Subtyping of osteoarthritic synoviopathy

OBJECTIVE: Osteoarthritis research is traditionally concentrating on events within the degenerated articular cartilage. Changes in the synovial membrane are largely neglected. In fact, they are generally interpreted as secondary to the cartilage changes and not pathogenetically involved in the disease process. In this study, we present a systematic analysis of the synovial reaction pattern in early and late stages of the osteoarthritic disease process. METHODS: A large series of synovial specimens derived from early and late stage osteoarthritic cartilage disease were investigated by histological and immunohistochemical means for tissue architecture and inflammatory cell infiltrates. For comparison, also samples with rheumatoid arthritis, seronegative arthritis, and septic arthritis were included as well as normal synovial membrane specimens. RESULTS: In all specimens derived from patients with diagnosed osteoarthritis alterations of the synovial tissue were observed. A large spectrum of alterations was found in different stages of osteoarthritic joint disease and four different basic pattern of synovial reactions could be identified: (i) hyperplastic, (ii) inflammatory, (iii) fibrotic, and (iv) detritus-rich synoviopathy. CONCLUSION: We show that in all cases of clinically overt osteoarthritic joint disease significant synovial pathology is associated. Furthermore, our study clearly documents that in osteoarthritic synovium significant inflammation can occur. This is suggestive of a distinct pathogenetic role of the synovium also in osteoarthritic cartilage degeneration at least in a subset of cases.     

Surface Ultrastructure of Rheumatoid Articular Cartilage

Six rheumatoid articular cartilage specimens, which appeared grossly normal and were shown to be free of pannus when examined under the light microscope, were examined electron microscopically. For comparison, normal-appearing cartilage specimens from 2 patients with meniscus injury and 2 with degenerative joint disease (DJD) were also examined. In all cases the normal-appearing joint surface of rheumatoid cartilage was abnormal. Amorphous-appearing material was present to a depth varying between 6 and 25 m̈m. Some of this material had the appearance of fibrin deposited at the cartilage surface, but much appeared to represent breakdown products of the cartilage matrix, i.e. degraded collagen and proteoglycan. DJD cartilage did not show similar changes. The findings suggest that the surface of rheumatoid articular cartilage, even when grossly normal in appearance, is degraded by enzymes either present in the synovial fluid or released by polymorphonuclear cells in close contact with the cartilage surface.     

Expression of osteopontin messenger RNA and protein in rheumatoid arthritis: effects of osteopontin on the release of collagenase 1 from articular chondrocytes and synovial fibroblasts

OBJECTIVE: Osteopontin (OPN) is an extracellular matrix protein that has been implicated in the interactions between tumor cells and host matrix, including those involved in invasion and spread of tumor cells. Because joint destruction in rheumatoid arthritis (RA) is mediated by the invasive growth of synovial tissue through its attachment to cartilage, we examined the expression of OPN in the synovia of patients with RA and the effect of OPN on the production of collagenase 1 in rheumatoid synovial fibroblasts and articular chondrocytes. METHODS: The expression of OPN messenger RNA (mRNA) and protein in synovia from 10 RA patients was examined by in situ hybridization and immunohistochemistry. Synovial fibroblasts from RA patients and articular chondrocytes from patients without joint disease were cultured in the presence of various concentrations of OPN, and levels of collagenase 1 in the culture supernatants were measured by enzyme-linked immunosorbent assay. RESULTS: The expression of OPN mRNA and protein was observed in 9 of 10 specimens obtained from patients with RA. OPN was expressed in the synovial lining and sublining layer and at the interface of cartilage and invading synovium. Double labeling revealed that the majority of OPN-expressing cells were positive for the fibroblast-specific enzyme prolyl 4-hydroxylase and negative for the macrophage marker CD68, while only a few, single OPN-expressing cells were positive for CD68 at sites of synovial invasion into cartilage. OPN staining was not observed in lymphocytic infiltrates or leukocyte common antigen (CD45)-positive cells. Three of 3 cultures of human articular chondrocytes secreted detectable basal amounts of collagenase, with a dose-dependent increase upon OPN stimulation, while synovial fibroblast cultures produced much lower levels of collagenase, with only 2 of 4 fibroblast cultures responding in a dose-dependent manner. CONCLUSION: These findings suggest that OPN produced by synovial fibroblasts in the synovial lining layer and at sites of cartilage invasion not only mediates attachment of these cells to cartilage, but also contributes to matrix degradation in RA by stimulating the secretion of collagenase 1 in articular chondrocytes.     

