transforming-growth-factor-beta and Pain

Osteoarthritis (OA) is the most common joint disease in the United States, affecting more than 30 million people, and is characterized by cartilage degeneration in articulating joints. OA can be viewed as a group of overlapping disorders, which result in functional joint failure. However, the precise cellular and molecular events within which lead to these clinically observable changes are neither well understood nor easily measurable. It is now clear that multiple factors, in multiple joint tissues, contribute to degeneration. Changes in subchondral bone are recognized as a hallmark of OA, but are normally associated with late-stage disease when degeneration is well established. However, early changes such as Bone Marrow Lesions (BMLs) in OA are a relatively recent discovery. BMLs are patterns from magnetic resonance images (MRI) that have been linked with pain and cartilage degeneration. Their potential utility in predicting progression, or as a target for therapy, is not yet fully understood. Here, we will review the current state-of-the-art in this field under three broad headings: (i) BMLs in symptomatic OA: malalignment, joint pain, and disease progression; (ii) biological considerations for bone-cartilage crosstalk in joint disease; and (iii) mechanical factors that may underlie BMLs and drive their communication with other joint tissues. Thus, this review will provide insights on this topic from a clinical, biological, and mechanical perspective. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1818-1825, 2018.

Topics: Animals; Bone Diseases; Bone Marrow; Cartilage Diseases; Cartilage, Articular; Disease Progression; Humans; Knee Joint; Magnetic Resonance Imaging; Osteoarthritis; Osteoarthritis, Knee; Pain; Transforming Growth Factor beta

Models available for the study of intervertebral disc degeneration are designed to answer many important questions. In vitro biologic models employ a variety of cell, tissue, or organ culture techniques with culture conditions that partially mimic the cellular environment of the degenerated human intervertebral disc. In vitro biomechanical models include intervertebral disc or motion-segment loading experiments as well as finite element modeling techniques. The literature describes numerous in vivo animal models for use in the study of intervertebral disc degeneration, each of which has its own advantages and disadvantages. Human-subject studies have included the use of magnetic resonance imaging and other techniques to assess diffusion into the intervertebral disc, to measure intradiscal pressure, to conduct kinematic or stiffness studies of lumbar motion segments, and to evaluate muscular forces on the spine. Although all of these studies are helpful in answering specific questions, their relevance in assessing disc degeneration in patients with symptoms of discogenic pain must be carefully considered.

Topics: Age Factors; Aged; Animals; Biomechanical Phenomena; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Disease Models, Animal; Disease Progression; Dogs; Humans; In Vitro Techniques; Intervertebral Disc; Middle Aged; Pain; Pain Measurement; Range of Motion, Articular; Risk Factors; Severity of Illness Index; Species Specificity; Spinal Diseases; Stress, Mechanical; Transforming Growth Factor beta

Difficulties in studying osteoarthritis in humans that stem from both the low sensitivity of diagnostic tools and the low availability of diseased tissues explain why research on animal models remains highly dynamic. This review will summarize the recent advances in this field.. With regard to the etiology of osteoarthritis, synovial macrophages mediate osteophyte formation, whereas increased ligament laxity could be responsible for spontaneous osteoarthritis in guinea pigs. The concomitant changes in subchondral bone and cartilage reported in several models, and the structure-modifying effects of some bone inhibitors have confirmed the importance of bone in osteoarthritis. With regard to cartilage pathobiology, ADAMTS-5 is the major aggrecanase responsible for cartilage destruction, whereas inadequate control of oxidative stress and decreased expression of transforming growth factor-beta receptors could predispose to osteoarthritis. New models include a postmenopausal rat model, the groove model and a joint-specific bone morphogenetic receptor-deficient mouse. The iodoacetate model was also validated as the first pain model of osteoarthritis.. In view of the multiple animal models available, there is a need to reach a consensus on one or several gold standard animal model(s). New studies indicate that important differences in therapeutic response exist between young and old animals, and between spontaneous and surgical models, suggesting that not all models are adequate models of osteoarthritis.

Topics: ADAM Proteins; ADAMTS5 Protein; Animals; Bone and Bones; Cartilage; Disease Models, Animal; Gene Expression Regulation; Guinea Pigs; Humans; Mice; Mice, Transgenic; Osteoarthritis; Oxidative Stress; Pain; Pain Management; Rats; Transforming Growth Factor beta

