Complement C1s activation in degenerating articular cartilage of rheumatoid arthritis patients: immunohistochemical studies with an active form specific antibody.
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OBJECTIVE: The first complement component C1s was reported to have novel functions to degrade matrix components, besides its activities in the classic complement pathway. This study explores participation of C1s in articular cartilage degradation in rheumatoid arthritis (RA). METHODS: Normal articular cartilage (n = 6) and cartilage obtained from joints with RA (n = 15) and osteoarthritis (OA, n = 10) were immunostained using anti-C1s monoclonal antibodies PG11, which recognises both active and inactive C1s, and M241, which is specifically reactive to activated C1s. The effects of inflammatory cytokines on C1s production by human articular chondrocytes were also examined by sandwich ELISA. RESULTS: In normal articular cartilage, C1s was negative in staining with both PG11 and M241. In contrast, degenerating cartilage of RA was stained with PG11 (14 of 15 cases), and in most of the cases (13 of 15 cases) C1s was activated as revealed by M241 staining. In OA, C1s staining was restricted in severely degrading part of cartilage (5 of 10 cases), and even in that part C1s was not activated. In addition, C1s production by chondrocytes in vitro was increased by an inflammatory cytokine, tumour necrosis factor alpha. CONCLUSION: These results suggest that C1s activated in degenerative cartilage matrix of RA but not in that of OA. C1s is thought to participate in the pathogenesis of RA through its collagenolytic activity in addition to the role in the classic cascade. (+info)
Hemoglobin protects from streptococcal cell wall-induced arthritis.
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OBJECTIVE: To investigate the ability of hemoglobin (Hgb), a nitric oxide (NO) scavenger, to deplete excess NO and reduce inflammation and injury in synovial tissue from joints with inflammatory arthritis. METHODS: The severity of streptococcal cell wall-induced arthritis was monitored following administration of Hgb. Plasma nitrite and nitrate levels were measured, and inducible NO synthase (iNOS) and cytokine messenger RNA (mRNA) expression in peripheral blood mononuclear cells (PBMC) and joint tissue were evaluated. RESULTS: Following systemic administration of Hgb to arthritic rats, plasma levels of nitrite and nitrate as well as iNOS mRNA expression in the joints and PBMC were significantly reduced. Moreover, inflammatory cell accumulation and disease pathology in the joint tissue were dramatically attenuated without obvious side effects. Consistent with this reduction in the inflammatory response, cytokine gene expression was decreased in the synovium of Hgb-treated rats. CONCLUSION: Modulation of NO levels through the use of a NO scavenger, Hgb, influences the development and severity of arthritis. These findings suggest that depletion of excess NO by NO scavengers provides a prototype for further exploration of potential treatments for chronic arthritis. (+info)
Kinetics of aggrecanase- and metalloproteinase-induced neoepitopes in various stages of cartilage destruction in murine arthritis.
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OBJECTIVE: Two major cleavage sites, one mediated by metalloproteinases (MMPs) and the other by an as-yet unidentified enzyme termed aggrecanase, have been observed in aggrecan. To learn more about the relative contribution of these enzymes during cartilage degradation, this study assessed the occurrence of both specific neoepitopes in cartilage during murine arthritis and examined the correlation between neoepitope formation and different aspects of cartilage damage. METHODS: Reversible cartilage damage was induced in mice in the zymosan-induced arthritis (ZIA) model, partly irreversible cartilage damage in the antigen-induced arthritis (AIA) model, and irreversible, destructive cartilage damage in the collagen-induced arthritis (CIA) model. Immunolocalization techniques were used to detect the specific C-terminal neoepitopes VDIPEN (MMPS) and NITEGE (aggrecanase). RESULTS: In normal cartilage from young adult mice, no VDIPEN epitopes were detected, but a limited amount of NITEGE epitopes were already present. During the early phase of proteoglycan (PG) depletion, NITEGE expression was raised substantially in all arthritis models. VDIPEN epitopes were not detected in this early phase of cartilage destruction. When PG depletion progressed toward advanced cartilage damage, VDIPEN epitopes were induced. During ZIA, minimal induction of VDIPEN was observed, whereas in AIA, strong, but partly reversible, VDIPEN staining was evident, and in CIA, an extensive presence and persistence of the MMP-induced neoepitope was seen. When VDIPEN epitopes were intensely present, NITEGE epitopes were greatly reduced at that site in the cartilage. CONCLUSION: Presence of VDIPEN epitopes in cartilage correlated with severe cartilage damage, but these epitopes were not detected during early PG degradation. This suggests a limited role for VDIPEN-inducing MMPs in early PG degradation during murine arthritis. In contrast, aggrecanase epitopes were induced before the appearance of VDIPEN epitopes, but they disappeared with progression of cartilage damage. (+info)
Collagenase 3 production by human osteoarthritic chondrocytes in response to growth factors and cytokines is a function of the physiologic state of the cells.