Cellular hypersensitivity in rheumatoid arthritis,ankylosing spondylitis,and anterior nongranulomatous uveitis

The humoral and cellular responses to normal human ocular and joint tissue antigens were studied in rheumatoid arthritis, ankylosing spondylitis, and anterior non-granulomatous uveitis. No free-circulating autoantibodies could be detected by hemagglutination, immunodiffusion, and immunofluorescence. Uvea-retina, synovial membrane, and articular cartilage antigen preparations inhibited the migration of leukocytes from patients with rheumatoid arthritis. In ankylosing spondylitis inhibition could be induced only by synovial membrane antigens. Patients with anterior nongranulomatous uveitis were hypersensitive to uvea-retina antigens alone.     

Identification of immunoglobulins and complement in rheumatoid articular collagenous tissues

Ninety-three patients with a variety of joint diseases were studied for evidence of immune complexes in articular collagenous tissues. Frozen sections of freshly obtained biopsies of hyaline articular cartilage and menisci were stained with fluoresceinated monospecific antisera for evidence of human immunoglobulins (IgG, IgM, IgA) and the β_1c component of complement. The criterion for the presence of complexes was the staining of two or more immunoglobulins and β_1c in an identical location of sequentially cut sections. Of the 42 patients with rheumatoid arthritis (RA) 83% were positive by this criterion. In those with classic RA the incidence was 92%. Sixteen patients with fresh joint trauma or nonarthritic disease had negative findings. Among 26 patients with noninflammatory disease, 4 of 8 with polyarthritis whose features suggested primary degeneration, 1 of 11 patients with secondary degenerative arthritis, and a single case of synovial osteochondromatosis had positive findings. Among 9 patients with miscellaneous inflammatory arthritides, all of 3 with psoriatic arthritis were negative; however 2 of 6 with other inflammatory arthritides were positive. The findings in classic RA suggest that immune complexes are deposited in the articular collagenous tissues. The persistence of these complexes may play a significant role in the chronicity of the synovitis.     

Quantitative detection of keratan sulfate specific epitopes in synovial fluid in inflammatory and degenerative joint diseases

The release of keratan sulphate (KS) bearing proteoglycan fragments from the extracellular matrix of cartilage into the synovial fluid is believed to be an early event in most joint pathologies. Quantitative analysis of KS in body fluids is therefore regarded as having a certain potential in monitoring articular cartilage catabolism. We describe the application of a non-competitive enzyme linked immunosorbent assay (ELISA) for the quantitation of KS-epitope in synovial fluids, using a monoclonal anti-KS antibody. Synovial fluids from 75 patients were analyzed, comprising the following disease groups: i) rheumatoid arthritis (n = 42), ii) osteoarthritis (n = 20), iii) gouty arthritis (n = 5), and iv) reactive arthritis (Reiter's disease, n = 8). Highest concentrations of synovial KS-epitope were found in reactive arthritis (median = 1410 ng/ml), and in gouty arthritis (median = 2105 ng/ml). However, significantly lower concentrations of KS-epitope (p less than 0.01) were observed in synovial fluids from patients with rheumatoid arthritis (median = 197 ng/ml) and osteoarthritis (median = 337 ng/ml). Although considerable variation of individual values was observed in all groups, a weak and inverse correlation between synovial levels of KS-epitope and inflammatory disease activity was seen only in patients with rheumatoid arthritis. However, KS-epitope levels did not correlate with either the synovial IL-1 activity, nor the number of synovial leucocytes.     

