transforming-growth-factor-beta and Synovitis

Osteoarthritis (OA), the most common form of degenerative joint disease, is linked to high morbidity. It is predicted to be the single greatest cause of disability in the general population by 2030. The development of disease-modifying therapy for OA currently face great obstacle mainly because the onset and development of the disease involve complex molecular mechanisms. In this review, we will comprehensively summarize biological and pathological mechanisms of three key aspects: degeneration of articular cartilage, synovial immunopathogenesis, and changes in subchondral bone. For each tissue, we will focus on the molecular receptors, cytokines, peptidases, related cell, and signal pathways. Agents that specifically block mechanisms involved in synovial inflammation, degeneration of articular cartilage, and subchondral bone remodeling can potentially be exploited to produce targeted therapy for OA. Such new comprehensive agents will benefit affected patients and bring exciting new hope for the treatment of OA.

Topics: Animals; Bone and Bones; Cartilage, Articular; Humans; Osteoarthritis; Signal Transduction; Synovitis; Transforming Growth Factor beta

An enhanced expression of the inflammatory mediators in the perimeniscal synovium in knee osteoarthritis (OA) has been suggested to contribute to progressive cartilage degeneration. However, whether the expression levels of these molecules correlated with the severity of OA still remained unclear. Medial perimeniscal synovial samples were obtained from 23 patients with Kellgren-Lawrence (K/L) grades 2 to 4 of medial knee OA. Immunohistochemical analysis of the synovium revealed that the MMP-1, COX-2 and IL-1β expression of the patients with K/L 4 to be significantly reduced in comparison to those with either K/L 2 or 3, while the TGF-β expression showed the opposite. The synovial expression of MMP-1 and IL-1β showed a significant negative correlation with the severity of OA, while that of TGF-β again showed the opposite. In conclusion, although synovial inflammation remained active, the MMP-1, COX-2 and IL-1β expression in synovium decreased depending upon the severity of OA, while the TGF-β expression increased.

Topics: Aged; Aged, 80 and over; Cyclooxygenase 2; Female; Humans; Inflammation Mediators; Interleukin-1beta; Male; Matrix Metalloproteinase 1; Menisci, Tibial; Middle Aged; Osteoarthritis, Knee; Severity of Illness Index; Synovial Membrane; Synovitis; Transforming Growth Factor beta

We and others have previously shown that IL-17 is elevated in the synovial fluid of patients with reactive arthritis (ReA)/undifferentiated spondyloarthropathy (uSpA) having acute synovitis. Major source for IL-17 is Th17 cells, which differentiate from Th0 cells under the influence of TGF-β and IL-6, IL1-β and are maintained by IL-21 and 23. There is a paucity of data on these cytokines in ReA/uSpA. Thus, we measured the levels of Th-17 differentiating and maintaining cytokines in synovial fluid of patients with ReA and uSpA. Fifty patients with ReA/uSpA (ReA 24, uSpA 26), 19 patients with rheumatoid arthritis (RA) and 11 patients with osteoarthritis (OA) were included in the study. Synovial fluid (SF) were collected from knee joint and stored at -80°C until analysis. Cytokines were assayed using ELISA in SF specimens. The median IL-17A levels were significantly elevated in ReA (48.3 pg/ml) and uSpA (32.5 pg/ml) as compared to non-inflammatory OA controls (<7.8 pg/ml; p < 0.0001), while comparable to RA (57.9 pg/ml). Further, IL-6 median values were higher in ReA (25.2 ng/ml) and uSpA (13.6 ng/ml) as compared to OA (0.76 ng/ml; p < 0.0001), and comparable to RA (15.8 ng/ml). The median levels of IL-1β, IL-21 levels were elevated in ReA, uSpA and RA as compared to OA but were not statistically significant. TGF-β levels in ReA and uSpA were similar to OA but lower than in RA (4340 pg/ml; p < 0.05). IL-23 was not detectable in any synovial fluid sample. However, levels of these cytokines did not correlate with disease activity parameters. Significant positive correlation was observed between IL-17 and IL-1β (r = 0.38, p < 0.005), IL-17 and IL-6 (r = 0.659, p < 0.0001), and IL-1β and IL-6 (r = 0.391, p < 0.0001) in ReA and uSpA group. Inflammatory synovitis in ReA/uSpA is mediated by pro-inflammatory cytokines like IL-17, IL-6, IL-1β, and IL-21. However, IL-23 was not detectable in SF. Good correlation between IL-17, IL-6, and IL 1β suggest that either they are co-regulated or they regulate each other.

