Activation and Inhibition of Endogenous Matrix Metalloproteinases in Articular Cartilage: Effects on Composition and Biophysical Properties

Bonassar, LJ; Jl, Stinn; Cg, Paguio; Eh, Frank; Vl, Moore; Mw, Lark; Jd, Sandy; Ap, Hollander; Ar, Poole; Aj, Grodzinsky

doi:10.1006/abbi.1996.0402

Cited by 33 publications

(26 citation statements)

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“…The efficacy of these inhibitors is most often assessed by biochemical outcomes, and the studies presented here extend previous work that examines the functional consequences of targeted perturbations in cell-mediated degradation (Bonassar, et al, 1996;. In the present study, treatment of immature bovine cartilage with metalloproteinase inhibitors delayed or reduced IL-1-induced matrix degradation.…”

Section: Discussionsupporting

confidence: 70%

“…Several MMPs, including the collagenases MMP-1, -8, and -13, MMP-3 (stromelysin-1), the gelatinases MMP-2 and -9, and membrane type MMP-14 and -17, are expressed in articular c artilage. Active MMPs readily degrade type II collagen and aggrecan (Beekman, et al, 1998;Koshy, et al, 2002), and exogenous MMPs were shown to modulate the composition and material properties of bovine cartilage explants (Bonassar, et al, 1996). The primary substrate for MMPs on the aggrecan core protein is within the interglobular domain (IGD) at the VIPEN 360 -361 FFG bond (the equivalent substrate in bovine aggrecan is VDIPES 360 -361 FFG) .…”

Section: Introductionmentioning

confidence: 99%

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Selective and non-selective metalloproteinase inhibitors reduce IL-1-induced cartilage degradation and loss of mechanical properties

et al. 2007

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Articular cartilage undergoes matrix degradation and loss of mechanical properties when stimulated with proinflammatory cytokines such as interleukin-1 (IL-1). Aggrecanases and matrix metalloproteinases (MMPs) are thought to be principal downstream effectors of cytokine-induced matrix catabolism, and aggrecanase-or MMP-selective inhibitors reduce or block matrix destruction in several model systems. The objective of this study was to use metalloproteinase inhibitors to perturb IL-1-induced matrix catabolism in bovine cartilage explants and examine their effects on changes in tissue compression and shear properties. Explanted tissue was stimulated with IL-1 for up to 24 days in the absence or presence of inhibitors which were aggrecanase-selective, MMP-selective, or non-selective. Analysis of conditioned media and explant digests revealed that aggrecanase-mediated aggrecanolysis was delayed to varying extents with all inhibitor treatments, but that aggrecan release persisted. Collagen degradation was abrogated by MMP-and non-selective inhibitors and reduced by the aggrecanase inhibitor. The inhibitors delayed but did not reduce loss of the equilibrium compression modulus, whereas the loss of dynamic compression and shear moduli was delayed and reduced. The data suggest that non-metalloproteinase mechanisms participate in IL-1-induced matrix degradation and loss of tissue material properties.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Selective and non-selective metalloproteinase inhibitors reduce IL-1-induced cartilage degradation and loss of mechanical properties

et al. 2007

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“…However, given the correlation between the release of sGAG and G1-NITEGE 373 in response to ADAMTS-4 or ADAMTS-5 treatment observed in the current study, it is unlikely that G1-VDIPES 341 fragments were generated under the conditions tested. Furthermore, while the concentrations of ADAMTS-4 and ADAMTS-5 (and MMP-13) used to treat the cartilage discs in this study may appear to be supraphysiologic, poor penetration and/or poor transport of exogenously added proteins into the highly anionic cartilage matrix has been described previously (17,38,39). In addition, the concentration and localization of ADAMTS-4 or ADAMTS-5 in the cartilage matrix are also likely to be dependent on the enzyme isoform(s) that is present.…”

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confidence: 69%

Release of hyaluronan and hyaladherins (aggrecan G1 domain and link proteins) from articular cartilage exposed to ADAMTS‐4 (aggrecanase 1) or ADAMTS‐5 (aggrecanase 2)

