Cyclosporin A inhibition of aggrecanase-mediated proteoglycan catabolism in articular cartilage

Little, C.; Hughes, Claire E.; Curtis, C. G.; Jones, Simon A.; Caterson, Bruce; Flannery, Carl R.

doi:10.1002/1529-0131(200201)46:1<124::aid-art10121>3.0.co;2-x

Cited by 56 publications

(35 citation statements)

References 19 publications

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“…There is a paucity of data regarding the effect of Cn on chondrogenesis and chondrocyte metabolism (22)(23)(24)(25). One study showed that the NF-AT transcription factor, NF-ATp, which is the downstream target of Cn, is a repressor of chondrogenesis (22).…”

Section: Discussioncontrasting

confidence: 99%

“…However, it is not known if the protection of cartilage is the result of a direct effect of CSA on chondrocytes or of an indirect effect mediated by a decrease in inflammation. A previous study showed that CSA could inhibit IL-1-induced aggrecanasemediated proteoglycan catabolism in bovine cartilage explants (25), suggesting a direct effect on chondrocytes. The results of the present study further support the notion that the Cn signaling pathway has a direct effect in chondrocytes.…”

Section: Discussionmentioning

confidence: 99%

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Calcineurin modulates the catabolic and anabolic activity of chondrocytes and participates in the progression of experimental osteoarthritis

Yoo

Park

Yoon

et al. 2007

Arthritis & Rheumatism

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Objective. To determine whether intracellular calcineurin (Cn), a calcium-activated phosphatase, regulates the anabolic and catabolic activities of chondrocytes, and is a potential target in the treatment of osteoarthritis (OA).Methods. CnA expression was examined in cartilage tissue samples and cultured chondrocytes from OA patients, using immunohistochemistry and Western blot analysis, respectively. Concentrations of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases 1 (TIMP-1) in the culture supernatants were determined using enzyme-linked immunosorbent assay. Levels of nitric oxide (NO) and type II collagen (CII) were measured using the Griess reaction and Western blot analysis, respectively. In addition, the pathologic role of Cn was examined in an in vivo model in which experimental OA was induced in mice by injecting type VII collagenase into the knee joints.Results. CnA was highly expressed in the chondrocytes of lesional OA cartilage. Cyclosporin A (CSA), a Cn inhibitor, inhibited spontaneous and interleukin-1␤-stimulated production of NO, MMP-1, and MMP-3 in chondrocytes. However, CSA increased the levels of production of CII, TIMP-1, and transforming growth factor ␤. Similar changes in MMP-1, NO, and CII expression levels in chondrocytes were observed after the targeted inhibition of Cn by overexpression of calcineurin binding protein 1, a natural Cn antagonist. Moreover, in the mouse model, animals treated with CSA showed a significant decrease in both the extent and the severity of cartilage damage, which were assessed macroscopically and microscopically, compared with vehicle-treated animals.Conclusion. These results suggest that CnA is critically involved in the catabolic and anabolic activities of chondrocytes as well as in the progression of experimental OA. Targeted inhibition of CnA may be an effective treatment strategy for OA.The failure of chondrocytes to maintain cartilage integrity is a key event leading to joint destruction in many arthritic conditions, including rheumatoid arthritis (RA), osteoarthritis (OA), and septic arthritis (1,2). Chondrocytes respond to a variety of stimuli, including proinflammatory cytokines and mechanical loading, by increasing the concentration of cartilage degradative enzymes and catabolic mediators. A disturbance in the regulation of the anabolic and catabolic activities of chondrocytes can result in a net loss of cartilage matrix components. Regardless of the initiating stimuli, the key process in cartilage degradation is similar, involving specific matrix metalloproteinases (MMPs), nitric oxide (NO), and aggrecanases, which are members of the ADAMTS family (3). Previous studies have demonstrated that interleukin-1␤ (IL-1␤) and tumor necrosis factor ␣ (TNF␣) also play key roles in cartilage degradation by stimulating their own production and inducing chondrocytes to produce MMPs and NO (4,5).

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Calcineurin modulates the catabolic and anabolic activity of chondrocytes and participates in the progression of experimental osteoarthritis

Yoo

Park

Yoon

et al. 2007

Arthritis & Rheumatism

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“…It was initially described as a constitutively expressed aggrecanase in bovine (16,17) and human (18) chondrocytes, although we and others have demonstrated regulation by inflammatory cytokines in murine (4), bovine (19), and human (9) tissue. The putative promoter region of the gene has predicted binding sites for a number of transcription factors, including NF-B, which are likely to be involved in gene expression following activation of inflammatory signaling (20).…”

Section: Discussionmentioning

confidence: 97%

Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS‐5 and delays cartilage degradation in murine osteoarthritis