Synovial fluid analysis of two groups of proteoglycan epitopes distinguishes early and late cartilage lesions.

OBJECTIVE. To investigate whether fragmentation of proteoglycans in arthritis results in domains that have different levels of release from cartilage at different stages of the disease. METHODS. Two regions of the proteoglycan, the hyaluronan-binding region and the glycosaminoglycan-rich region of the core protein, were measured, by immunoassay, in knee joint synovial fluids of patients with rheumatoid arthritis or reactive arthritis. RESULTS. Synovial fluid concentrations of the glycosaminoglycan-rich region were highest in rheumatoid arthritis patients who had little cartilage damage as determined by radiography, whereas release of the hyaluronan-binding region predominated in patients with advanced cartilage destruction. In reactive arthritis, release of the glycosaminoglycan-rich region predominated. CONCLUSION. These findings indicate that the hyaluronan-binding region is initially retained in the tissue during the development of cartilage destruction. The combined analysis of these markers offers a new avenue for assessment of the degree of cartilage damage in arthritis.     

Synovial collagenase: Its presence in culture from joint disease of diverse etiology

Closed needle biopsy of synovium from inflamed joints yields enough tissue to detect production and/or release of collagenase from these tissues. Collagenase activity was found in synovium from 8 of 8 patients with probable rheumatoid arthritis, in 6 of 9 patients with nonrheumatoid inflammatory synovitis, and in 1 of 6 patients with degenerative joint disease. One of 2 patients with classic rheumatoid arthritis had activity in synovium regrown after synovectomy. Therefore synovial collagenase is not unique to rheumatoid arthritis.     

Detritus synovitis in chronic polyarthritis: a clinical and operation histologic evaluation

In rheumatoid arthritis (RA) joint inflammation is due to two processes: 1) the underlying inflammatory process (UIP) characterized by a lymphoplasmacellular infiltration of the synovial tissue, as well as pannus formation, and 2) the detritogenic synovitis (DS), a synovial response to articular wear products from cartilage and bone (detritus) that induces a preferentially fibrinous inflammation. In order to estimate the role of DS in the clinical presentation of such joints, 40 patients with RA undergoing knee-joint surgery on 48 occasions were evaluated for clinical parameters, radiological stage (Larsen), and histopathological characteristics of UIP and DS. The clinical parameters were comparable in knee joints with predominantly UIP or DS. However, DS was regularly seen in knees with advanced destruction according to Larsen's stages 4 to 5, while UIP occurres in joints even without radiological damage. In conclusion, it is assumed that the poor response of patients with advanced RA to so-called long-term drug therapy may be in part explained by the modifying influence of joint detritus on the underlying "rheumatoid" inflammatory process.     

Isolation and propagation of endothelial cells derived from rheumatoid synovial microvasculature.

Synovial angiogenesis may play an important part in the destruction of articular cartilage in patients with rheumatoid arthritis (RA). As an important first step towards developing in vitro models of synovial angiogenesis, microvascular endothelial cells have been isolated, purified, and cultured from operative synovial specimens obtained from adult patients with RA.     