Maintenance of epithelial tissues needs the stroma. When the epithelium changes, the stroma inevitably follows. In cancer, changes in the stroma drive invasion and metastasis, the hallmarks of malignancy. Stromal changes at the invasion front include the appearance of myofibroblasts, cells sharing characteristics with fibroblasts and smooth muscle cells. The main precursors of myofibroblasts are fibroblasts. The transdifferentiation of fibroblasts into myofibroblasts is modulated by cancer cell-derived cytokines, such as transforming growth factor-beta (TGF-beta). TGF-beta causes cancer progression through paracrine and autocrine effects. Paracrine effects of TGF-beta implicate stimulation of angiogenesis, escape from immunosurveillance and recruitment of myofibroblasts. Autocrine effects of TGF-beta in cancer cells with a functional TGF-beta receptor complex may be caused by a convergence between TGF-beta signalling and beta-catenin or activating Ras mutations. Experimental and clinical observations indicate that myofibroblasts produce pro-invasive signals. Such signals may also be implicated in cancer pain. N-Cadherin and its soluble form act as invasion-promoters. N-Cadherin is expressed in invasive cancer cells and in host cells such as myofibroblasts, neurons, smooth muscle cells, and endothelial cells. N-Cadherin-dependent heterotypic contacts may promote matrix invasion, perineural invasion, muscular invasion, and transendothelial migration; the extracellular, the juxtamembrane and the beta-catenin binding domain of N-cadherin are implicated in positive invasion signalling pathways. A better understanding of stromal contributions to cancer progression will likely increase our awareness of the importance of the combinatorial signals that support and promote growth, dedifferentiation, invasion, and ectopic survival and eventually result in the identification of new therapeutics targeting the stroma.

Topics: Cadherins; Epithelial Cells; Extracellular Matrix; Fibroblasts; Humans; Muscle Cells; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Pain; Receptors, Transforming Growth Factor beta; Signal Transduction; Stromal Cells; Transforming Growth Factor beta

Sustained pain relief following radon spa therapy in patients suffering from chronic painful diseases has been well described. But still, the underlying mechanisms are not fully understood. We conducted the prospective and explorative RAD-ON01 study which included 103 patients who suffered from chronic painful musculoskeletal disorders of the spine and/or joints and present here the data of the examination of pro- and anti-inflammatory cytokines in the serum of the patients before and at weeks 6, 12 and 30 after therapy. While TNFα, IL-1β, IFNγ, IL-1Ra and IL-10 were not altered, TGFβ was temporarily significantly (p = 0.013) elevated 6 weeks after therapy. Importantly, this elevation positively correlated with lowered pain sensitivity (r = 0.41). Further, the amount of IL-18 in the serum positively correlated with lowered pain sensitivity. Therefore, IL-18 can be considered as predictive marker for pain sensitivity of radon spa patients. We conclude that alterations in TGFβ and general IL-18 levels in serum have prognostic and predictive value in situations of lowered pain by exposure of patients to very low-doses of radiation as it is the case in radon spa.

Topics: Baths; Biomarkers; Female; Humans; Interleukin-18; Male; Pain; Prospective Studies; Radon; Transforming Growth Factor beta

The primary objectives of this phase I/II study were to evaluate the safety and immunogenicity of combination therapy consisting of concurrent trastuzumab and human epidermal growth factor receptor 2 (HER2)/neu-specific vaccination in patients with HER2/neu-overexpressing metastatic breast cancer.. Twenty-two patients with stage IV HER2/neu-positive breast cancer receiving trastuzumab therapy were vaccinated with an HER2/neu T-helper peptide-based vaccine. Toxicity was graded according to National Cancer Institute criteria, and antigen specific T-cell immunity was assessed by interferon gamma enzyme-linked immunosorbent spot assay. Data on progression-free and overall survival were collected.. Concurrent trastuzumab and HER2/neu vaccinations were well tolerated, with 15% of patients experiencing an asymptomatic decline in left ventricular ejection fraction below the normal range during combination therapy. Although many patients had pre-existing immunity specific for HER2/neu and other breast cancer antigens while treated with trastuzumab alone, that immunity could be significantly boosted and maintained with vaccination. Epitope spreading within HER2/neu and to additional tumor-related proteins was stimulated by immunization, and the magnitude of the T-cell response generated was significantly inversely correlated with serum transforming growth factor beta levels. At a median follow-up of 36 months from the first vaccine, the median overall survival in the study population has not been reached.. Combination therapy with trastuzumab and a HER2/neu vaccine is associated with minimal toxicity and results in prolonged, robust, antigen-specific immune responses in treated patients.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Cancer Vaccines; Combined Modality Therapy; Fatigue; Female; Headache; Humans; Kaplan-Meier Estimate; Middle Aged; Molecular Sequence Data; Neoplasm Metastasis; Pain; Peptides; Receptor, ErbB-2; T-Lymphocytes; Transforming Growth Factor beta; Trastuzumab; Treatment Outcome; Vaccination

Signaling by the transforming growth factor (TGF)-β superfamily is necessary for proper neural development and is involved in pain processing under both physiological and pathological conditions. Sensory neurons that reside in the dorsal root ganglia (DRGs) initially begin to perceive noxious signaling from their innervating peripheral target tissues and further convey pain signaling to the central nervous system. However, the transcriptional profile of the TGF-β superfamily members in DRGs during chronic inflammatory pain remains elusive. We developed a custom microarray to screen for transcriptional changes in members of the TGF-β superfamily in lumbar DRGs of rats with chronic inflammatory pain and found that the transcription of the TGF-β superfamily members tends to be downregulated. Among them, signaling of the activin/inhibin and bone morphogenetic protein/growth and differentiation factor (BMP/GDF) families dramatically decreased. In addition, peripherally pre-local administration of activins A and C worsened formalin-induced acute inflammatory pain, whereas activin C, but not activin A, improved formalin-induced persistent inflammatory pain by inhibiting the activation of astrocytes. This is the first report of the TGF-β superfamily transcriptional profiles in lumbar DRGs under chronic inflammatory pain conditions, in which transcriptional changes in cytokines or pathway components were found to contribute to, or be involved in, inflammatory pain processing. Our data will provide more targets for pain research.

