Targeted Inhibition of Aggrecanases Prevents Articular Cartilage Degradation and Augments Bone Mass in the STR/Ort Mouse Model of Spontaneous Osteoarthritis



Kanakis, Ioannis ORCID: 0000-0001-6410-1482, Liu, Ke, Poulet, Blandine, Javaheri, Behzad, van 't Hof, Rob J ORCID: 0000-0002-8193-6788, Pitsillides, Andrew A and Bou-Gharios, George
(2019) Targeted Inhibition of Aggrecanases Prevents Articular Cartilage Degradation and Augments Bone Mass in the STR/Ort Mouse Model of Spontaneous Osteoarthritis. Arthritis and Rheumatology, 71 (4). pp. 571-582.

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Abstract

BACKGROUND:Cartilage destruction in osteoarthritis (OA) is mediated mainly by MMPs and ADAMTSs. The therapeutic candidature of targeting aggrecanases has not yet been defined in joints where spontaneous OA arises due to genetic susceptibility, without a traumatic or load- induced aetiology such as the STR/Ort mouse. Nor do we know the long-term effect of aggrecanase inhibition on bone. METHODS:Using the STR/Ort spontaneously OA background, we have generated transgenic mice that overexpress [-1A]TIMP-3, either ubiquitously or conditionally in chondrocytes. [-1A]TIMP-3 is a variant of tissue inhibitor of metalloproteinase-3 (TIMP-3) that has an extra alanine at the N- terminus that selectively inhibits ADAMTSs, but not MMPs. We analysed a range of OA-related measures in all mice at 40 weeks of age. RESULTS:Mice expressing high [-1A]TIMP-3 levels were protected against the development of the OA whilst low expressers were not. Interestingly, we also found that high levels of [-1A]TIMP-3 transgene overexpression resulted in raised bone mass particularly in females. This regulation of bone mass is, at least, partly direct as primary adult osteoblasts infected with [-1A]TIMP-3 in vitro show elevated rates of mineralisation. CONCLUSIONS:The results provide evidence that [-1A]TIMP-3-mediated inhibition of aggrecanases can protect from cartilage degradation in naturally occurring OA mouse model and highlight a novel role that aggrecanases' inhibition may play in increased bone mass. This article is protected by copyright. All rights reserved.

Item Type: Article
Uncontrolled Keywords: Cartilage, Articular, Chondrocytes, Animals, Mice, Transgenic, Mice, Osteoarthritis, Disease Models, Animal, Endopeptidases, Tissue Inhibitor of Metalloproteinase-3, Protease Inhibitors, Bone Density, Female, Male
Depositing User: Symplectic Admin
Date Deposited: 06 Nov 2018 11:00
Last Modified: 19 Jan 2023 01:13
DOI: 10.1002/art.40765
Open Access URL: https://onlinelibrary.wiley.com/doi/epdf/10.1002/a...
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3028425