Trichostatin A increases the TIMP-1/MMP ratio to protect against osteoarthritis in an animal model of the disease

Abstract

The histone deacetylase inhibitor trichostatin A (TSA) has been demonstrated to alleviate certain symptoms associated with osteoarthritis (OA). However, the exact mechanisms underlying this protective effect remain to be elucidated. The present study therefore examined the effects of TSA on the expression levels of interleukin-1β (IL-1β)-induced matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in vitro and in vivo. In vitro, reverse transcription-quantitative polymerase chain reaction was performed to investigate alterations in mRNA expression levels in TSA-treated chondrocytes in the presence or absence of IL-1β; in addition, protein expression and acetylation levels were assessed by western blotting. In vivo, TSA was administered to rats by intra-articular injection, following which the mRNA and protein expression levels were analyzed. In addition, macroscopic and histological observations were conducted. Chondrocytes treated with IL-1β demonstrated increased mRNA and protein expression levels of MMP-1, MMP-3 and MMP-13, and decreased expression levels of TIMP-1 mRNA and protein; these alterations were significantly attenuated by TSA treatment. In addition, increased MMPs and decreased TIMP-1 expression levels were observed in vivo in the OA rat model. TSA treatment demonstrated in vivo efficacy through the attenuation of various OA-associated molecular and physiological changes. Taken together, the results of the present study suggest that TSA has potential therapeutic value for the treatment of OA.