Sirt1 enzymatic activity is required for cartilage homeostasis in vivo

Abstract

homozygous for wild type or sirt1tm2.1Mcby (sirt1y/y), an allele carrying a point mutation that encodes a Sirt1 protein with no enzymatic activity. Mice aged 2 days and 6/7 days were also examinated. Joint cartilage was processed for histologic examination or biochemical analyses of chondrocyte cultures. Results: We found that articular cartilage tissue sections from sirt1y/y mice, up to 6 months of age, contained reduced levels of type 2 collagen, aggrecan, and glycosaminoglycan. In contrast, protein levels of MMP-8, MMP-9, and MMP-13 were elevated in the sirt1y/y mice cartilage. Additional results showed elevated chondrocyte apoptosis in Sirt1 mutant mice as compared to wild type littermates. In line with these observations, PTP1b (protein tyrosine phosphatase b) was elevated in the sirt1y/y mice. Conclusion: Our in vivo findings from this animal model demonstrated that mice with defective Sirt1 also had defective cartilage with elevated rates of cartilage degradation with age. Hence, normal cartilage homeostasis requires enzymatically active Sirt1 protein.