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 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.
Highlights
Osteoarthritis (OA) is a pathological condition resulting from the degradation of articular cartilage[1]
The present study aimed to investigate whether inhibiting a class of enzyme: either aggrecanases or collagenases is sufficient in protecting the cartilage from the onset of OA using surgically induced OA model in mice overexpressing aggrecanase-specific inhibitor ([-1A]TIMP3) compared with a broad-spectrum TIMP3 inhibitor
X-gal staining of 2-weeks old mouse knee joints indicated that the transgenes were seen in the articular cartilage chondrocytes of the transgenic (Tg/+) mice but not in wildtype mice (WT) (Fig. 1b)
Summary
Osteoarthritis (OA) is a pathological condition resulting from the degradation of articular cartilage[1]. In order to identify the metalloproteinases responsible for degrading the cartilage ECM in OA and could, be the best targets for therapeutic intervention, MMP- or ADAMTS-knockout mice have been generated. In order to inhibit these enzymes, mammals synthesise tissue inhibitors of metalloproteinases (TIMPs), four of which have been identified in humans and mice and characterised as endogenous inhibitors of collagenases and aggrecanases. The N-terminal inhibitory domain of TIMP3 (N-TIMP3) effectively blocked IL-1a-induced cartilage degradation, while TIMP-1 and TIMP-2 were not effective[19]. The present study aimed to investigate whether inhibiting a class of enzyme: either aggrecanases or collagenases is sufficient in protecting the cartilage from the onset of OA using surgically induced OA model in mice overexpressing aggrecanase-specific inhibitor ([-1A]TIMP3) compared with a broad-spectrum TIMP3 inhibitor
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