Topics: Adult; Arthritis, Reactive; Arthritis, Rheumatoid; Case-Control Studies; Female; Humans; Interleukin-17; Interleukin-1beta; Interleukin-23; Interleukin-6; Interleukins; Male; Osteoarthritis; Prohibitins; Retrospective Studies; Spondylarthropathies; Synovial Fluid; Synovitis; Th17 Cells; Transforming Growth Factor beta

Platelet-rich plasma (PRP) can promote the repair of soft tissue, wound, and bone defect. To investigate the effect of PRP on synovitis by establishing papain-induced osteoarthritis model of rabbit knee and interfering with PRP.. Twenty healthy 6-month-old rabbits (male or female, weighing 2.5-3.5 kg) were randomly divided into the experimental group (n = 10) and the control group (n = 10). The whole blood (10 mL) was extracted from the central aural artery and PRP was prepared with the Landesberg's method. Meanwhile, the platelet derived growth factor (PDGF), transforming growth factor (TGF), and vascular endothelial growth factor (VEGF) concentrations in the circulating blood and PRP were measured. The 4% papain solution (0.3 mL) was injected into the knee joint cavity to establish the osteoarthritis model. After that, PRP (0.3 mL) was injected into the knee joints every week for 10 weeks in the experimental group, while normal saline of the same volume in the control group. At 2nd, 4th, 6th, 8th, and 10th weeks after the first injection, the erythrocyte sedimentation rate (ESR) and interleukin 1beta (IL-1beta) concentrations in the whole blood were tested, and the histological changes of the synovium were observed by HE staining and the Mankin scores were made.. The blood cell counting showed that the platelet concentration of PRP was 6.8 times as that of the circulating blood. PDGF, TGF-beta, and VEGF were 5, 8, and 7 times as those of the circulating blood, showing significant differences (P < 0.05). All animals survived to the end of experiment. There were significant differences in the ESR at 2nd, 6th, 8th, and 10th weeks and in the IL-1beta at 4th, 6th, 8th, and 10th weeks between 2 groups (P < 0.05). In the control group, the synovium was edematous and thickened with fibrous effusion and pannus on surface; in the experimental group, the effusion of the synovium was decreased and less congestion and edema were observed at the 2nd week; the synovium was observed to be a bit thickened without obvious edema, with slight amount of yellowish joint fluid on surface and no conglutination at the 10th weeks. There were significant differences in the Mankin score at 4th, 6th, 8th, and 10th weeks (P < 0.05) between 2 groups.. PRP is beneficial to the alleviation of synovitis induced by papain according to restoring the damaged tissue and depressing the inflammatory factors.

Topics: Animals; Disease Models, Animal; Female; Interleukin-1beta; Knee Joint; Male; Platelet-Derived Growth Factor; Platelet-Rich Plasma; Rabbits; Synovitis; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

