1α,25-(OH)2-D3 promotes osteoclast-precursor autophagy and osteoclast differentiation by promoting BECN1...

1α,25-(OH)2-D3 can promote autophagy of osteoclast precursors (OCPs), resulting in its pro-osteoclastogenic effect, which limits its anti-osteoporotic efficacy. To address the above challenges, we need to explore the targets of autophagy-enhancing effect of 1α,25-(OH)2-D3. These results showed that 1α,25-(OH)2-D3 promoted the expression of BECN1 mRNA and Beclin1 protein in OCPs under RANKL induction. Furthermore, 1α,25-(OH)2-D3 enhances p65 phosphorylation and nuclear translocation. The lentiviral-mediated silencing of both BECN1 and p65 impeded the facilitation of 1α,25-(OH)2-D3 on osteoclast differentiation and OCP autophagy. Moreover, p65 silencing blocked the enhancement of BECN1 mRNA expression and Beclin1 protein expression by 1α,25-(OH)2-D3. In conclusion, 1α,25-(OH)2-D3 enhances Beclin1-dependent autophagy in OCPs by promoting BECN1 transcription, thereby promoting osteoclast differentiation; this indicates that the therapeutic strategies for BECN1 or p65 targeted inhibition have the potential to optimize the anti-osteoporotic function of 1α,25-(OH)2-D3.