Topics: Animals; Bone Morphogenetic Proteins; Diagnosis-Related Groups; Ganglia, Spinal; Intercellular Signaling Peptides and Proteins; Pain; Rats; Transforming Growth Factor beta

Although sympathetic blockade is clinically used to treat pain, the underlying mechanisms remain unclear. We developed a localized microsympathectomy (mSYMPX), by cutting the grey rami entering the spinal nerves near the rodent lumbar dorsal root ganglia (DRG). In a chemotherapy-induced peripheral neuropathy model, mSYMPX attenuated pain behaviors via DRG macrophages and the anti-inflammatory actions of transforming growth factor-β (TGF-β) and its receptor TGF-βR1. Here, we examined the role of TGF-β in sympathetic-mediated radiculopathy produced by local inflammation of the DRG (LID). Mice showed mechanical hypersensitivity and transcriptional and protein upregulation of TGF-β1 and TGF-βR1 three days after LID. Microsympathectomy prevented mechanical hypersensitivity and further upregulated Tgfb1 and Tgfbr1. Intrathecal delivery of TGF-β1 rapidly relieved the LID-induced mechanical hypersensitivity, and TGF-βR1 antagonists rapidly unmasked the mechanical hypersensitivity after LID+mSYMPX. In situ hybridization showed that Tgfb1 was largely expressed in DRG macrophages, and Tgfbr1 in neurons. We suggest that TGF-β signaling is a general underlying mechanism of local sympathetic blockade.

Topics: Analgesics; Animals; Ganglia, Spinal; Hyperalgesia; Mice; Pain; Radiculopathy; Receptor, Transforming Growth Factor-beta Type I; Transforming Growth Factor beta; Transforming Growth Factor beta1

Glial-cell-line-derived neurotrophic factor (GDNF) family ligands (GFLs) contribute to the sensitization of primary afferents and are involved in the pathogenesis of inflammatory pain. The purpose of this preliminary study was to examine the expression of other GFLs (neurturin (NRTN), artemin (ARTN), persephin (PSPN)) and receptors in human IVD cells and tissues exhibiting early and advanced stages of degeneration. Human IVD cells were cultured as a monolayer after isolation from the nucleus pulposus (NP) and anulus fibrosus (AF) tissues. The mRNA expression of NRTN, ARTN, PSPN, and their receptors (GFRA2-GFRA4) was quantified using real-time PCR. Protein expression was evaluated using immunohistochemistry and Western blotting. The expression of NRTN, ARTN, PSPN, and their co-receptors (GFRA2-GFRA4) was identified in human IVD cells at both mRNA and protein levels. A trend was noted wherein the mRNA expression of ARTN, PSPN, and GFRA2 was upregulated by IL-1β treatment in a dose-dependent manner. The percentages of immunopositive cells in the advanced degenerate stage of ARTN, PSPN, and GFRA2 were significantly higher than those in the early degenerate stage. Their expression was enhanced in advanced tissue degeneration, which suggests that GFLs (ARTN and PSPN) may be involved in the pathogenesis of discogenic pain.

Topics: Glial Cell Line-Derived Neurotrophic Factor; Glial Cell Line-Derived Neurotrophic Factor Receptors; Humans; Intervertebral Disc; Pain; RNA, Messenger; Transforming Growth Factor beta

Chronic non-bacterial prostatitis (CNBP) accounts for more than 90 % of clinical prostatitis cases, and there is no specific and effective treatment for CNBP. The regulatory role of Jiedu Huoxue decoction (JDHXD)in CNBP remains unclear. We investigated if JDHXD could improve CNBP METHODS: The animal model of CNBP was established by carrageenan injection with 1 % carrageenan (50 μL). The prostate index, epithelial thickness, lumen area, and pain response time were investigated. The apoptosis levels were measured with TUNEL staining and flow cytometry, respectively. Inflammatory factors in the serum were measured with ELISA method.. Treatment with JDHXD significantly improve prostate tissues injury in CNBP rats. Some parameters, such as prostate index, and pain response time, reflecting the prostate function were improved by JDHXD. Inhibition of apoptosis, reactive oxygen species (ROS), and inflammatory response were achieved by JDHXD in vivo. JDHXD markedly suppressed the TGF-β/SMAD signaling pathway, and activation of TGF-β/SMAD signaling pathway could reverse the improvement of CNBP injury by JDHXD. The anti-inflammatory, anti-oxidative and anti-apoptotic effects of JDHXD were proved.. JDHXD might improve CNBP injury through suppressing inflammation response, ROS, and apoptosis by targeting TGF-β/SMAD signaling pathway. This research might provide a new thought for the prevention and treatment of CNBP through inhibiting TGF-β/SMAD signaling pathway.

