Sirtuins and FoxOs in osteoporosis and osteoarthritis.

The sirtuin family of NAD+-dependent protein deacetylases promotes longevity and counteracts age-related diseases. One of the major targets of Sirtuins are the FoxO family of transcription factors. FoxOs play a major role in the adaptation of cells to a variety of stressors such as oxidative stress and growth factor deprivation. Studies with murine models of cell-specific loss- or gain-of-function of Sirtuins or FoxOs and with Sirtuin1 stimulators have provided novel insights into the function and signaling of these proteins on the skeleton. These studies have revealed that both Sirtuins and FoxOs acting directly in cartilage and bone cells are critical for normal skeletal development, homeostasis and that their dysregulation might contribute to skeletal disease. Deacetylation of FoxOs by Sirt1 in osteoblasts and osteoclasts stimulates bone formation and inhibits bone resorption, making Sirt1 ligands promising therapeutic agents for diseases of low bone mass. While a similar link has not been established in chondrocytes, Sirt1 and FoxOs both have chondroprotective actions, suggesting that Sirt1 activators may have similar efficacy in preventing cartilage degeneration due to aging or injury. In this review we summarize these advances and discuss their implications for the pathogenesis of age-related osteoporosis and osteoarthritis.