Susceptibility of stromelysin 1-deficient mice to collagen-induced arthritis and cartilage destruction

Mudgett, John S.; Hutchinson, Nancy I.; Chartrain, N; Forsyth, A. J.; McDonnell, Joseph; Singer, Irwin; Bayne, Ellen K.; Flanagan, J.; Kawka, Douglas W.; Shen, Chong; Stevens, Karla; Chen, H.; Trumbauer, Myrna E.; Visco, Denise M.

doi:10.1002/1529-0131(199801)41:1<110::aid-art14>3.0.co;2-g

Cited by 196 publications

(97 citation statements)

References 62 publications

(21 reference statements)

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“…In both investigations, MMP-3 (stromelysin 1) was, by far, the most abundantly expressed protease, and MMP-3 was significantly down-regulated in OA cartilage. These data suggest that MMP-3 does not represent the driving force in final matrix degradation in OA cartilage, which is further documented by the fact that MMP-3 knockout mice and their wild-type littermates are equally susceptible to cartilage destruction (51). Rather, MMP-3 appears to be a major contributor to physiologic matrix turnover in normal articular cartilage (52,53).…”

Section: Discussionmentioning

confidence: 93%

Relative messenger RNA expression profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro

Bau¹,

Gebhard²,

Haag³

et al. 2002

Arthritis & Rheumatism

370

322

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Objective. Osteoarthritic (OA) cartilage destruction depends on collagen-and aggrecan-degrading proteases such as collagenases (MMP-1 and MMP-13), stromelysin (MMP-3), MMP-14, as well as the so-called aggrecanases (ADAM-TS4 and ADAM-TS5). In this study, we tried to clarify whether these proteases are expressed in vivo in human normal and OA cartilage (and whether they are up-regulated or down-regulated during the disease process) and in interleukin-1␤ (IL-1␤)-stimulated chondrocytes in vitro.Methods. Quantitative polymerase chain reaction assays were developed and performed on RNA isolated directly from normal and degenerative cartilage tissue as well as from primary human articular chondrocytes cultured with and without IL-1␤.Results. In vivo, MMP-1 was detectable only at very low levels in any condition. MMP-13 expression was low in normal and early degenerative cartilage but was strongly up-regulated in late-stage OA specimens. MMP-1 and MMP-13 were expressed much higher in vitro than in vivo and were up-regulated by IL-1␤. Among all proteases, MMP-3 was by far the most strongly expressed, although it was strongly downregulated in late-stage OA specimens. Expression of MMP-3 was higher in vitro than in vivo and was up-regulated by IL-1␤. ADAM-TS5 and MMP-14 were expressed in all sample groups. Expression of ADAM-TS4 was very low in vivo and was induced in vitro after stimulation by IL-1␤.Conclusion. Our expression data clearly support MMP-13 as the major collagenase in OA cartilage. The most strongly expressed aggrecanase was ADAM-TS5. ADAM-TS4 was expressed only at a very low level in normal cartilage and was only slightly up-regulated in OA cartilage, casting doubt on this enzyme being the relevant aggrecanase of articular cartilage. Results of our study show that expression of many enzymes is significantly different in vitro and in vivo and suggest that IL-1␤ stimulation of articular chondrocytes might not be a good model for the matrix catabolism in OA cartilage.Osteoarthritic (OA) cartilage degeneration as well as cartilage destruction in rheumatoid arthritis depend, at least to a significant degree, on enzymatic degradation of matrix components. Two types of molecules, collagen fibrils and the proteoglycan aggrecan, represent the major targets in terms of enzymatic activity and functional loss of the cartilage matrix as a result of damage to these molecules. Whereas degradation of collagen fibrils leads to matrix instability with tissue swelling, degradation of proteoglycans leads to cartilage softening and loss of fixed charges (1), both of which are classic features of cartilage destruction.Catabolism of both types of molecules is supposed to involve different types of enzymes, largely from 2 protease families: matrix metalloproteinases (MMPs) and the "A disintegrin and metalloproteinases with thrombospondin type 1 motif" (ADAM-TS). The initial degradation of collagen fibrils (within the triple-helical region) depends on cleavage at the collagenase site, for which there exist 2 major candidate enzymes...