Chia¹,

Sawaji²,

Burleigh³

et al. 2009

Arthritis & Rheumatism

184

172

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Objective. We have previously identified in articular cartilage an abundant pool of the heparin-binding growth factor, fibroblast growth factor 2 (FGF-2), which is bound to the pericellular matrix heparan sulfate proteoglycan, perlecan. This pool of FGF-2 activates chondrocytes upon tissue loading and is released following mechanical injury. In vitro, FGF-2 suppresses interleukin-1-driven aggrecanase activity in human cartilage explants, suggesting a chondroprotective role in vivo. We undertook this study to investigate the in vivo role of FGF-2 in murine cartilage.Methods. Basal characteristics of the articular cartilage of Fgf2 -/-and Fgf2 ؉/؉ mice were determined by histomorphometry, nanoindentation, and quantitative reverse transcriptase-polymerase chain reaction. The articular cartilage was graded histologically in aged mice as well as in mice in which osteoarthritis (OA) had been induced by surgical destabilization of the medial meniscus. RNA was extracted from the joints of Fgf2 -/-and Fgf2 ؉/؉ mice following surgery and quantitatively assessed for key regulatory molecules. The effect of subcutaneous administration of recombinant FGF-2 on OA progression was assessed in Fgf2 -/-mice.Results. Fgf2 -/-mice were morphologically indistinguishable from wild-type (WT) animals up to age 12 weeks; the cartilage thickness and proteoglycan staining were equivalent, as was the mechanical integrity of the matrix. However, Fgf2 -/-mice exhibited accelerated spontaneous and surgically induced OA. Surgically induced OA in Fgf2 -/-mice was suppressed to levels in WT mice by subcutaneous administration of recombinant FGF-2. Increased disease in Fgf2 -/-mice was associated with increased expression of messenger RNA of Adamts5, the key murine aggrecanase. Conclusion. These data identify FGF-2 as a novel endogenous chondroprotective agent in articular cartilage.The structural integrity of articular cartilage is determined principally by homeostasis of the 2 major macromolecules of the extracellular matrix, type II collagen and the chondroitin sulfate-rich proteoglycan aggrecan. In healthy tissue, there is a balance between anabolic (synthetic) and catabolic (degradative) processes that allows matrix turnover. Excessive catabolic activity results in matrix breakdown, a hallmark of osteoarthritis (OA). One key early event in matrix breakdown is loss of aggrecan, which is caused by aggrecanase enzymes, members of the ADAMTS family. In humans, ADAMTS-4 and ADAMTS-5 are thought to be the major aggrecanases in cartilage (1,2). In the mouse, deletion of ADAMTS-5, but not ADAMTS-4, was shown to protect against the development of OA and inflammatory arthritis, suggesting that ADAMTS-5 is the main murine aggrecanase (3,4).We have identified fibroblast growth factor 2 (FGF-2) as a potential regulatory molecule in articular cartilage. It is bound to the heparan sulfate chains of the proteoglycan perlecan in the pericellular matrix of hu-

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“…shown to be capable of cleaving aggrecan, they are much less efficient in cleaving this substrate than in cleaving collagen as well as several logs less potent than aggrecanases in cleaving aggrecan. These data, together with the lack of detection of MMP-generated aggrecan neoepitopes either in the media or cartilage in this or similar explant systems (15,17,25,26,32,35), suggest that this is not a viable explanation. Alternatively, the aggrecan molecules may physically protect the type II collagen by preventing access of the proteases.…”

Section: Fig 4 Effect Of An Mmp Inhibitor On Matrix Degradationmentioning

confidence: 94%

Aggrecan Protects Cartilage Collagen from Proteolytic Cleavage

Pratta

Yao²,

Decicco

et al. 2003

Journal of Biological Chemistry

261

212

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The matrix components responsible for cartilage mechanical properties, type II collagen and aggrecan, are degraded in osteoarthritis through proteolytic cleavage by matrix metalloproteinases (MMPs) and aggrecanases, respectively. We now show that aggrecan may serve to protect cartilage collagen from degradation. Although collagen in freeze-thawed cartilage depleted of aggrecan was completely degraded following incubation with MMP-1, collagen in cartilage with intact aggrecan was not. Using interleukin-1-stimulated bovine nasal cartilage explants where aggrecan depletion occurs during the first week of culture, followed by collagen loss during the second week, we evaluated the effect of selective MMP and aggrecanase inhibitors on degradation. A selective MMP inhibitor did not block aggrecan degradation but caused complete inhibition of collagen breakdown. Similar inhibition was seen with inhibitor addition following aggrecan depletion on day 6 -8, suggesting that MMPs are not causing significant collagen degradation prior to the second week of culture. Inclusion of a selective aggrecanase inhibitor blocked aggrecan degradation, and, in addition, inhibited collagen degradation. When the inhibitor was introduced following aggrecan depletion, it had no effect on collagen breakdown, ruling out a direct effect through inhibition of collagenase. These data suggest that aggrecan plays a protective role in preventing degradation of collagen fibrils, and that an aggrecanase inhibitor may impart overall cartilage protection.Cartilage plays a critical role in joint function, where it acts as a shock absorber during joint loading and motion. The extracellular matrix molecules, type II collagen and aggrecan, provide the properties that enable the cartilage to serve this shock-absorbing function. Type II collagen is present as triple helical fibrils that provide cartilage with its structure and tensile strength (3). Aggrecan monomers consist of a core protein with three globular domains. The amino-terminal region contains two of these globular domains, G1 and G2, separated by an interglobular domain. The G2 is followed by a long region along which are attached the sulfated glycosaminoglycan side chains, keratan sulfate and chondroitin sulfate and by the C-terminal globular domain, G3 (4). Multiple aggrecan monomers bind to hyaluronan through their G1 domains to form huge aggregates that are trapped within the collagen network. Because of their high negative charge and water-binding capacity, the aggrecan molecules provide the mechanical properties of compressibility and elasticity to the cartilage. The mechanical properties of the matrix as a whole depend on both major components and their stabilization by intermolecular interactions. The ability of the cartilage to withstand mechanical stress, therefore, is dependent upon its structural integrity and upon the various interactions between the matrix components.Cartilage degradation leading to a loss of joint function in osteoarthritis involves proteolytic cleavage of both aggr...

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Cyclosporin A inhibition of aggrecanase-mediated proteoglycan catabolism in articular cartilage

Cited by 56 publications

References 19 publications

Calcineurin modulates the catabolic and anabolic activity of chondrocytes and participates in the progression of experimental osteoarthritis

Calcineurin modulates the catabolic and anabolic activity of chondrocytes and participates in the progression of experimental osteoarthritis

Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS‐5 and delays cartilage degradation in murine osteoarthritis

Aggrecan Protects Cartilage Collagen from Proteolytic Cleavage

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