Topics: Animals; Carrageenan; Humans; Male; Pain; Prostatitis; Rats; Reactive Oxygen Species; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

Catechol-O-methyltransferase (COMT) has been shown to influence clinical pain, descending modulation, and exercise-induced symptom worsening. COMT regulates nociceptive processing and inflammation, key pathophysiological features of Chronic Fatigue Syndrome and Fibromyalgia (CFS/FM). We aimed to determine the interactions between genetic and epigenetic mechanisms regulating COMT and its influence on inflammatory markers and symptoms in patients with CFS/FM.. A case-control study with repeated-measures design was used to reduce the chance of false positive and increase the power of our findings. Fifty-four participants (28 patients with CFS/FM and 26 controls) were assessed twice within 4 days. The assessment included clinical questionnaires, neurophysiological assessment (pain thresholds, temporal summation, and conditioned pain modulation), and blood withdrawal in order to assess rs4818, rs4633, and rs4680 COMT polymorphisms and perform haplotype estimation, DNA methylation in the COMT gene (both MB-COMT and S-COMT promoters), and cytokine expression (TNF-α, IFN-γ, IL-6, and TGF-β).. COMT haplotypes were associated with DNA methylation in the S-COMT promoter, TGF-β expression, and symptoms. However, this was not specific for one condition. Significant between-group differences were found for increased DNA methylation in the MB-COMT promoter and decreased IFN-γ expression in patients.. Our results are consistent with basic and clinical research, providing interesting insights into genetic-epigenetic regulatory mechanisms. MB-COMT DNA methylation might be an independent factor contributing to the pathophysiology of CFS/FM. Further research on DNA methylation in complex conditions such as CFS/FM is warranted. We recommend future research to employ a repeated-measure design to control for biomarkers variability and within-subject changes.

Topics: Case-Control Studies; Catechol O-Methyltransferase; Epigenesis, Genetic; Fatigue Syndrome, Chronic; Fibromyalgia; Humans; Inflammation; Interleukin-6; Pain; Polymorphism, Single Nucleotide; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Aphthous ulcers are very common disorders among different age groups and are very noxious and painful. The incidence of aphthous ulcer recurrence is very high and it may even last for a maximum of 6 days and usually, patients cannot stand its pain. This study aims to prepare a buccoadhesive fast dissolving film containing

Topics: Antioxidants; Corchorus; Glycogen Synthase Kinase 3; Healthy Volunteers; Humans; Hydrogen Peroxide; Interleukin-1; Molecular Docking Simulation; Pain; Plant Extracts; Seeds; Stomatitis, Aphthous; Superoxides; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Chronic pancreatitis (CP) is characterized by pancreatic inflammation and fibrosis, associated with increased pancreatic expression of transforming growth factor beta (TGFB). It is not clear how these might contribute to pain. We investigated whether TGFB signaling via SMAD induces sensitization of pancreatic sensory neurons to increase nociception.. CP was induced in Sprague-Dawley rats by infusion of trinitrobenzene sulfonic acid; some rats were given intrathecal infusions of TGFB1. CP was induced in control mice by administration of cerulein; we also studied β1glo/Ptf1acre-ER mice, which on induction overexpress TGFB1 in pancreatic acinar cells, and TGFBr1. Overexpression of TGFB in pancreatic acinar cells of mice and infusion of TGFB1 into rats resulted in sensory neuron hyperexcitability, SMAD3 activation, and increased nociception. This was accompanied by a reduction in the transient A-type current in pancreas-specific sensory neurons in rats, a characteristic of nociceptive sensitization in animal models of CP. Conversely, pancreata from TGFBr1. In pancreata of mice and rats, TGFB promotes peripheral nociceptive sensitization via a direct effect on primary sensory neurons mediated by intra-neuronal SMAD3. This is distinct from the central nervous system, where TGFB reduces nociception. These results provide an explanation for the link between fibrosis and pain in patients with CP. This signaling pathway might be targeted therapeutically to reduce pain in patients with CP.

Topics: Animals; Ceruletide; Disease Models, Animal; Fibrosis; Humans; Hyperalgesia; Male; Mice; Mice, Transgenic; Nociceptors; Pain; Pancreas; Pancreatitis, Chronic; Patch-Clamp Techniques; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Recombinant Proteins; Signal Transduction; Smad3 Protein; Synaptic Potentials; Transforming Growth Factor beta; Trinitrobenzenesulfonic Acid

