Cytokines in osteoarthritis: Mediators or markers of joint destruction?

Westacott, C. I.; Sharif, Mohammed

doi:10.1016/s0049-0172(96)80036-9

Cited by 221 publications

(156 citation statements)

References 101 publications

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“…OA changes are not limited to cartilage, because remodeling of the underlying bone and development of osteophytes are also observed in osteoarthritic joints. Several inflammatory components such as tumor necrosis factor ␣ and IL-1 have been detected in the synovial fluid (SF) of patients with OA and have been implicated in the degenerative process by inhibiting extracellular matrix synthesis and increasing catabolic activities of metalloproteinases (26)(27)(28)(29). In response to cartilage damage, various growth factors, including insulin-like growth factor 1 (IGF-1) or transforming growth factor ␤ (TGF␤), are activated and stimulate chondrocytes to repair the damaged extracellular matrix by forming cell clusters and increasing their anabolic activity (30)(31)(32)(33).…”

Section: Conclusion These Findings Suggest a New Peripheral Functionmentioning

confidence: 99%

Evidence for a key role of leptin in osteoarthritis

Dumond¹,

Presle²,

Terlain³

et al. 2003

Arthritis & Rheumatism

498

416

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Objective. To evaluate the contribution of leptin (an adipose tissue-derived hormone) to the pathophysiology of osteoarthritis (OA), by determining the level of leptin in both synovial fluid (SF) and cartilage specimens obtained from human joints. We also investigated the effect of leptin on cartilage, using intraarticular injections of leptin in rats.Methods. Leptin levels in SF samples obtained from OA patients undergoing either knee replacement surgery or knee arthroscopy were measured by enzymelinked immunosorbent assay. In addition, histologic sections of articular cartilage and osteophytes obtained during surgery for total knee replacement were graded using the Mankin score, and were immunostained using antibodies to leptin, transforming growth factor ␤ (TGF␤), and insulin-like growth factor 1 (IGF-1). For experimental studies, various doses of leptin (10, 30, 100, and 300 g) were injected into the knee joints of rats. Tibial plateaus were collected and processed for proteoglycan synthesis by radiolabeled sulfate incorporation, and for expression of leptin, its receptor (ObRb), and growth factors by reverse transcriptasepolymerase chain reaction and immunohistochemical analysis.Results. Leptin was observed in SF obtained from human OA-affected joints, and leptin concentrations correlated with the body mass index. Marked expression of the protein was observed in OA cartilage and in osteophytes, while in normal cartilage, few chondrocytes produced leptin. Furthermore, the pattern and level of leptin expression were related to the grade of cartilage destruction and paralleled those of growth factors (IGF-1 and TGF␤1). Animal studies showed that leptin strongly stimulated anabolic functions of chondrocytes and induced the synthesis of IGF-1 and TGF␤1 in cartilage at both the messenger RNA and the protein levels.Conclusion. These findings suggest a new peripheral function of leptin as a key regulator of chondrocyte metabolism, and indicate that leptin may play an important role in the pathophysiology of OA.

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Section: Conclusion These Findings Suggest a New Peripheral Functionmentioning

confidence: 99%

Evidence for a key role of leptin in osteoarthritis

Dumond¹,

Presle²,

Terlain³

et al. 2003

Arthritis & Rheumatism

498

416

View full text Add to dashboard Cite

show abstract

“…1,2 Increased levels of this cytokine have been detected in synovial fluids from patients with rheumatoid arthritis and osteoarthritis, 3,4 and its up-regulation in osteoarthritic cartilage tissue has also been reported. 5 Osteoarthritic chondrocytes also seem to express higher levels of IL-1 receptor type 1 6 compared with normal chondrocytes.…”

mentioning

confidence: 98%

Activation of Interleukin-1 Signaling Cascades in Normal and Osteoarthritic Articular Cartilage

Fan

Söder

Oehler³

et al. 2007

The American Journal of Pathology

122

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Interleukin (IL)-1 is one of the most important catabolic cytokines in rheumatoid arthritis. In this study, we were interested in whether we could identify IL-1 expression and activity within normal and osteoarthritic cartilage. mRNA expression of IL-1␤ and of one of its major target genes, IL-6, was observed at very low levels in normal cartilage, whereas only a minor up-regulation of these cytokines was noted in osteoarthritic cartilage, suggesting that IL-1 signaling is not a major event in osteoarthritis. However, immunolocalization of central mediators involved in IL-1 signaling pathways [38-kd protein kinases, phospho (P)-38-kd protein kinases, extracellular signal-regulated kinase 1/2, P-extracellular signal-regulated kinase 1/2, c-Jun NH 2 -terminal kinase 1/2, P-c-Jun NH 2 -terminal kinase 1/2, and nuclear factor B] showed that the four IL-1 signaling cascades are functional in normal and osteoarthritic articular chondrocytes. In vivo, we found that IL-1 expression and signaling mechanisms were detectible in the upper zones of normal cartilage, whereas these observations were more pronounced in the upper portions of osteoarthritic cartilage. Given these expression and distribution patterns, our data support two roles for IL-1 in the pathophysiology of articular cartilage. First, chondrocytes in the upper zone of osteoarthritic articular cartilage seem to activate catabolic signaling pathways that may be in response to diffusion of external IL-1 from the synovial fluid. Second, IL-1 seems to be involved in normal cartilage tissue homeostasis as shown by identification of baseline expression patterns and signaling cascade activation.

