Inhibition of ADAM-TS4 and ADAM-TS5 Prevents Aggrecan Degradation in Osteoarthritic Cartilage

Malfait, Anne‐Marie; Liu, Rui‐Qin; Ijiri, Kosei; Komiya, Setsuro; Tortorella, Micky D.

doi:10.1074/jbc.m200431200

Cited by 278 publications

(249 citation statements)

References 46 publications

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“…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).…”

mentioning

confidence: 99%

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

182

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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mentioning

confidence: 99%

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

182

172

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“…ADAM family members may participate in inflammatory processes through the proteolytic release of inflammatory mediators from the cell membrane, such as the cleavage by ADAM-17 of membrane-bound tumor necrosis factor ␣ (TNF␣) to the more proinflammatory soluble form (10). The ADAMTS family consists of 19 human gene products, which include N-terminal procollagen propeptidases (ADAMTS-2, -3, and -14) and aggrecanases (ADAMTS-1, -4, -5, -8, -9, and -15) that appear to participate in early degradative events of arthritic cartilage, and are implicated in tendon-matrix turnover (11)(12)(13). Aggrecanases cleave aggrecan at characteristic sites located C-terminal to a glutamate residue (14), but some members also cleave related proteoglycans such as versican and brevican at equivalent sites (15)(16)(17).…”

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confidence: 99%

Expression profiling of metalloproteinases and tissue inhibitors of metalloproteinases in normal and degenerate human achilles tendon

Jones¹,

Corps²,

Pennington³

et al. 2006

Arthritis & Rheumatism

259

284

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Objective. To profile the messenger RNA (mRNA) expression for the 23 known genes of matrix metalloproteinases (MMPs), 19 genes of ADAMTS, 4 genes of tissue inhibitors of metalloproteinases (TIMPs), and ADAM genes 8, 10, 12, and 17 in normal, painful, and ruptured Achilles tendons.Methods. Tendon samples were obtained from cadavers or from patients undergoing surgical procedures to treat chronic painful tendinopathy or ruptured tendon. Total RNA was extracted and mRNA expression was analyzed by quantitative real-time reverse transcription-polymerase chain reaction, normalized to 18S ribosomal RNA.Results. In comparing expression of all genes, the normal, painful, and ruptured Achilles tendon groups each had a distinct mRNA expression signature. Three mRNA were not detected and 14 showed no significant difference in expression levels between the groups. Statistically significant (P < 0.05) differences in mRNA expression, when adjusted for age, included lower levels of MMPs 3 and 10 and TIMP-3 and higher levels of ADAM-12 and MMP-23 in painful compared with normal tendons, and lower levels of MMPs 3 and 7 and TIMPs 2, 3, and 4 and higher levels of ADAMs 8 and 12, MMPs 1, 9, 19, and 25, and TIMP-1 in ruptured compared with normal tendons.Conclusion. The distinct mRNA profile of each tendon group suggests differences in extracellular proteolytic activity, which would affect the production and remodeling of the tendon extracellular matrix. Some proteolytic activities are implicated in the maintenance of normal tendon, while chronically painful tendons and ruptured tendons are shown to be distinct groups. These data will provide a foundation for further study of the role and activity of many of these enzymes that underlie the pathologic processes in the tendon.

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“…The expression patterns of Mmp-3 and Mmp-13 in the articular cartilage of TM joints in both mutant mice at 3 months of age suggests that other molecules, such as aggrecanases or other Mmps, may play a significant role in the cartilage degeneration at this stage. Interestingly, an in vitro study shows that aggrecanase inhibitors can block aggrecan degradation in OA cartilage, whereas MMP inhibitors do not (15).…”

Section: Discussionmentioning

confidence: 99%

Age-dependent increase of discoidin domain receptor 2 and matrix metalloproteinase 13 expression in temporomandibular joint cartilage of type IX and type XI collagen-deficient mice

Lam¹,

Li²,

Waldman³

et al. 2007

Archives of Oral Biology

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Our previous studies demonstrated that mutations in type IX and type XI collagens in mice caused osteoarthritis (OA)-like changes in knee and temporomandibular (TM) joints. We also found that the overexpression of matrix metalloproteinase 13 (Mmp-13) was probably due to the upregulation of a collagen receptor, discoidin domain receptor 2 (Ddr2), which was responsible for knee cartilage degeneration in mutant mice. The objective of our study was to determine whether the expression of Mmp-3, Mmp-13 and Ddr2 was increased in OA-like TM joints in mutant mice using immunohistochemistry. We found that the staining for Ddr2, Mmp-13 and Mmp-derived type II collagen fragments in tissue sections from 6 month-old mice was increased in TM joints of the mutant mice. In contrast, we found no difference in the staining for Mmp-3 amongst the two mutant mice and their wild-type littermates. We conclude that, similar to previous observations in knee joints, the overexpression of Ddr2 and Mmp-13 may be responsible for the OA-like change in TM joints in mutant mice.

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Inhibition of ADAM-TS4 and ADAM-TS5 Prevents Aggrecan Degradation in Osteoarthritic Cartilage

Cited by 278 publications

References 46 publications

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

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

Expression profiling of metalloproteinases and tissue inhibitors of metalloproteinases in normal and degenerate human achilles tendon

Age-dependent increase of discoidin domain receptor 2 and matrix metalloproteinase 13 expression in temporomandibular joint cartilage of type IX and type XI collagen-deficient mice

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