Ghrelin is a peptide with attenuating effect on inflammatory pain. Both anti- and pro-inflammatory mediators have a role in the nociception and development of pain and hyperalgesia. IL-10 and TGF-β are anti-inflammatory cytokines and inhibit the expression of pro-inflammatory cytokines related to peripheral and central inflammatory pain. In this study, the effects of i.p. injection of ghrelin on the early and the late phases of pain, as well as serum levels of IL-10 and TGF-β, as anti-inflammatory cytokines, were investigated in formalin-induced pain in male rats.. Adult male Wistar rats (n=48) were randomly divided into six groups: control, formalin+saline, ghrelin (40, 80, and 160 μg/kg), and morphine. Ghrelin was administered i.p. 30 min before inducing pain by formalin. Pain induced by intraplantar (i.pl.) injection of 50 µl formalin 5%, and pain behavior was studied for 60 min. Serum IL-10 and TGF-β levels were assessed by ELISA method.. The findings of the present study showed that ghrelin with high doses (80 and 160 μg/kg) significantly reduced pain intensity in both the early and the late phases of pain. The serum levels of cytokines, IL-10, and TGF-β1 showed a significant elevation with ghrelin at the dose of 160 μg/kg.. Ghrelin is effective in reducing the intensity of both the early and the late phases of inflammatory pain. It seems that ghrelin exerts its analgesic effects in part by increasing the serum levels of anti-inflammatory cytokines.

Topics: Analgesics; Animals; Disease Models, Animal; Ghrelin; Inflammation; Interleukin-10; Male; Morphine; Nociception; Pain; Rats, Wistar; Transforming Growth Factor beta

OBJECTIVE It has been hypothesized that the recombinant human bone morphogenetic protein-2 (rhBMP-2) amplification of the host inflammatory response interacts with nerves in the spine and contributes to the occurrence of new, postoperative complaints of radiculitis. This in vivo rat study was conducted to assess the capacity for rhBMP-2/ACS (rhBMP-2 applied to absorbable collagen sponge [ACS]) to stimulate pain-associated behaviors in the rat chronic constriction injury (CCI) model. METHODS Rats were randomly assigned to one of 14 treatment groups. Half of the animals underwent a sham procedure in which the left sciatic nerve was exposed and manipulated but no ligature was placed (Sham cohort), while the remaining animals had chromic gut sutures tied around the sciatic nerve to induce CCI (CCI cohort). The following test articles were applied to the sciatic nerve in each cohort: saline alone, saline applied to ACS, 0.1 mg/ml rhBMP-2 applied to ACS, or 1.0 mg/ml rhBMP-2 applied to ACS. The ACS was either wrapped around the sciatic nerve or implanted adjacent to the nerve. Thermal withdrawal latency was assessed on Days 7, 14, 21, and 28 postoperatively. Isolated nerves from selected rats in each group were examined and assessed for histopathological changes on Days 3, 7, 14, and 28. RESULTS CCI produced a significant pain behavioral response for all treatment groups at all time points. In the Sham cohort, 0.1 mg/ml rhBMP-2/ACS wrapped around the nerve (WRP) decreased thermal withdrawal on Day 28, and 1.0 mg/ml rhBMP-2/ACS placed adjacent to the nerve (ADJ) decreased thermal withdrawal on Days 21 and 28. Conversely, in the CCI cohort, 0.1 mg/ml rhBMP-2/ACS ADJ increased thermal withdrawal latencies on Day 7; 1.0 mg/ml rhBMP-2/ACS ADJ increased thermal withdrawal latencies on Day 7; and 1.0 mg/ml rhBMP-2/ACS WRP increased thermal withdrawal on Days 7 and 14. Histologically, the effect of rhBMP-2 on nerve inflammation was unclear, as inflammatory cell infiltration was similar in the rhBMP-2/ACS and saline/ACS groups. rhBMP-2 was variably associated with bone formation within the epineurium at 14 days, and more prevalently at 28 days, with no clear relationship between dose or ACS positioning. CONCLUSIONS In this study, rhBMP-2/ACS did not appear to induce pain independent of grossly visible ectopic bone formation. At the earliest time points, rhBMP-2 appeared to have a neuroprotective effect as evidenced by decreased pain exhibited by the rhBMP-2-treated anim

Topics: Absorbable Implants; Animals; Bone Morphogenetic Protein 2; Chronic Disease; Collagen; Constriction, Pathologic; Disease Models, Animal; Drug Implants; Hot Temperature; Hyperalgesia; Male; Motor Activity; Osteogenesis; Pain; Pain Measurement; Random Allocation; Rats, Sprague-Dawley; Recombinant Proteins; Sciatic Nerve; Sciatic Neuropathy; Transforming Growth Factor beta

Topics: Animals; Dietary Supplements; Fibrosis; Glucosamine; Humans; Kidney; Osteoarthritis, Knee; Pain; Signal Transduction; Transforming Growth Factor beta

Periapical lesions are a host response that involves immune reaction to prevent dissemination of bacteria from an infected root canal. The purpose of this study was to evaluate the levels of nitric oxide (NO), IL-4, TGF-beta, tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) in chronic periapical lesions and to determine their possible association with clinical and radiographic parameters.. Seventeen human radicular cysts and 30 periapical granulomas were used in this study. Cytokines and NO were assessed by enzyme-linked immunosorbent assay and by the Griess reaction respectively confirmed by immunohistochemical.. TNF-alpha and IFN-gamma were detected in 10% of granulomas and in 41.2% and 70% of radicular cysts. IL-4 was reactive in 24% of cysts, and TGF-beta was positive in all samples. Patients with tenderness showed significantly higher levels of IFN-gamma and IL-4 (P < 0.05). Swelling was associated with high levels of TNF-alpha, IFN-gamma, and IL-4 (P < 0.05). Lesions presenting bone resorption were associated with high levels of NO (P < 0.05).. Periapical granulomas display a regulatory environment characterized by high TGF-beta and low inflammatory cytokine levels, while radicular cysts has mist Th1 and Th2 inflammatory reaction with the presence of IFN-gamma, TNF-alpha, and IL-4.