Arthroscopic and immunohistologic characterization of knee joint synovitis in osteoarthritis

We studied 10 patients who had arthritis of the knee joint, but no other signs of rheumatic disease. The clinical diagnosis of osteoarthritis was corroborated by arthroscopic evidence of characteristic cartilage degeneration. Signs of inflammation were confined to areas of the synovial membrane that lay near the cartilage; thus, the major part of the joint cavity was not affected. The intensity of the synovial inflammation varied within the areas involved, but was always most pronounced in regions rimming the cartilage. Biopsy samples selected from regions of intensely inflamed synovium contained foci of T lymphocytes, which were bordered by immunoglobulin-carrying B lymphocytes and plasma cells, as well as strongly HLA-DR positive dendritic-like cells adjoined to alpha Leu-3a+ T helper lymphocytes. In tissue samples taken from macroscopically noninflamed areas, only a few infiltrating lymphocytes were seen. Thus, the inflammatory synovial changes found in osteoarthritis appear to be anatomically restricted and of varied intensity but, when present, are microscopically indistinguishable from the changes that have been previously described as indicative of rheumatoid arthritis.     

Vitamin D receptors in the rheumatoid lesion: expression by chondrocytes, macrophages, and synoviocytes

OBJECTIVES: The active form of vitamin D3, 1 alpha,25 dihydroxyvitamin D3 (1,25D3), through its interaction with vitamin D receptors (VDR), is reported to effect a variety of anabolic and catabolic events, especially in bone and cartilage tissues. As cartilage degradation and tissue remodelling are characteristic features of the rheumatoid lesion, the distribution and expression of VDR at sites of cartilage erosion was examined. METHODS: Immunolocalisation techniques using a rat monoclonal antibody to VDR and an alkaline phosphatase conjugated avidin/biotin detection system were used to examine VDR in 18 specimens of cartilage-pannus junction, 10 specimens of rheumatoid synovium or cartilage tissue, and four primary cultures of adherent rheumatoid synovial cells (RSC). For comparison, VDR expression was examined in 10 specimens of normal, healthy age matched articular cartilage. RESULTS: VDR was demonstrated in 15 of 18 cartilage-pannus junctions either at the interface (8 of 18), within the pannus tissue (12 of 18), and by chondrocytes often close to the erosive lesion (10 of 18). All the rheumatoid synovial tissue and 5 of 10 cartilage specimens showed cells with positive staining, but the extent of this was variable. Negligible VDR staining was observed for normal cartilage. Primary cultures of RSC also showed variability in both the numbers and proportions of macrophages or synovial fibroblasts stained for VDR (range 10-50%), this being more common in cultures with a high proportion of macrophages. CONCLUSIONS: VDR expression has been demonstrated by most specimens of cartilage-pannus junction; was associated with various cell types, including chondrocytes, but not exclusively with CD68+ macrophages. The focal nature of VDR expression within the rheumatoid lesion suggests a contributory role for 1 alpha,25D3 in the pathophysiological processes of rheumatoid arthritis.     

A new model for rheumatoid arthritis generated by engraftment of rheumatoid synovial tissue and normal human cartilage into scid mice

Objective. A new animal model was used to study the interaction between rheumatoid synovial cells and cartilage and to explore the cellular basis of rheumatoid joint destruction. Methods. Fresh synovial tissue derived from patients with rheumatoid arthritis was implanted with normal human cartilage into SCID mice, either subcutaneously or under the renal capsule, for up to 304 days. The implants were analyzed by light and electron microscopy, as well as by immunohistochemistry and in situ hybridization. Results. Human synovial tissue and cartilage implanted in SCID mice are maintained by the animals for up to 304 days. After 35 days, focal erosions occur at the site of attachment of synovial lining cells to the cartilage. After 105 days, a pannus-like formation, consisting of proliferating synovial fibroblast-like cells invading the cartilage, is observed. The fibroblast nature of these cells was supported by observation of only focal expression of the macrophage markers CD14 and CD68. Cells at the immediate site of cartilage destruction express messenger RNA for cathepsin L, whereas cathepsin D messenger RNA was detected in subsynovial regions away from the site of destruction. The human origin of the tissue involved in cartilage destruction was demonstrated using monoclonal antibodies to HLA-ABC and human type IV collagen. Conclusion. The present approach introduces a novel in vivo model of rheumatoid arthritis for the study of the molecular and cellular mechanisms of rheumatoid joint destruction at sites of synovial attachment to cartilage. In this model, the SCID mouse acts as a useful host for studying the properties of rheumatoid synovium in the absence of circulating human blood components.     

