Autophagy exerts pivotal roles in regulatory effects of 1α,25-(OH)2D3 on the osteoclastogenesis

Abstract

As an active form of vitamin D3, 1α,25-(OH)2D3 has a positive therapeutical effect on osteoporosis. However, 1α,25-(OH)2D3 can not only promote the osteoclastogenesis, but also inhibit the proliferation of osteoclast precursors (OCPs). Autophagy is regulated by 1α,25-(OH)2D3 and is considered to promote the osteoclastogenesis. Nevertheless, the role of 1α,25-(OH)2D3 in OCPs' autophagy remains unknown. Our study aims to explore whether the effect of 1α,25-(OH)2D3 on osteoclastogenesis is related to its regulation in autophagy. The results showed that 1α,25-(OH)2D3 exhibited a direct inhibitory effect on the autophagy activity and the proliferation of OCPs derived from bone marrow-derived macrophages (BMMs), which was reversed by the overexpression of autophagy-related gene. In presence of RANKL, the autophagy capacity of OCPs and the differentiation from OCPs into mature osteoclasts were significantly enhanced by 1α,25-(OH)2D3, while the suppression of autophagy with spautin-1 or 3-MA downregulated the osteoclastogenesis capacity. In summary, 1α,25-(OH)2D3 can directly suppress OCPs autophagy, which negatively regulates the proliferation of OCPs without RANKL. 1α,25-(OH)2D3 can indirectly upregulate the autophagy response of OCPs, thereby enhancing the osteoclasts formation in presence of RANKL. Therefore, our study found that 1α,25-(OH)2D3 had a dual effect on osteoclastogenesis by regulating autophagy, suggesting that some drugs targeting autophagy may act as an effective supplement of 1α,25-(OH)2D3 in treating osteoporosis.