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Section: Discussionmentioning

confidence: 93%

Relative messenger RNA expression profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro

Bau¹,

Gebhard²,

Haag³

et al. 2002

Arthritis & Rheumatism

370

322

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“…Additionally, patients with high serum/plasma levels of MMP-3/MMP-9 might be susceptible to rapid destruction of the large joints. However, studies in MMP-3-deficient mice revealed that collagen-induced arthritis, in which MMP-3 messenger RNA is highly induced, was not prevented (6).…”

Section: Discussionmentioning

confidence: 99%

“…Matrix metalloproteinases (MMPs) are thought to play an important role in the matrix degradation of OA (4)(5)(6). Although the mechanism of the rapid destruction of the hip joint in this subgroup of OA is still unknown, previous biochemical studies suggest that fibroblasts from the synovium and subchondral cysts may secrete much higher levels of MMPs than are typically secreted in ordinary OA (7,8).…”

Section: Discussionmentioning

confidence: 99%

Significant increases in serum and plasma concentrations of matrix metalloproteinases 3 and 9 in patients with rapidly destructive osteoarthritis of the hip

Masuhara

Nakai

Yamaguchi

et al. 2002

Arthritis & Rheumatism

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Objective. Rapidly destructive osteoarthritis (OA) of the hip is an uncommon subset of OA that affects mainly elderly women. Previous studies indicate that elevated levels of matrix metalloproteinases (MMPs) are produced within the tissue of patients with the condition. In the present study, we sought to determine whether serum and plasma levels of MMPs and tissue inhibitors of metalloproteinases (TIMPs) are also elevated.Methods. Blood samples were obtained from 16 patients with rapidly destructive hip OA and from 20 patients with OA before total hip arthroplasty was performed. Synovial specimens were obtained during surgery. Synovial fibroblasts that had migrated sufficiently from explants were subcultured in vitro for 72 hours after confluency, and harvested supernatants were collected. Blood, tissue samples, and fibroblasts were assayed for MMPs 1, 2, 3, and 9, and TIMPs 1 and 2 by sandwich enzyme immunoassay.Results. In blood samples, the levels of MMP-3 and MMP-9 in the group with rapidly destructive hip OA were significantly higher than the normal range and were also significantly higher than those in the OA group. In tissue samples, the levels of MMP-1, MMP-3, MMP-9, and TIMP-1 in the group with rapidly destructive hip OA were significantly higher than those in the OA group. Conclusion.The results of this study show that serum and plasma levels of MMP-3 and MMP-9 are significantly increased in patients with rapidly destructive hip OA. Significantly large amounts of these MMPs produced in synovial tissues within the hip joint could contribute in part to elevation of blood levels. Detection of increased levels of MMP-3 and MMP-9 in patients with painful, disabling hip OA may be of diagnostic value for rapidly destructive hip OA.

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“…MMP-3-deficient mice were generated by homologous recombination as described previously and maintained on a 129/SvEv background. [16][17][18] Experimental protocols were approved by the Institutional Animal Care and Use Committee of the University of Yamanashi (No 19-105), Japan.…”

Section: Micementioning

confidence: 99%

Age‐related expression of MCP‐1 and MMP‐3 in mouse intervertebral disc in relation to TWEAK and TNF‐α stimulation

Fujita

Ando

Ohba

et al. 2011

Journal Orthopaedic Research

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This study was undertaken to investigate the age-related differences of monocyte chemotactic protein-1 (MCP-1) and matrix metalloproteinase-3 (MMP-3) expression in mouse intervertebral disc (IVD) and to determine whether MMP-3 plays a role in disc degeneration. Expression of MCP-1 and MMP-3 mRNA in mouse IVD was assessed by quantitative PCR. The ability of MCP-1 and MMP-3 expression in IVD to respond to TNF-a or TWEAK stimulation was examined by quantitative PCR, WB, ELISA, and immunohistochemistry. IVD derived from MMP-3-deficient and wild-type mice were compared using Safranin-O staining and immunohistochemistry. mRNA levels of MCP-1 and MMP-3 in IVD significantly diminished and the ability of MCP-1 or MMP-3 expression to respond to TNF-a or TWEAK stimulation was significantly reduced as age increased. IVD derived from 64-week-old wild-type mice showed clearly diffuse proteoglycan loss by Safranin-O staining and immunohistochemistry compared with younger mice. However, no loss of proteoglycan and typeII collagen were observed in IVD derived from 64-week-old MMP-3-deficient mice. MCP-1 and MMP-3 expression in mouse IVD showed age-related decreases. The response to inflammation in IVD also displayed age-related changes. Therefore, disc degeneration may vary with the patients' age and targeting MMP-3 may be a possible future therapeutic strategy for disc degeneration. ß

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Susceptibility of stromelysin 1-deficient mice to collagen-induced arthritis and cartilage destruction

Abstract: Disruption of the SLN1 gene neither prevents nor reduces the cartilage destruction associated with CIA. Moreover, SLN1 depletion does not prevent the cleavage of the aggrecan Asn341-Phe342 bond.

Cited by 196 publications

References 62 publications

Relative messenger RNA expression profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro

Relative messenger RNA expression profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro

Significant increases in serum and plasma concentrations of matrix metalloproteinases 3 and 9 in patients with rapidly destructive osteoarthritis of the hip

Age‐related expression of MCP‐1 and MMP‐3 in mouse intervertebral disc in relation to TWEAK and TNF‐α stimulation

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