Role of tenascin-C in articular cartilage

Tenascin-C (TN-C) is a glycoprotein component of the extracellular matrix (ECM). TN-C consists of four distinct domains, including the tenascin assembly domain, epidermal growth factor-like repeats, fibronectin type III-like repeats, and the fibrinogen-like globe (FBG) domain. This review summarizes the role of TN-C in articular cartilage. Expression of TN-C is associated with the development of articular cartilage but markedly decreases during maturation of chondrocytes and disappears almost completely in adult articular cartilage. Increased expression of TN-C has been found at diseased cartilage and synovial sites in osteoarthritis (OA) and rheumatoid arthritis (RA). TN-C is increased in the synovial fluid in patients with OA and RA. In addition, serum TN-C is elevated in RA patients. TN-C could be a useful biochemical marker for joint disease. The addition of TN-C results in different effects among TN-C domains. TN-C fragments might be endogenous inducers of cartilage matrix degradation; however, full-length TN-C could promote cartilage repair and prevent cartilage degeneration. The deficiency of TN-C enhanced cartilage degeneration in the spontaneous OA in aged joints and surgical OA model. The clinical significance of TN-C effects on cartilage is not straightforward.     

Contribution of synovial mesenchymal cells to the pathogenesis of rheumatoid arthritis.

Rheumatoid joint destruction is caused by (1) enzymatic digestion from articular surfaces of cartilage, (2) pannus formation, and (3) lysis of the matrix by activated chondrocytes. Pannus, a vascular and fibrous granulation tissue arising from the perichondral synovial membrane, extends onto cartilage surfaces as a layer of morphologically quiescent fibroblastic mesenchymal cells. Pannus subsequently starts invasion into cartilage matrix with the appearance of macrophagelike cells. Synovial mesenchymal cells are thought to play important roles in the pathogenesis of rheumatoid joint destruction in relation to la expression and antigen presentation as well as the elaboration of inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha. By experimentally inducing antigen-induced arthritis in H-2-c-fos transgenic mice whose immunoglobulin G antibody response against immunizing antigen was defective, the investigators produced destructive arthritis without lymphocyte infiltration. The only cells invading the joints in these mice were similar to a previously recognized subset of human synovial cells that had a mesenchymal appearance. These mesenchymal cells invaded the cartilage matrix upon in vitro culture. The role of synovial mesenchymal cells in the pathogenesis of rheumatoid joint destruction is discussed.     

Co-existent sickle cell disease and juvenile rheumatoid arthritis. Two cases with delayed diagnosis and severe destructive arthropathy

We describe 2 pediatric patients with sickle cell disease (SCD) who developed seropositive juvenile rheumatoid arthritis (JRA). Both patients have severe joint damage, the compound effect of both disease processes. The bone and cartilage destruction, which poses serious therapeutic challenges, highlights the difficulty of making a diagnosis of chronic inflammatory disease in the setting of SCD. There may be a correlation between increased levels of tumor necrosis factor-alpha in the synovial tissue of joints damaged by arthritis and local sickling. The resultant ischemia and corresponding inflammatory infiltrates could in turn worsen existing synovial proliferation and cartilage destruction as well as trigger further sickling.     

