on days 3 and 7.. MMF weakens the integrity of colonic anastomosis, and this effect is more significant during the inflammatory phase of healing. MMF has a negative effect on macrophages and TGF-beta1 expression, resulting in decreased collagen accumulation at the anastomosis.

Topics: Anastomosis, Surgical; Animals; Colon; Fibroblasts; Hydroxyproline; Immunohistochemistry; Immunosuppressive Agents; Inflammation; Macrophages; Male; Mycophenolic Acid; Pressure; Rats; Rats, Wistar; Rupture; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Wound Healing

Extracellular matrix (ECM) molecules such as elastin and collagen provide mechanical support to the vessel wall and are essential for vascular function. Evidence that genetic factors influence aortic ECM composition and organization was concluded from our previous studies showing that the inbred Brown Norway (BN) rat differs significantly from the outbred Long-Evans (LE) and the inbred LOU rat with respect to both thoracic aortic elastin content and internal elastic lamina (IEL) rupture in the abdominal aorta and iliac arteries. Here, we measured aortic elastin and collagen contents as well as factors that may modulate these parameters [insulin growth factor (IGF)-I, transforming growth factor (TGF)-beta(1), and matrix metalloproteinase (MMP)-2] in seven inbred rat strains, including BN and LOU. We also investigated whether IEL ruptures occur in strains other than BN. We showed that LOU, LE, BN, and Fischer 344 (F344) rats were significantly different for aortic elastin content and elastin-to-collagen ratio, whereas LE, Lewis, WAG, and Wistar-Furth (WF) were similar for these parameters. BN and F344 had the lowest values. BN was the only strain to present numerous IEL ruptures, whereas F344, LE, and WF presented a few and the other strains presented none. In addition, IGF-I and TGF-beta(1) levels in the plasma and aorta differed significantly between strains, suggesting genetic control of their production. Because inbred rat strains provide interesting models for quantitative trait locus analysis, our results concerning elastin, collagen, IEL ruptures, and cytokines may provide a basis for the search for candidate genes involved in the control of these phenotypes.

Topics: Animals; Aorta, Abdominal; Aorta, Thoracic; Blood Pressure; Collagen; Elasticity; Elastin; Heart Rate; Iliac Artery; Insulin-Like Growth Factor I; Male; Matrix Metalloproteinase 2; Organ Size; Phenotype; Rats; Rats, Inbred BN; Rats, Inbred F344; Rats, Inbred Lew; Rats, Inbred WF; Rats, Long-Evans; Rupture; Species Specificity; Transforming Growth Factor beta; Transforming Growth Factor beta1

No studies have been conducted to clarify the in vivo effect of growth factor application on healing in the injured anterior cruciate ligament.. Administration of exogenous growth factors significantly increases the structural properties of the injured anterior cruciate ligament.. Controlled laboratory study.. Thirty-six rabbits were randomly divided into 4 groups of 9 animals each after an overstretched injury was made in the right anterior cruciate ligament. In group 1, no treatment was applied around the injured anterior cruciate ligament. In group 2, 0.2 mL fibrin sealant was applied around it. In group 3, 4 ng transforming growth factor-beta1 mixed with 0.2 mL fibrin sealant was applied. In group 4, 20 microg platelet-derived growth factor-BB mixed with 0.2 mL fibrin sealant was applied. Each rabbit was sacrificed at 12 weeks after the surgery. In addition, 9 knees randomly harvested from all the left knees were used to obtain normal control data. The femur-anterior cruciate ligament-tibia complex specimens were biomechanically and histologically evaluated.. Concerning the maximum load and the stiffness, group 3 was significantly greater than groups 1 and 2, whereas there were no significant differences among groups 1, 2, and 4. Groups 1, 2, 3, and 4 were significantly lower than the control group.. The application of 4 ng transforming growth factor-beta1 significantly enhances healing in the injured anterior cruciate ligament.. Administration of certain growth factors is of value to be studied as one of the future therapeutic options for the overstretched anterior cruciate ligament injury.

