Abstract
BackgroundSenile osteoporosis can cause bone fragility and increased risk for fractures and has been one of the most prevalent and severe diseases affecting the elderly population worldwidely. The underlying mechanisms are currently intensive areas of investigation. In age-related bone loss, decreased bone formation overweighs increased bone resorption. The molecular mechanisms underlying defective bone formation in age-related bone loss are not completely understood. In particular, the specific role of histone acetylation in age-related bone loss has not been examined thoroughly.MethodsWe employed 6- and 18-month-old mice to investigate the mechanisms of defective bone formation in age-related bone loss. Bone marrow stromal cells (BMSCs) were induced to undergo in vitro osteogenic differentiation. Chromatin immunoprecipitation (ChIP) was used to investigate the binding of histone deacetylases (HDACs) on Runx2 promoter in BMSCs. Luciferase reporter and transient transfection assay were employed to study Runx2 gene expression modulation by HDAC and androgen receptor (AR). siRNA and HDAC6 inhibitor, Tubastatin A, were used to inhibit HDAC6 in vitro. And systemic administration of Tubastatin A was used to block HDAC6 in vivo.ResultsAge-related trabecular bone loss was observed in 18-month-old mice compared with 6-month-old mice. In vitro osteogenic differentiation potential of BMSCs from 18-month-old mice was weaker than 6-month-old mice, in which there was Runx2 expression inactivation in BMSCs of 18-month-old mice compared with 6-month-old mice, which was attributable to HDAC6-mediated histone hypoacetylation in Runx2 promoter. There was competitive binding of HDAC6 and AR on Runx2 promoter to modulate Runx2 expression in BMSCs. More importantly, through siRNA- or specific inhibitor-mediated HDAC6 inhibition, we could activate Runx2 expression, rescue in vitro osteogenesis potential of BMSCs, and alleviate in vivo age-related bone loss of mice.ConclusionHDAC6 accumulation and histone hypoacetylation on Runx2 promoter contributed to the attenuation of in vitro osteogenic differentiation potential of BMSCs from aged mice. Through HDAC6 inhibition, we could activate Runx2 expression and osteogenic differentiation potential of BMSCs from aged mice and alleviate the age-related bone loss of aged mice. Our study will benefit not only for understanding the age-related bone loss, but also for finding new therapies to treat senile osteoporosis.
Highlights
Age-related bone loss in elderly people, a disease known as senile osteoporosis, is associated with human aging
The results revealed Runt-related transcription factor 2 (Runx2) expression inactivation in Bone marrow stromal cells (BMSCs) of 18-month-old mice compared with 6-monthold mice, which was attributable to HDAC6-mediated histone hypoacetylation in Runx2 promoter
The results revealed significant increases in Runx2 expression in BMSCs from aged mice in response to HDAC6 knockdown compared with scramble control (Fig. 5E)
Summary
Age-related bone loss in elderly people, a disease known as senile osteoporosis, is associated with human aging It can cause bone fragility and increased risk for fractures. The cellular and molecular mechanisms underlying age-related bone loss are currently intensive areas of investigation with the aim of developing new approaches to prevent and treat it in elderly people [1]. The amount of bone removed by the osteoclasts remains relatively equal to the amount of bone formed by the osteoblasts In constrast, this is not the case during aging. Senile osteoporosis can cause bone fragility and increased risk for fractures and has been one of the most prevalent and severe diseases affecting the elderly population worldwidely. The specific role of histone acetylation in age-related bone loss has not been examined thoroughly
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