磁共振成像在类风湿关节炎患者膝关节病变研究中的意义

目的　初步探讨磁共振成像 (MRI)技术在类风湿关节炎 (RA)患者膝关节病变临床诊断中的应用价值。方法　对 2 0例RA患者的 34个膝关节进行多种序列成像并分析其MRI表现。结果　MRI可清晰显示RA膝关节的滑膜增生及血管翳形成、关节软骨破坏、骨质受侵、关节囊积液、半月板及韧带异常、窝囊肿形成以及皮下结节等改变 ,并能通过血管翳的信号和强化程度判断疾病是否处于活动期。结论　与X线相比 ,MRI对RA的骨质侵蚀破坏更为敏感 (P <0 0 1)。MRI能直接显示RA患者膝关节不同时期的各种改变 ,有助于疾病的早期诊断和临床分期     

Detailed analysis of the cell infiltrate and the expression of mediators of synovial inflammation and joint destruction in the synovium of patients with psoriatic arthritis: implications for treatment

BACKGROUND: The synovial tissue is a primary target of many inflammatory arthropathies, including psoriatic arthritis (PsA). Identification of proinflammatory molecules in the synovium may help to identify potentially therapeutic targets. OBJECTIVE: To investigate extensively the features of cell infiltration and expression of mediators of inflammation and joint destruction in the synovium of patients with PsA compared with patients with rheumatoid arthritis matched for disease duration and use of drugs. METHODS: Multiple synovial tissue biopsy specimens were obtained by arthroscopy from an inflamed joint in 19 patients with PsA (eight oligoarthritis, 11 polyarthritis) and 24 patients with rheumatoid arthritis. Biopsy specimens were analysed by immunohistochemistry to detect T cells, plasma cells, fibroblast-like synoviocytes, macrophages, proinflammatory cytokines, matrix metalloproteinases and tissue inhibitor metalloproteinase-1, adhesion molecules and vascular markers. Stained sections were evaluated by digital image analysis. RESULTS: The synovial infiltrate of patients with PsA and rheumatoid arthritis was comparable with regard to numbers of fibroblast-like synoviocytes and macrophages. T cell numbers were considerably lower in the synovium of patients with PsA. The number of plasma cells also tended to be lower in PsA. The expression of tumour necrosis factor alpha (TNFalpha), interleukin (IL) 1beta, IL6 and IL18 was as high in PsA as in rheumatoid arthritis. The expression of matrix metalloproteinases, adhesion molecules and vascular markers was comparable for PsA and rheumatoid arthritis. CONCLUSION: These data show increased proinflammatory cytokine expression in PsA synovium, comparable to results obtained for rheumatoid arthritis, and support the notion that, in addition to TNFalpha blockade, there may be a rationale for treatments directed at IL1beta, IL6 and IL18.     

YKL-39 (chitinase 3-like protein 2), but not YKL-40 (chitinase 3-like protein 1), is up regulated in osteoarthritic chondrocytes

OBJECTIVE: To investigate quantitatively the mRNA expression levels of YKL-40, an established marker of rheumatoid and osteoarthritic cartilage degeneration in synovial fluid and serum, and a closely related molecule YKL-39, in articular chondrocytes. METHODS: cDNA array and online quantitative polymerase chain reaction (PCR) were used to measure mRNA expression levels of YKL-39 and YKL-40 in chondrocytes in normal, early degenerative, and late stage osteoarthritic cartilage samples. RESULTS: Expression analysis showed high levels of both proteins in normal articular chondrocytes, with lower levels of YKL-39 than YKL-40. Whereas YKL-40 was significantly down regulated in late stage osteoarthritic chondrocytes, YKL-39 was significantly up regulated. In vitro both YKLs were down regulated by interleukin 1beta. CONCLUSIONS: The up regulation of YKL-39 in osteoarthritic cartilage suggests that YKL-39 may be a more accurate marker of chondrocyte activation than YKL-40, although it has yet to be established as a suitable marker in synovial fluid and serum. The decreased expression of YKL-40 by osteoarthritic chondrocytes is surprising as increased levels have been reported in rheumatoid and osteoarthritic synovial fluid, where it may derive from activated synovial cells or osteophytic tissue or by increased matrix destruction in the osteoarthritic joint. YKL-39 and YKL-40 are potentially interesting marker molecules for arthritic joint disease because they are abundantly expressed by both normal and osteoarthritic chondrocytes.