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“…Although OA is not considered an inflammatory disease by traditional standards, elevated levels of proinflammatory cytokines, such as interleukin-1␤ (IL-1␤) and tumor necrosis factor ␣, have been observed in OA synovial fluid (SF), supporting the notion that there is an inflammatory component associated with the pathogenesis of OA (for review, see refs. [1][2][3].…”

mentioning

confidence: 99%

Neutrophil gelatinase–associated lipocalin is expressed in osteoarthritis and forms a complex with matrix metalloproteinase 9

Gupta¹,

Shukla²,

Cowland³

et al. 2007

Arthritis & Rheumatism

121

119

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Objective. Expression of matrix metalloproteinase 9 (MMP-9) is up-regulated in osteoarthritis (OA) and usually presents as multiple bands when synovial fluid (SF) from OA patients is analyzed by zymography. Among these bands is an ϳ125-130-kd band for high molecular weight (HMW) gelatinase, which has not been characterized. This study was undertaken to characterize the HMW MMP activity in OA SF.Methods. MMP activity in OA SF was determined by gelatin zymography. Recombinant MMPs were used to identify MMP activity on the zymogram. Western immunoblotting, immunoprecipitation, and immunodepletion analyses were performed using antibodies specific for human MMP-9 and human neutrophil gelatinase-associated lipocalin (NGAL). Human cartilage matrix degradation was determined by dimethylmethylene blue assay.Results. Zymographic analysis showed that the HMW gelatinase in OA SF comigrated with a purified NGAL-MMP-9 complex. Results of Western immunoblotting showed that the HMW gelatinase was also recognized by antibodies specific for human NGAL or human MMP-9. These same antibodies also immunoprecipitated the HMW gelatinase activity from OA SF. The NGAL-MMP-9 complex was reconstituted in vitro in gelatinase buffer. In the presence of NGAL, MMP-9 activity was stabilized; in the absence of NGAL, rapid loss of MMP-9 activity occurred. MMP-9-mediated release of cartilage matrix proteoglycans was significantly higher in the presence of NGAL (P < 0.05).Conclusion. Our findings demonstrate that the HMW gelatinase activity in OA SF represents a complex of NGAL and MMP-9. The ability of NGAL to protect MMP-9 activity is relevant to cartilage matrix degradation in OA and may represent an important mechanism by which NGAL may contribute to the loss of cartilage matrix proteins in OA.The developed world's aging population has experienced a dramatic increase in the incidence of joint dysfunction and osteoarthritis (OA), leading to a compromised quality of life. Aging, biomechanical stress, and oxidative stress, in addition to genetic factors and trauma, all appear to be associated with degenerative and progressive cartilage and bone changes in OA, particularly in the weight-bearing joints. Although OA is not considered an inflammatory disease by traditional standards, elevated levels of proinflammatory cytokines, such as interleukin-1␤ (IL-1␤) and tumor necrosis factor ␣, have been observed in OA synovial fluid (SF), supporting the notion that there is an inflammatory component associated with the pathogenesis of OA (for review, see refs. 1-3).The only cell type present in articular cartilage is the chondrocyte, which is embedded within an extracellular matrix (ECM) primarily composed of type II collagen and aggrecan. Chondrocytes arise from a mesenchymal progenitor cell and are responsible for the biosynthesis of ECM proteins and their transport into the space occupied by the ECM. Chondrocytes play an important role in cartilage homeostasis by maintaining the proper balance between anabolic pathways, which Supported in part by the NIH...

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Cytokines in osteoarthritis: Mediators or markers of joint destruction?

Cited by 221 publications

References 101 publications

Evidence for a key role of leptin in osteoarthritis

Evidence for a key role of leptin in osteoarthritis

Activation of Interleukin-1 Signaling Cascades in Normal and Osteoarthritic Articular Cartilage

Neutrophil gelatinase–associated lipocalin is expressed in osteoarthritis and forms a complex with matrix metalloproteinase 9

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