Topics: Bone Resorption; Chronic Disease; Cytokines; Edema; Female; Humans; Interferon-gamma; Interleukin-4; Male; Nitric Oxide; Pain; Periapical Granuloma; Radicular Cyst; Radiography; T-Lymphocytes, Regulatory; Th1 Cells; Th2 Cells; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Twenty-four-month outcomes have been reported for patients with degenerative lumbar disc disease who were treated with stand-alone anterior lumbar interbody arthrodesis with use of dual tapered interbody fusion cages and recombinant human bone morphogenetic protein-2. This report represents an update of the clinical and radiographic results of this treatment at six years.. Two hundred and seventy-seven patients with single-level degenerative disc disease with up to grade-I spondylolisthesis were enrolled in two prospective, multicenter, U.S. Food and Drug Administration-approved investigational device exemption studies and were treated with an open or a laparoscopic surgical procedure. The patients received recombinant human bone morphogenetic protein-2 on an absorbable collagen sponge with lumbar fusion cage implants. One hundred and forty-six patients completed the six-year clinical follow-up evaluations, and 130 patients had complete radiographic follow-up at six years. Outcomes were determined with use of well-established clinical outcome measurements (Oswestry Disability Index, Short Form-36, and back and leg pain scores) and radiographic assessments.. At six years, 128 (98%) of the 130 patients treated with recombinant human bone morphogenetic protein-2 and stand-alone fusion cages had a fusion. The second surgery rate was 6.7% (eighteen patients) prior to two years and 3.7% (seven patients) from two to six years. A worst-case scenario analysis, which includes all second surgical procedures due to pseudarthrosis, resulted in a fusion rate at seventy-two months of 91% (128 of 141). Significant improvements in the Oswestry Disability Index scores, Short Form-36 health survey physical component summary scores, and back and leg pain scores were achieved by six weeks in both the open and laparoscopic groups and were sustained at six years (p < 0.001). The percentage of patients who were working at six months (63%) was higher than the percentage who had been working preoperatively (52%), and this improvement was sustained at six years (68%).. The use of dual tapered threaded fusion cages and recombinant human bone morphogenetic protein-2 on an absorbable collagen sponge obtained and maintained intervertebral spinal fusion, improved clinical outcomes, and reduced pain after anterior lumbar interbody arthrodesis in patients with degenerative lumbar disc disease.

Topics: Adult; Arthrodesis; Back Pain; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Female; Gelatin Sponge, Absorbable; Humans; Leg; Lumbar Vertebrae; Male; Outcome Assessment, Health Care; Pain; Prospective Studies; Radiography; Recombinant Proteins; Reoperation; Spondylolisthesis; Transforming Growth Factor beta; Treatment Outcome

Excess reactive oxygen species and oxidative damage have been associated with the pathogenesis of osteoarthritis (OA). Extracellular superoxide dismutase (EC-SOD or SOD3) scavenges superoxide is the major catalytic antioxidant in joint fluid and is decreased in OA cartilage. We studied human joint fluid samples to test whether there is an association between OA and EC-SOD or other low molecular antioxidants in the joint fluid.. Joint fluid samples were obtained from 28 subjects with severe OA undergoing arthrocentesis or knee joint replacement and compared to joint fluid from 12 subjects undergoing knee arthroscopy for chronic knee pain, meniscal tears or anterior cruciate ligament reconstruction. EC-SOD protein was assayed by enzyme-linked immunosorbent assay (ELISA). Ascorbate and urate were measured with high performance liquid chromatography (HPLC) and total nitrates by the Greiss reaction. Glutathione (GSH) and oxidized glutathione were measured using a colorimetric method. Interleukin-6 (IL-6) and transforming growth factor-beta (TGF-beta) were both measured with ELISA.. Human joint fluid contains significant amounts of the extracellular, catalytic antioxidant EC-SOD. Joint fluid from OA subjects is characterized by significantly decreased EC-SOD levels and significant decreases in GSH, and ascorbate compared to the reference group of knee joints with pain or subacute injury but macroscopically intact cartilage. GSH and ascorbate show only an age effect with no effect from disease state on regression modeling. Urate is present in joint fluid but does not show a significant difference between groups. IL-6 and TGF-beta both show non-significant trends to increases in the arthritic subjects. There was no correlation of EC-SOD levels with IL-6 as a marker of inflammation in either the comparison group or the OA group.. EC-SOD, the major scavenger of reactive oxygen species (ROS) in extracellular spaces and fluids, is decreased in late stage OA joint fluid compared to fluid from injured/painful joints with intact cartilage. Injured joints may be able to increase or maintain secretion of EC-SOD but it appears that late stage OA joints fail to do so in spite of increased oxidative stress seen in the disease. Associated age related declines in GSH and ascorbate might also contribute to the development of severe OA. The net effect of these changes in joint fluid antioxidants is likely to accelerate the damaging oxidant effects on extracellular matrix stability in cartilage tissue.