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OBJECTIVE: We investigated the response of human osteoarthritic (OA) chondrocytes, in terms of collagenase 3 production, to growth factors and cytokines involved in the anabolism and catabolism of articular cartilage, and explored the major signaling pathways leading to its up-regulation. METHODS: Human OA chondrocytes were treated with the following factors: the proinflammatory cytokine interleukin-1beta (IL-1beta), the growth factors basic fibroblast growth factor (bFGF), platelet-derived growth factor BB (PDGF-BB), parathyroid hormone (PTH), insulin-like growth factor 1 (IGF-1), transforming growth factor gamma1 (TGFbeta1), and TGFbeta2, the protein kinase (PK) activator antagonists for PKC, PKA, and PKG pathways, and phospholipase A2 and tyrosine kinases, as well as the antiinflammatory cytokines IL-4, IL-10, and IL-13. Collagenase 3 expression and synthesis were determined. Comparison was made with collagenase 1. RESULTS: The human OA chondrocyte population could be divided into 2 categories: the L chondrocytes, showing low collagenase 3 basal synthesis levels and high sensitivity to IL-1beta stimulation; and the H chondrocytes, high collagenase 3 basal synthesis levels and low IL-1beta inducibility. In L chondrocytes, all growth factors stimulated collagenase 3 production. In H chondrocytes, PTH, IGF-1, and TGFbeta had little or no impact; bFGF slightly stimulated it and PDGF-BB showed the same pattern as in the L chondrocytes. The effects of all growth factors, except TGFbeta, on collagenase 1 synthesis followed those of collagenase 3, albeit to a higher degree. Interestingly and unlike collagenase 3, the effects of TGFbeta on collagenase 1 could not be related to the state of the cells, but rather, depended on the isoform. Indeed, TGFbeta2 did not induce collagenase 1 synthesis, whereas TGFbeta1 stimulated it. Among the PK activators tested, phorbol myristate acetate was the strongest inducer, suggesting a major involvement of the PKC pathway. IL-13 inhibited collagenase 3 production, IL-4 had little effect, and IL-10 had none. CONCLUSION: This study shows that collagenase 3 production in human OA chondrocytes depends on the physiologic state of the cell. TGFbeta might be responsible for the change in cells from the L to the H state. Importantly, our in vitro data implicate TGFbeta2 as a possible in vivo agent capable of specifically triggering collagenase 3 production over that of collagenase 1 in OA cartilage. (+info)
Treatment with calcitonin suppresses the responses of bone, cartilage, and synovium in the early stages of canine experimental osteoarthritis and significantly reduces the severity of the cartilage lesions.
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OBJECTIVE: To relate the rate of bone resorption to serum levels of both hyaluronan (HA) and antigenic keratan sulfate (KS) in canine experimental osteoarthritis (OA) and to evaluate the effects of calcitonin on these parameters and the OA lesions of the unstable knee. METHODS: Twenty-two dogs underwent anterior cruciate ligament transection (ACLT) and 6 dogs underwent sham operation. Urinary pyridinium crosslinks were quantified by high-performance liquid chromatography. Immunoassays quantified hyaluronan (HA) and antigenic KS. Macroscopic and histologic OA lesions were scored. Calcitonin treatment was started on day 14 postsurgery and stopped on either day 49 or day 104 postsurgery. Control dogs and all treated dogs were killed on day 105. RESULTS: All ACLT joints developed OA. In contrast to sham-operated animals, all operated dogs exhibited an early and sustained rise in the levels of their urinary and serum markers. Calcitonin markedly reduced the levels of these markers and the severity of OA lesions. Furthermore, the longer the period of calcitonin therapy, the lower the score of the OA lesions. CONCLUSION: Bone, synovium, and articular cartilage all appear to be involved in the state of hypermetabolism that develops in unstable joints. Furthermore, the rate of bone resorption increases markedly in the early stages of this OA model and is likely to contribute to cartilage breakdown. Since calcitonin reduced the severity of OA changes, this form of therapy may have benefits for humans who have recently experienced a traumatic knee injury. (+info)
Altered mechanics of cartilage with osteoarthritis: human osteoarthritis and an experimental model of joint degeneration.