A Th1 biased immune response in synovial fluid has been reported in children with polyarticular and extended oligoarticular-type juvenile idiopathic arthritis (JIA). We investigated T cell phenotypes including Th1, Th2, Th17, and Treg with emphasis on Th17 and Treg, in order to differentiate cytokines in the enthesitis-related arthritis (ERA) form of JIA.. The frequencies of Th1, Th2, Th17, and Treg cells were determined by flow cytometry in peripheral blood (PB) and synovial fluid from patients with ERA and healthy subjects. Levels of interleukin 1ss (IL-1ss), IL-6, IL-21, IL-23, and transforming growth factor ss (TGF-ss), cytokines that influence Th17 lineage cells, were measured in paired plasma and synovial fluid (SF) samples by ELISA. Frequencies are expressed as percentages and cytokine levels as pg/ml.. There were no differences in blood samples in the frequency of Th1, Th2, Th17, and Treg cells between patients and controls. In paired samples, the median frequency of CD4+IFN-gamma+ (20.49 vs 4.03; p < 0.005) and CD4+IL-17+ (2.27 vs 0.57; p < 0.01) cells was significantly higher in SF compared to PB, respectively; whereas the frequency of CD4+IL-4+ (1.79 vs 2.29; p < 0.04) cells was significantly reduced in the SF compared to PB. There was no difference in the frequency of regulatory T cells. Patients receiving methotrexate had fewer Th2 cells, whereas the Childhood Health Assessment Questionnaire score had a negative association with the frequency of Treg. Median levels of IL-1ss (p < 0.008), IL-6 (p < 0.0001), and IL-17 (p < 0.0001) were higher in SF than in plasma and levels of TGF-ss were lower (p < 0.001). Levels of IL-21 were similar in SF and plasma, whereas IL-23 was undetectable.. In patients with ERA, peripheral blood Th1, Th2, Th17, and Treg cells were unchanged, but Th1 and Th17 cells were increased and Th2 cells were reduced in the SF compared to blood. Elevated IL-1ss and IL-6 in SF may be responsible for increased Th17 cells.

Topics: Adolescent; Adult; Arthritis, Juvenile; Cell Lineage; Child; Flow Cytometry; Humans; Immunophenotyping; Interleukin-17; Interleukin-1beta; Interleukin-23; Interleukin-6; Interleukins; Male; Synovitis; T-Lymphocytes, Regulatory; Th1 Cells; Th2 Cells; Transforming Growth Factor beta; Young Adult

To examine angiogenic growth factors in patients with early, untreated inflammatory arthritides and controls.. Synovial membrane (SM) infiltrate and Ang1, Ang2, and vascular endothelial growth factor (VEGF) mRNA and protein expression were examined using immunohistochemistry and in situ hybridization. Synovial fluid (SF) VEGF, transforming growth factor-beta (TGF-beta 1), and tumor necrosis factor-alpha (TNF-alpha) protein were measured by ELISA. Vascular morphology was assessed at arthroscopy.. Ang2 mRNA and protein expression was observed in early psoriatic arthritis (PsA) and rheumatoid arthritis (RA) SM. Expression of Ang2 and VEGF was significantly greater in early PsA SM and correlated strongly. SF VEGF and TGF-beta 1 concentrations were also significantly higher in early PsA compared to RA. Distinct vascular morphology, with tortuous vessels in PsA, correlated with microscopic vascular scores (r = 0.54, p = 0.005) and VEGF levels (r = 0.51, p = 0.01). Ang1 mRNA and protein expression was observed, but concentrations were markedly lower than for Ang2 and VEGF. Clinical disease activity, SM infiltration, and SF TNF-alpha concentrations were similar in both groups.. This is the first report of angiopoietin expression in early inflammatory arthritis. There is a close relationship between angiopoietins, VEGF, TGF-beta, and vascular morphology. There is differential angiogenesis at an early stage of inflammation, with major pathogenic and therapeutic implications.