Topics: Age Factors; Cartilage, Articular; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Female; Free Radical Scavengers; Glutathione; Humans; Interleukin-6; Knee Joint; Male; Middle Aged; Nitrates; Nitrites; Osteoarthritis, Knee; Pain; Reactive Oxygen Species; Superoxide Dismutase; Synovial Fluid; Transforming Growth Factor beta; Uric Acid

Topics: Bone Marrow; Cartilage Diseases; Cartilage, Articular; Chondrocytes; Collagen Type X; Humans; Joints; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Pain; Tissue Engineering; Transforming Growth Factor beta

Single nucleotide polymorphisms (SNPs) in cytokine genes have been associated with risk of a number of autoimmune diseases. Moreover, some SNPs are associated with variations in rates of in vitro gene expression, and it is therefore possible that these functional polymorphisms may differentially affect inflammatory processes and disease outcome. This project's objective was to determine whether cytokine genotypes correlate with disease outcomes in patients with juvenile rheumatoid arthritis (JRA).. Genotypes of SNPs of pro-inflammatory cytokines, tumour necrosis factor-alpha -308G -->A, interleukin-6 (IL-6) -174G -->C and interferon-gamma +874G -->A, and anti-inflammatory, immunosuppressive cytokines, interleukin-10 -1082G -->A, -819C -->T and -592A -->C and transforming growth factor-beta1 (TGF-beta1) codon 10T -->C and codon 25G -->C, were determined for patients with JRA who previously participated in a long-term outcome study. Cytokine genotypes and clinical variables showing significant correlations with clinical outcomes at the alpha = 0.100 level in univariate analyses were entered in multivariate tests.. In multivariate tests, the IL-6 genotype -174G/G was positively correlated with pain [regression coefficient B = 0.899, 95% confidence intervals (CI) 0.185, 1.612, P = 0.014]. The homozygous TGF-beta1 codon 25G/G genotype showed a protective effect against joint space narrowing on radiographs taken within 2 yr of disease onset, but confidence intervals were wide [odds ratio (OR) 0.176, 95% CI 0.037, 0.837 P = 0.029].. The correlation of IL-6 genotype with pain and the possible association of the TGF-beta1 codon 25 genotype with short-term radiographic damage (G/C with greater risk and G/G with decreased risk) suggests that both these polymorphisms may be useful early prognostic indicators. Further studies of the relation between cytokine genotypes and outcomes in patients with all forms of juvenile idiopathic arthritis (JIA) are warranted.

Topics: Adolescent; Adult; Age of Onset; Arthritis, Juvenile; Child; Cytokines; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Interleukin-6; Male; Multivariate Analysis; Pain; Polymorphism, Single Nucleotide; Prognosis; Radiography; Transforming Growth Factor beta; Transforming Growth Factor beta1

To study the therapeutic efficacy of intradiscal injection of osteogenic protein-1 (OP-1) to reduce degeneration and associated discogenic pain.. To evaluate if intradiscal injection of OP-1 can reverse disc degeneration and reduce hyperalgesia, a pain-related behavior.. We showed that induction of hyperalgesia was higher in rats exposed to compressed nucleus pulposus (NP). It has been reported that intradiscal injection of OP-1 stimulates synthesis of proteoglycans and collagen in normal intervertebral discs.. Rats were divided into several groups. In the sham group, the rings of an Ilizarov-type apparatus were only applied to the tail without compression. In the compressed NP group, the apparatus was used to apply chronically compression to the tail. Four weeks after surgery, the NP group was subdivided into 3 groups: saline-treated and OP-1-treated, which was divided into 2 groups (i.e., the continuous compression OP-1 [COP-1] group, in which compression was continuously applied to the tail for 4 weeks after OP-1 treatment and the release compression OP-1 [ROP-1] group, in which compression was released at treatment. Either physiologic saline or OP-1 was injected into the instrumented NP. The treated NP was harvested and applied to the left lumbar nerve roots 4 weeks after injection. Hyperalgesia was measured up to 3 weeks after surgery. The degree of disc degeneration and the appearance of the extracellular matrix in the intervertebral discs were evaluated by histology.. Mechanical hyperalgesia was observed in the sham and saline groups, but not in the OP-1 treated group. In the saline group, NP cells became spindle-shaped. In the OP-1 group, the NP cells became swollen with vacuolated cytoplasm, and the content of the extracellular matrix was markedly increased.. OP-1 injection into degenerative intervertebral disc resulted in the enhancement of the extracellular matrix and the inhibition of pain-related behavior.

