Is SirT1 a therapeutic target for Osteoarthritis?

P.K Sacitharan1,2, J Edwards2, T Vincent1. 1The Kennedy Institute of Rheumatology, Oxford, UK, 2The Botnar Research Centre, Oxford, UK

Osteoarthritis (OA) is the most common form of arthritis worldwide and is characterised by the progressive degradation of articular cartilage with secondary synovitis1 ,2. The current endpoint treatment for OA still remains joint replacement surgery2. Here we investigate if SirT1, an epigenetic modifier can be a viable therapeutic target for OA.

Gene expression profiles were examined in the chondrocyte cell line (HTB-94) with an inhibitor of SirT1 (EX-527; 100nM), by siRNA knockdown (25nM), or by activation of SirT1 using SRT1720 (500nM). Conditional deletion of SirT1 was achieved by crossing SirT1fl/fl x ROSA Cre (pan tissue KO) or SirT1fl/fl x Aggrecan Cre (cartilage specific KO).

SirT1 inhibition in HTB-94 cells by either EX-527 or siRNA reduced gene expression of COL2A1 (p<0.01), Aggrecan (p<0.01) and SOX-9 (p<0.01) whilst not affecting MMP-13 or ADAMTS-5. Pharmacological activation of SirT1 stimulated the expression of COL2A1 (p<0.01), Aggrecan (p<0.01) and SOX-9 (p<0.01). When whole joints from naïve SirT1 deficient animals were examined, many inflammatory genes were increased including IL-1β (p<0.01), IL-6 (p<0.01), CCR2 (p<0.001), TSG-6 (p<0.01), ADAMTS-1 (p<0.01) and ADAMTS-4 (p<0.001), MMP-13 (p<0.01), NPY (p<0.0001) and TIMP-1 (p<0.01). However, COL2A1 and Aggrecan gene expressions were not regulated in these animals; they were down-regulated in joints from animals following cartilage specific deletion of SirT1. In the latter inflammatory gene expression was unchanged. These results suggest that SirT1 has both anti-inflammatory effects globally as well as pro-anabolic cartilage effects, both of which may explain a possible chondroprotective role in vivo. Future directions will define the molecular response in vivo of SirT1 deletion following OA induction and if pharmacological activation of SirT1 can alleviate pain and reduce disease progression.

(1) Goldring, M. B. & Marcu, K. B. (2009). Arthritis Res. Ther. 11: 224.

(2) Bijlsma, J. W. J. et al., (2011). Lancet. 377: 2115–26.