Topics: Animals; Anterior Cruciate Ligament Injuries; Becaplermin; Biomechanical Phenomena; Female; Fibrin Tissue Adhesive; Lacerations; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Rabbits; Recombinant Proteins; Rupture; Tensile Strength; Transforming Growth Factor beta; Transforming Growth Factor beta1; Wound Healing

The inability of the ruptured anterior cruciate ligament (ACL) of the knee joint to heal spontaneously presents numerous clinical problems. Here we describe a novel, gene-based approach to augment ACL healing. It is based upon the migration of cells from the ruptured ends of the ligament into a collagen hydrogel laden with recombinant adenovirus. Cells entering the gel become transduced by the vector, which provides a basis for the local synthesis of gene products that aid repair. Monolayers of bovine ACL cells were readily transduced by first-generation, recombinant adenovirus, and transgene expression remained high after the cells were incorporated into collagen hydrogels. Using an in vitro model of ligament repair, cells migrated from the cut ends of the ACL into the hydrogel and were readily transduced by recombinant adenovirus contained within it. The results of experiments in which GFP was used as the transgene suggest highly efficient transduction of ACL cells in this manner. Moreover, during a 21-day period GFP+ cells were observed more than 6 mm from the severed ligament. This distance is ample for the projected clinical application of this technology. In response to TGF-beta1 as the transgene, greater numbers of ACL cells accumulated in the hydrogels, where they deposited larger amounts of type III collagen. These data confirm that it is possible to transduce ACL cells efficiently in situ as they migrate from the ruptured ACL, that transduction does not interfere with the cells' ability to migrate distances necessary for successful repair, and that ACL cells will respond in a suitable manner to the products of the transgenes they express. This permits optimism over a possible clinical use for this technology.

Topics: Adenoviridae; Animals; Anterior Cruciate Ligament; Anterior Cruciate Ligament Injuries; Cattle; Cell Movement; Cells, Cultured; Collagen Type III; Gene Expression; Genetic Therapy; Green Fluorescent Proteins; Hydrogel, Polyethylene Glycol Dimethacrylate; Rupture; Transduction, Genetic; Transforming Growth Factor beta; Transforming Growth Factor beta1; Wound Healing

Approximately 44% of patients develop osteoarthritis (OA) following rupture of the anterior cruciate ligament (ACL) if the injury is left unrepaired. Restoring knee stability through reconstruction, while providing symptomatic relief, has not been shown to reduce the incidence of degenerative changes. In fact, recent studies have shown that 50%-60% of ACL-reconstructed patients go on to develop degenerative changes or frank osteoarthritis. In light of these data, our group suggests that the cause of post-traumatic osteoarthritis is not biomechanical but biochemical. To test this hypothesis, we measured levels of nine cytokines which are important in modulating physiological and pathophysiological metabolism of cartilage in knee joint synovial fluid following ACL rupture. Our patient population contained both acute and chronic ACL ruptures. A total of 84 samples were collected and analyzed by enzyme-linked immunosorbent assay. On the basis of the data collected, we were able to identify subgroups of patients who, on the basis of their synovial fluid cytokine profile, may be at greater or lesser risk of developing post-traumatic OA. In general, patients displayed concentrations of interleukin-1 alpha (IL-1 alpha), basic fibroblastic growth factor (bFGF), transforming growth factor-beta (TGF-beta), granulocyte/macrophage-colony stimulating factor (GM-CSF), IL-6, and IL-8 that we interpreted as being consistent with an inflammatory reaction. Of great interest is the fact that the levels of these cytokines were very similar in patients 4 weeks after injury and in chronic patients, leading us to hypothesize that a chronic smoldering inflammatory reaction persists after resolution of the acute effusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anterior Cruciate Ligament Injuries; Chronic Disease; Cytokines; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukins; Knee Injuries; Prognosis; Recombinant Proteins; Rupture; Sialoglycoproteins; Synovial Fluid; Transforming Growth Factor beta