Preventing SIRT1 cleavage mitigates OA pathogenesis

Osteoarthritis (OA) is the most prevalent arthritic disease, affecting millions worldwide. During OA progression articular cartilage is gradually destroyed rendering pain and disability.

Our accumulated research evidence supports that healthy articular cartilage is largely dependent on the proper action of the multi-functional protein deacetylase Silent mating type Information Regulation 2 homolog (SIRT) 1. However, during the development of OA we reported that SIRT1 activity is gradually reduced partially due to its cleavage by cathepsin B under pro-inflammatory conditions.

One target gene target activated following Sirt1 cleavage is Lef1, which contributes to a pro-catabolic switch in cartilage. In fact, by genetically ablating Lef1 in cartilage, post-traumatic OA is attenuated. Similarly, recent work has aimed to genetically or chemically block Sirt1 cleavage, to assess its impact in age or post-traumatic OA development. To this end, we generated a novel mutant (DSIRT1) resistant to cleavage and assessed OA development following induction. Additionally, we intra-articularly co-administered CA-074me (cathepsin B inhibitor) and/or SRT1720 (Sirt1 activator) blocking cathepsin B activity and simultaneously activating SIRT1, respectively. Results show that the ΔSirt1 aged mice (16months) are resistant to OA development, and exhibit lesser articular cartilage damage, osteophyte formation and synovitis. In parallel, co-treatment of CA074me and SRT1720 was efficacious in preventing articular damage, compared to vehicle or each treatment individually. Moreover, CA074me/SRT1720 co-treated mice displayed decreased pain thresholds, similar to the DSirt1 mice. Thus, we conclude that genetic manipulation or pharmacological treatment preventing SIRT1 cleavage reduced OA severity, and may serve as a pharmacological approach prevent OA development.