Topics: Adult; Aged; Angiogenesis Inducing Agents; Angiopoietin-1; Angiopoietin-2; Arthritis, Psoriatic; Arthritis, Rheumatoid; Arthroscopy; Endothelial Growth Factors; Humans; In Situ Hybridization; Intercellular Signaling Peptides and Proteins; Lymphokines; Membrane Glycoproteins; Middle Aged; RNA, Messenger; Synovial Membrane; Synovitis; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Oncostatin M (OSM) has been described as a bone-remodeling factor either stimulating osteoblast activity or osteoclast formation in vitro. To elucidate the in vivo effect of OSM on bone remodeling, we injected an adenoviral vector encoding murine OSM in knee joints of mice. OSM strongly induced interleukin (IL)-6 gene expression, a known mediator of osteoclast development. We investigated the OSM effect in wild-type and IL-6-deficient mice and found a similar degree of OSM-induced joint inflammation. Within the first week of inflammation, the periosteum along the femur and tibia increased in cell number and stained positive for the osteoblast marker alkaline phosphatase. At these sites bone apposition occurred in both strains as demonstrated by Goldner and Von Kossa staining. In vitro OSM enhanced the effect of bone morphogenetic protein-2 on osteoblast differentiation. Immunohistochemistry demonstrated expression of receptor activator of nuclear factor-kappa B ligand (RANKL) and its receptor, receptor activator of nuclear factor-kappa B (RANK), in the periosteum but osteoclasts were not detected at sites of bone apposition. Induced mRNA expression for the receptor activator of nuclear factor-kappa B ligand inhibitor osteoprotegerin probably controlled osteoclast development during OSM overexpression. Our results show that OSM favors bone apposition at periosteal sites instead of resorption in vivo. This effect was not dependent on or inhibited by IL-6.

Topics: Adenoviridae; Alkaline Phosphatase; Animals; Arthritis; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Carrier Proteins; Cell Line; Dose-Response Relationship, Drug; Gene Expression; Gene Transfer Techniques; Genotype; Glycoproteins; Interleukin-6; Knee Joint; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Oncostatin M; Osteogenesis; Osteoprotegerin; Peptides; Periosteum; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Recombinant Proteins; Specific Pathogen-Free Organisms; Synovitis; Transforming Growth Factor beta; Up-Regulation

Oral administration of autoantigens can influence the outcome of experimental autoimmune diseases, yet little is known about nonself Ag-induced tolerance. In this study, we administered group A streptococcal cell wall (SCW) peptidoglycan-polysaccharide complexes orally and monitored the impact on SCW-induced erosive polyarthritis. Oral administration of low dose SCW (3 microg/day), initiated 7 days before an arthritogenic dose of systemic SCW, virtually eliminated the joint swelling and destruction typically observed during both the acute and chronic phases of the arthritis. High (300 microg), but not intermediate (30 microg), dose regimens also profoundly inhibited the disease. Most previous studies have demonstrated that prior feeding is required for efficacy, yet oral feeding of low dose SCW suppressed the evolution of arthritis even when administration was begun 10-15 days after induction of the arthritis. While the synovial inflammatory cell infiltration and expression of proinflammatory cytokines were markedly suppressed, no local enhancement of the regulatory cytokines IL-4, IL-10, and TGF-beta was detected. Oral administration of low dose SCW, however, up-regulated circulating levels of TGF-beta, concomitant with decreased circulating TNF-alpha and suppression of chronic arthritis. Moreover, IL-10 was increased in tolerized spleen lymphocytes, and unexpectedly, this SCW-specific IL-10 production was TGF-beta dependent. These data support a pivotal role for TGF-beta, although not necessarily in the joint, in the regulation of specific immune tolerance responsible for suppressed synovial inflammation and matrix destruction. The distant induction and up-regulation of regulatory cytokines and/or cells may contribute to the inhibition of the immune response through blunted infiltration of inflammatory cells to the joint.

