Journal Article

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

Ke Liu, Ioannis Kanakis, George Bou-Gharios, Hiroyuki Nakamura, Phoung Vo

2020

Overview

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 provides the possibility of modifying TIMP3 to specifically target a class of cartilage-degrading proteinases and to minimize adverse effects on bone and possibly other tissues.

• Publisher: Springer Science and Business Media LLC,Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 692/308/1426 / 692/308/153 / 692/4017 / 692/699/1670/407 / ADAM protein / ADAM17 Protein / ADAM17 Protein - antagonists & inhibitors / ADAMTS4 Protein / ADAMTS4 Protein - antagonists & inhibitors / ADAMTS5 Protein / ADAMTS5 Protein - antagonists & inhibitors / Animals / Arthritis / Biodegradation / Bone and Bones / Bone and Bones - pathology / Cartilage / Cartilage diseases / Cartilage, Articular / Cartilage, Articular - drug effects / Cartilage, Articular - pathology / Chondrocytes / Collagen (type II) / Disease Models, Animal / Drug Evaluation, Preclinical / Endopeptidases / Endopeptidases - genetics / Endopeptidases - metabolism / Humanities and Social Sciences / Matrix metalloproteinase / Medicine / Mice / Mice, Inbred C57BL / Mice, Inbred CBA / Mice, Transgenic / multidisciplinary / Osteoarthritis / Osteoarthritis - pathology / Osteoarthritis - therapy / Q / R / Rodents / Science / Science (multidisciplinary) / Stress, Mechanical / Thrombospondin / Tissue Inhibitor of Metalloproteinase-3 / Tissue Inhibitor of Metalloproteinase-3 - genetics / Tissue Inhibitor of Metalloproteinase-3 - metabolism / Transgenes / Transgenes - genetics / Transgenic animals / Transgenic mice