Age-dependent role of SIRT6 in jawbone via regulating senescence and autophagy of bone marrow stromal cells.

Age-related jawbone loss directly impact the function of oral cavity resulted from tooth loss, implant failure, and jaw fracture. Numerous evidences show that age-related senescence of bone marrow stromal cells (BMSCs) play a critical role in bone loss, but little attention has been paid to jawbone. Here, we delineated the critical role of sirtuin family protein 6 (SIRT6) in senescence, autophagy, and osteogenesis of BMSCs from jawbones. Radiography analysis showed less jawbone quality in elderly than young people. We also showed that SIRT6 expression decreased in bone tissue and BMSCs from the elderly by immunochemical staining. BMSCs from the elderly exhibited decreased osteogenic differentiation and inclined senescence which these phenotypes could be simulated by SIRT6 knockdown. Furthermore, accompanied with the inhibition of SIRT6, the autophagy level and ostogenesis of BMSCs was also decreased. However, using rapamycin, an autophagy activator, could rescue these adverse effects of BMSCs caused by SIRT6 inhibition. Mechanistically, SIRT6 regulated the autophagy and osteogenesis of BMSCs by activating AKT-mTOR pathway, at least in part. Finally, a decreased jawbone quality was shown in SIRT6 haploinsufficiency mice by Wnt1 specific tissue knockdown (Wnt1-Cre;SIRT6fl/+) model. Taken together, our data revealed that SIRT6 adjusted senescence and osteogenesis of BMSCs via altering autophagy level, and associated with age-related bone loss. SIRT6 could be as a promising therapeutic target for age-related osteoporosis of jawbone.