Topics: Acute Disease; Adjuvants, Immunologic; Administration, Oral; Animals; Arthritis; Cell Movement; Cell Wall; Chronic Disease; Cytokines; Female; Immune Tolerance; Immunity, Mucosal; Immunosuppressive Agents; Interleukin-10; Lymphoid Tissue; Peptidoglycan; Rats; Rats, Inbred Lew; Spleen; Streptococcus pyogenes; Synovitis; Transforming Growth Factor beta; Up-Regulation

Rheumatoid arthritis (RA) is a chronic inflammatory disease with primary manifestations in the synovial membrane. Tissue infiltrates are composed of T cells, B cells, and macrophages, but histopathological appearances vary widely and are rarely pathognomonic. Mechanisms underlying the phenotypic heterogeneity of rheumatoid synovitis are not known. To explore whether a correlation exists between the microscopic patterns of rheumatoid synovitis and in situ production of cytokines, tissue samples from 21 consecutive patients with clinically active RA were examined. Based upon the organization of the lymphocyte infiltrate, the synovial biopsies were categorized into three distinct subsets. Ten samples were characterized by diffuse lymphoid infiltrates without further microarrangement. In seven samples, lymphoid follicles with germinal center formation were detected, and in four specimens, granuloma formation was identified. In all specimens, cytokine transcription of interferon (IFN)-gamma, interleukin (IL)-4, IL-1 beta, tumor necrosis factor (TNF)-alpha, IL-10, and transforming growth factor-beta 1 was semiquantified with polymerase chain reaction and liquid phase hybridization. Each of the morphologically defined variants of synovitis displayed a unique cytokine profile. Low-level transcription of IFN-gamma, IL-4, IL-1 beta, and TNF-alpha was typical of diffuse synovitis. In follicular synovitis, IFN-gamma was the dominant cytokine, IL-4 was virtually undetectable, and IL-10 was abundant. Granulomatous synovitis demonstrated high transcription of IFN-gamma, IL-4, IL-1 beta, and TNF-alpha and could be clearly distinguished from the other phenotypes. To investigate whether differences in the synovial lesions were related to host factors, patients were compared for clinical parameters. Diffuse synovitis was seen in most of the patients with seronegative RA, the mildest form of the disease. In contrast, extra-articular spreading of RA with nodule formation was typically associated with granulomatous synovitis. In summary, RA patients display reproducible patterns in the organization and activity of synovial infiltrates. The correlation of microanatomy with tissue cytokine production suggests that several pathomechanisms can modulate the expression of the immune response in the synovial membrane.

Topics: Adult; Aged; Arthritis, Rheumatoid; Cytokines; Female; Humans; Interleukin-10; Macrophages; Male; Middle Aged; RNA, Messenger; Synovial Membrane; Synovitis; T-Lymphocytes; Tissue Distribution; Transforming Growth Factor beta

Transforming growth factor-beta (TGF-beta) has been shown to antagonise interleukin-1 (IL-1) effects in different systems. Investigations were carried out to study whether TGF-beta 1 modulates IL-1 induced inflammation and IL-1 effects on articular cartilage in the murine knee joint.. IL-1, TGF-beta 1 or both factors together were injected into the knee joint. Inflammation was studied in whole knee histological sections. Patellar cartilage proteoglycan synthesis was measured using 35S-sulphate incorporation while patellar cartilage glycosaminoglycan content was determined with automated image analysis on joint sections.. Co-injection of TGF-beta 1 and IL-1 resulted in synergistic attraction of inflammatory cells. In contrast, TGF-beta 1 counteracted IL-1 induced suppression of articular cartilage proteoglycan synthesis. Proteoglycan depletion was similar shortly after the last injection of IL-1 or IL-1/TGF-beta 1, but accelerated recovery was found with the combination at later days. This protective effect of TGF-beta 1 could not be demonstrated in older mice.. TGF-beta 1 aggravates IL-1 induced knee joint inflammation, but counteracts the deleterious effects of IL-1 on articular cartilage proteoglycan synthesis and content. The data indicate that TGF-beta 1 could play an important part in articular cartilage restoration after IL-1 induced proteoglycan depletion.