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OBJECTIVE: Studies of cartilage mechanics seek to determine the fundamental relationships between mechanical behavior and the composition and structure of healthy cartilage and to determine mechanisms for changes associated with degeneration. METHOD: The mechanics of normal and osteoarthritic (OA) human articular cartilage are reviewed. Studies of the initiation and pathogenesis of cartilage degeneration in the anterior cruciate ligament transection (ACLT) model of joint instability are also presented. RESULTS: In human cartilage with OA, tensile, compressive and shear behaviors are dramatically altered. These changes present as decreases in the modulus or stiffness of OA cartilage in tension, compression and shear loading, and increases in the propensity to swell as compared to healthy cartilage. In the ACL transection model of OA, similar changes in the mechanics of cartilage have been observed. In addition, changes in structure, composition, and as metabolism consistent with human OA have been found. Deterioration of the collagen-proteoglycan solid network, which appears to be focused at the articular surface, has been the earliest cartilage changes in the model. It remains to be determined if the initial disruption of the cartilage surface is a direct result of mechanical forces or a product of altered chondrocyte activity. CONCLUSIONS: These data and continued research using experimental models of OA provide a basis for our understanding of the pathogenesis and the time course of events in OA and will lead to the development of better procedures for disease intervention and treatment. (+info)
Articular cartilage repair: are the intrinsic biological constraints undermining this process insuperable?
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This article reviews the experimental and clinical strategies currently in use or under development for the treatment of articular cartilage lesions. The vast majority of protocols under investigation pertain to the treatment of full-thickness defects (i.e., those which penetrate the subchondral bone and trabecular-bone spaces) rather than partial-thickness ones (i.e., those which are confined to the substance of articular cartilage tissue itself). This bias probably reflects the circumstance that partial-thickness defects do not heal spontaneously whereas full-thickness ones below a critical size do, albeit transiently. And it is, of course, a seemingly easier task to manipulate a process which is readily set in train than it is to overcome an induction-problem which Nature herself has not solved. Indeed, the reasons for this inert state of partial-thickness defects have only recently been elucidated, and these are briefly discussed. However, the main body of this review deals with the various transplantation concepts implemented for the repair of full-thickness defects. These fall into two broad categories: tissue-based (entailing the grafting of perichondrial, periosteal, cartilage or bone-cartilage material) and cell-based (utilizing chondroblasts, chondrocytes, periochondrial cells or mesenchymal stem cells). Cell-based systems are further subdivided according to whether cells are transplanted within a matrix (biodegradable, non-biodegradable or synthetic) or free in suspension. Thus far, the application of cell suspensions has always been combined with the grafting of a periosteal flap. The strengths and weaknesses of each concept are discussed. (+info)
Biomechanics of integrative cartilage repair.
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Cartilage repair is required in a number of orthopaedic conditions and rheumatic diseases. From a macroscopic viewpoint, the complete repair of an articular cartilage defect requires integration of opposing cartilage surfaces or the integration of repair tissue with the surrounding host cartilage. However, integrative cartilage repair does not occur readily or predictably in vivo. Consideration of the 'integrative cartilage repair process', at least in the relatively early stages, as the formation of a adhesive suggests several biomechanical approaches for characterizing the properties of the repair tissue. Both strength of materials and fracture mechanics approaches for characterizing adhesives have recently been applied to the study of integrative cartilage repair. Experimental configurations, such as the single-lap adhesive test, have been adapted to determine the strength of the biological repair that occurs between sections of bovine cartilage during explant culture, as well as the strength of adhesive materials that are applied to opposing cartilage surfaces. A variety of fracture mechanics test procedures, such as the (modified) single edge notch, 'T' peel, dynamic shear, and trouser tear tests, have been used to assess Mode I, II, and III fracture toughness values of normal articular cartilage and, in some cases, cartilaginous tissue undergoing integrative repair. The relationships between adhesive biomechanical properties and underlying cellular and molecular processes during integrative cartilage repair remain to be elucidated. The determination of such relationships may allow the design of tissue engineering procedures to stimulate integrative cartilage repair. (+info)