Aggrecanase-selective tissue inhibitor of metalloproteinase-3 (TIMP3) protects articular cartilage in a surgical mouse model of osteoarthritis.

Scientific Reports
Hiroyuki NakamuraGeorge Bou-Gharios

Abstract

A key feature of osteoarthritis is the gradual loss of articular cartilage and bone deformation, resulting in the impairment of joint function. The primary cause of cartilage destruction is considered to be the presence of elevated proteases, such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs). However, clinically tested global MMP inhibitors have low efficacy that may be due to their lack of selectivity. We previously demonstrated in vitro that a variant of tissue inhibitor of metalloproteinase-3 ([-1A]TIMP3) inhibits ADAMTSs but not MMPs. In this study, we tested whether the selectivity of [-1A]TIMP3 is beneficial compared with that of the wild-type TIMP3 in preventing or delaying the onset of the degenerative effects in a mouse model of osteoarthritis. We generated transgenic mice that overexpressed TIMP3 or [-1A]TIMP3 driven by a chondrocyte-specific type II collagen promoter. TIMP3 transgenic mice showed compromised bone integrity as opposed to [-1A]TIMP3 mice. After surgically induced joint instability, TIMP3 overexpression proved to be less protective in cartilage destruction than [-1A]TIMP3 at late stages of OA. The selective inhibition of ADAMTSs provide...Continue Reading

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Citations

Feb 14, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Matteo CalligarisSimone Dario Scilabra
May 6, 2021·Journal of Clinical Medicine·Susanne GrässelHenning Madry
Jul 17, 2021·Frontiers in Molecular Biosciences·Keron W J RoseDirk Hubmacher

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Methods Mentioned

BETA
transgenic
Protein Assay

Software Mentioned

OARSI
NRecon
SPSS
CTAn

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