Topics: Age Factors; Animals; Cartilage, Articular; Drug Synergism; Interleukin-1; Male; Mice; Mice, Inbred C57BL; Patella; Proteoglycans; Recombinant Proteins; Synovitis; Transforming Growth Factor beta

Transforming growth factor beta (TGF-beta) induces leukocyte recruitment and activation, events central to an inflammatory response. In this study, we demonstrate that antagonism of TGF-beta with a neutralizing antibody not only blocks inflammatory cell accumulation, but also tissue pathology in an experimental model of chronic erosive polyarthritis. Intraarticular injection of monoclonal antibody 1D11.16, which inhibits both TGF-beta 1 and TGF-beta 2 bioactivity, into animals receiving an arthropathic dose of bacterial cell walls significantly inhibits arthritis. Inhibition was observed with a single injection of 50 micrograms antibody, and a 1-mg injection blocked acute inflammation > 75% compared with the contralateral joints injected with an irrelevant isotype control antibody (MOPC21) as quantitated by an articular index (AI = 0.93 +/- 0.23 for 1D11.16, and AI = 4.0 +/- 0 on day 4; p < 0.001). Moreover, suppression of the acute arthritis achieved with a single injection of antibody was sustained into the chronic, destructive phase of the disease (on day 18, AI = 0.93 +/- 0.07 vs. AI = 2.6 +/- 0.5; p < 0.01). The decreased inflammatory index associated with anti-TGF-beta treatment was consistent with histopathologic and radiologic evidence of a therapeutic response. These data implicate TGF-beta as a profound agonist not only in the early events responsible for synovial inflammation, but also in the chronicity of streptococcal cell wall fragment-induced inflammation culminating in destructive pathology. Interrupting the cycle of leukocyte recruitment and activation with TGF-beta antagonists may provide a mechanism for resolution of chronic destructive lesions.

Topics: Acute Disease; Animals; Antibodies, Monoclonal; Bone Resorption; Chronic Disease; Female; Rats; Rats, Inbred Lew; Synovitis; Transforming Growth Factor beta

We have studied the consequences of introducing human recombinant transforming growth factor beta 1 (hrTGF-beta 1) into synovial tissue of the rat, to begin to better understand the significance of the fact that biologically active TGF-beta is found in human arthritic synovial effusions. Within 4-6 h after the intra-articular injection of 1 microgram of hrTGF-beta 1 into rat knee joints, extensive recruitment of polymorphonuclear leukocytes (PMNs) was observed. Cytochemistry and high resolution histological techniques were used to quantitate the influx of PMNs, which peaked 6 h post-injection. In a Boyden chamber assay, hrTGF-beta 1 at 1-10 fg/ml elicited a chemotactic response from PMNs greater in magnitude than that evoked by FMLP, establishing that TGF-beta 1 is an effective chemotactic agent for PMNs in vitro as well as in vivo. That PMNs may represent an important source of TGF-beta in inflammatory infiltrates was strongly suggested by a demonstration that stored TGF-beta 1 was secreted during phorbol myristate acetate-stimulated degranulation in vitro. Acid/ethanol extracts of human PMNs assayed by ELISA contained an average of 355 ng of TGF/beta 1 per 10(9) cells potentially available for secretion during degranulation of PMNs. [3H]Thymidine incorporation in vivo and autoradiography of tissue sections revealed that widespread cell proliferation was triggered by TGF-beta 1 injection. Synovial lining cells and cells located deep within the subsynovial connective tissue were identified as sources of at least some of the new cells that contribute to TGF-beta 1-induced hyperplasia. Our results demonstrate that TGF-beta is capable of exerting pathogenic effects on synovial tissue and that PMNs may represent a significant source of the TGF-beta present in synovial effusions.

Topics: Animals; Cell Division; Chemotaxis, Leukocyte; DNA; Enzyme-Linked Immunosorbent Assay; Female; Hyperplasia; Injections, Intra-Articular; Microscopy, Electron; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Rats; Recombinant Proteins; Synovial Membrane; Synovitis; Thymidine; Transforming Growth Factor beta; Tritium