Topics: Animals; Behavior, Animal; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Extracellular Matrix; Female; Hot Temperature; Hyperalgesia; Injections, Spinal; Intervertebral Disc; Pain; Pressure; Rats; Rats, Sprague-Dawley; Spinal Diseases; Tail; Transforming Growth Factor beta

In a preliminary study the hypothesis was tested that cytokine profiles in peripheral blood were higher in women with deep infiltrating endometriosis and cytokine profiles in peritoneal fluid were higher in women with superficial endometriosis. Thirteen women of reproductive age having laparoscopy for infertility (n=9), pain (n=3) or combined pain and infertility (n=1). Peripheral blood and peritoneal fluid were obtained and analyzed for Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin-10 (IL-10), Transforming Growth Factor-betal (TGFbeta1), and Interferon-gamma (IFN-gamma). No significant cytokine differences were observed in either peritoneal fluid or peripheral blood between IL-6, TGFbeta1, IFNgamma, TNF-alpha and IL-10 of women with superficial endometriosis (n=7) and women with deeply infiltrating endometriosis (n=6). The results of this preliminary study do not show significant differences in peripheral blood and peritoneal fluid cytokine levels between women with deep infiltrating endometriosis compared to women with superficial disease. Future studies with increased sample size are required to either confirm or refute these preliminary findings.

Topics: Adult; Ascitic Fluid; Cytokines; Endometriosis; Female; Humans; Infertility, Female; Interferon-gamma; Interleukin-10; Interleukin-6; Laparoscopy; Pain; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Inflammation in the subacromial bursa causes pain in patients suffering from rotator cuff tear, with this long-lasting inflammation leading to fibrosis and thickening of the subacromial bursa. Both inflammatory cytokines and mechanical stress, and impingement in the subacromial space, might induce and worsen this inflammation. However, little is known of the mechanism of this inflammation. In this study, we used immunohistological staining to demonstrate the expression of Interleukin-1 beta (IL-1 beta), Tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), and basic fibroblast growth factor (bFGF) in subacromial bursa derived from the patients suffering from rotator cuff tear. On the other hand the expression of these inflammatory cytokines and growth factors were little detected only to a small degree in patients with anterior shoulder instability who did not have severe shoulder pain and impingement in the subacromial space. Our findings suggest that those inflammatory cytokines and growth factors may play an important role in inflammation of the subacromial bursa. Controlling the expression of these cytokines and growth factors might be important for treating patients suffering from shoulder pain due to rotator cuff tear.

Topics: Acromion; Adult; Aged; Bursa, Synovial; Bursitis; Cytokines; Female; Fibroblast Growth Factor 2; Growth Substances; Humans; Interleukin-1; Male; Middle Aged; Pain; Rotator Cuff; Rotator Cuff Injuries; Shoulder Impingement Syndrome; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

A conditioning lesion in the sciatic nerve increases in vivo axonal regeneration in the nerve after a second transection. We studied whether this increased regeneration also occurs in the contralateral nerve. The left sciatic nerve was transected and sutured in Wistar rats; the nerve was exposed but not transected in controls. After 5 days, the right sciatic nerves of all rats were transected and sutured. Neuronal regeneration was measured at 0, 1, 3, 5, and 7 days with the pinch test and histological staining. IL-1beta and TGF-beta1 expression was also measured. The initial delay in the experimental group was significantly shorter, but the regeneration rates were the same. The expression of IL-1beta and TGF-beta1 in the right dorsal root ganglia was significantly higher in the experimental group. Nerve injury enhances cytokine expression in the contralateral dorsal root ganglion and promotes contralateral nerve regeneration in vivo by shortening the initial delay.

Topics: Animals; Axons; Functional Laterality; Ganglia, Spinal; Interleukin-1; Male; Nerve Regeneration; Pain; Physical Stimulation; Rats; Rats, Wistar; Sciatic Nerve; Time Factors; Transforming Growth Factor beta

Full-thickness skin biopsies obtained from four patients with rapidly progressive diffuse fasciitis associated with the Eosinophilia-Myalgia syndrome (EMS) were examined for the expression of transforming growth factor-beta 1 (TGF-beta 1), type VI collagen, and fibronectin genes employing immunohistochemistry and in situ hybridizations. The immunohistochemical studies demonstrated increased deposition of TGF-beta, type VI collagen, and fibronectin epitopes in the extracellular matrix of the fascia in comparison to the adjacent dermis in the same specimens. Increased levels of type VI collagen mRNA, as evidenced by positive in situ hybridization signals with an alpha 2(VI) collagen cDNA, were also found in the fascia in comparison with the dermis. In situ hybridizations of affected fascia with a human sequence-specific TGF-beta 1 cDNA demonstrated numerous fibroblasts displaying positive hybridization signals indicative of high levels of transcripts for this cytokine. In contrast, no hybridization signal for TGF-beta 1 was detected in fibroblasts in the adjacent dermis. These findings suggest that TGF-beta 1 may play an important role in the development of the connective tissue alterations present in EMS-associated diffuse fasciitis.

Topics: Aged; Collagen; Eosinophilia; Epitopes; Fasciitis; Female; Fibronectins; Fluorescent Antibody Technique; Gene Expression; Humans; Male; Middle Aged; Muscles; Nucleic Acid Hybridization; Pain; Skin; Syndrome; Transforming Growth Factor beta; Tryptophan