Chockalingam¹,

Zeng²,

Morris³

et al. 2004

Arthritis & Rheumatism

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Objective. To determine whether aggrecanase (ADAMTS) activities in articular cartilage can directly lead to the release of hyaluronan (HA) and hyaladherins (aggrecan G1 domain and link proteins), as may occur ex vivo during stimulation of cartilage explants with interleukin-1 (IL-1) or retinoic acid or in vivo in synovial joints during aging and joint pathology.Methods. Bovine articular cartilage discs (live or freeze-killed) were cultured in the presence of IL-1 or were incubated in digestion buffer containing recombinant human ADAMTS-4 (rHuADAMTS-4; aggrecanase 1) or rHuADAMTS-5 (aggrecanase 2). Culture media, digestion supernatants, and tissue extracts were assayed for sulfated glycosaminoglycan (sGAG) content and analyzed by Western blotting to detect aggrecanasegenerated G1 domain (using neoepitope monoclonal antibody AGG-C1/anti-NITEGE 373 ) and link proteins (using monoclonal antibody 8-A-4), as well as by quantitative enzyme-linked immunosorbent assays to detect aggrecanase-generated G1 domain (G1-NITEGE 373 ) and HA.Results. IL-1 treatment of live cartilage explants induced a time-dependent release of sGAG, aggrecanase-generated G1 domain (G1-NITEGE 373 ), and HA into the culture media. Exposure of live or freeze-killed articular cartilage discs to rHuADAMTS-4 or rHuADAMTS-5 resulted in a dose-and timedependent release of sGAG and hyaluronan from the tissue, accompanied by a concomitant release of functionally intact hyaladherins (aggrecan G1-NITEGE 373 and link proteins).Conclusion. Coincident with aggrecanolysis, aggrecanase activities in articular cartilage may actuate the release of HA and associated hyaladherins, thereby further compromising the integrity of the cartilage matrix during degenerative joint diseases such as osteoarthritis.

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“…wt. 45 kd (BioRad prestained standards) and were calculated to have a molecular weight of 53-55 kd, the same as stromelysin (-50 kd) [5]. The same bands gave a positive reaction with the stromelysin antibody (anti-CAP) (Fig.…”

Section: Resultsmentioning

confidence: 94%

“…However in these experiments there was a definite strong and positive reaction with the anti-FVDIPEN. Experiments by Bonassar et al [5] used cultured bovine cartilage explants and analyzed the media for aggrecan degradation products. Using an FVDIPEN antibody prepared in the same manner as the one used in these experiments, they obtained a positive reaction with the stromelysin cleavage site.…”

Section: Resultsmentioning

confidence: 99%

Identification of the metalloproteinase stromelysin in the physis

Barrach

Ehrlich

2002

Journal Orthopaedic Research

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For long bone growth to occur, calcification of the matrix must commence in the lower hypertrophic zone of the growth plate. It is generally accepted that physeal proteoglycans help regulate mineralization, and that at least in vitro, intact proteoglycans can inhibit mineralization. Thus degradation of proteoglycan may be a necessary step prior to calcification. Previous work in o u r laboratory has demonstrated the presence of neutral metallo-proteases in the growth plate with highest levels in the hypertrophic zone, where calcification occurs.Stromelysin (MMP-3) is a connective tissue matrix-degrading enzyme. It was formerly known as proteoglycanase and is generally considered to be one of the major proteoglycan degrading enzymes in cartilage. Stromelysin is implicated in cartilage destruction in osteoarthritis and may also be involved in tissue remodeling in the physis. Our goal was to determine if the neutral protease previously reported by the authors in the physis was stromelysin.In this study we used Western blots and antibodies to stromelysin and to the stromelysin cleavage site in aggrecan, the most common form of proteoglycan, to demonstrate the presence of stromelysin in the bovine physis. When an antibody raised against the stromelysin cleavage site of aggrecan (FVDIPEN) was incubated with a Western blot, which had been run with aggrecan extracted from bovine physes, a positive reaction resulted. This suggests that there is stromelysin degradation in vivo in the physis. Two different polyclonal antibodies to stromelysin gave positive results on Western blots of purified media from growth plate cultures indicating that stromelysin is produced in vitro in culture. These antibodies also reacted with active stromelysin.The presence of stromelysin in the physis implicates it in physeal physiology. The concentration of its activity in the lower hypertrophic zone and zone of provisional calcification suggests that it may be particularly important in mineralization. 0 3002 Orthopaedic Research Society. Published by

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Activation and Inhibition of Endogenous Matrix Metalloproteinases in Articular Cartilage: Effects on Composition and Biophysical Properties

Cited by 33 publications

References 0 publications

Selective and non-selective metalloproteinase inhibitors reduce IL-1-induced cartilage degradation and loss of mechanical properties

Selective and non-selective metalloproteinase inhibitors reduce IL-1-induced cartilage degradation and loss of mechanical properties

Release of hyaluronan and hyaladherins (aggrecan G1 domain and link proteins) from articular cartilage exposed to ADAMTS‐4 (aggrecanase 1) or ADAMTS‐5 (aggrecanase 2)

Identification of the metalloproteinase stromelysin in the physis

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