1α,25-(OH)2-D3 promotes the autophagy during osteoclastogenesis by enhancing RANKL-RANK-TRAF6 signaling

In Vitro Cell Dev Biol Anim. 2021 Oct;57(9):878-885. doi: 10.1007/s11626-021-00632-z. Epub 2021 Nov 15.

Abstract

As the active form of vitamin D3, 1α,25-(OH)2-D3 promotes receptor activator for nuclear factor-κB ligand (RANKL)-induced autophagy in osteoclast precursors (OCPs). However, the relationship between 1α,25-(OH)2-D3 and RANKL signaling is still unknown. This study aimed to explore whether 1α,25-(OH)2-D3 regulates OCP autophagy and osteoclastogenesis through RANKL signaling. Our results showed that 1α,25-(OH)2-D3 directly decreased OCP autophagy while significantly enhancing the ability of RANKL to promote OCP autophagy. Moreover, 1α,25-(OH)2-D3 not only promoted the expression of key signaling proteins in OCPs induced by RANKL but also enhanced the coimmunoprecipitation levels of RANK and TRAF6. Notably, 1α,25-(OH)2-D3 significantly enhanced the autophagic activity and osteoclast differentiation of RANK-positive OCPs but did not affect the autophagic activity or osteoclast differentiation of RANK-negative OCPs. More importantly, 1α,25-(OH)2-D3 had no effect on autophagy or osteoclastogenesis in TRAF6-silenced OCPs. Overall, 1α,25-(OH)2-D3 could upregulate RANKL-RANK-TRAF6 signaling in OCPs, thereby promoting OCP autophagy and osteoclastogenesis.

Keywords: 1α,25-(OH)2-D3; Autophagy; Osteoclast; RANK; RANKL; TRAF6.

MeSH terms

  • Animals
  • Autophagy / drug effects*
  • Autophagy / physiology
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Mice
  • Mice, Inbred C57BL
  • Osteoclasts / cytology
  • Osteoclasts / drug effects*
  • Osteoclasts / metabolism
  • Osteogenesis / drug effects*
  • Osteogenesis / physiology
  • RANK Ligand / metabolism
  • Receptor Activator of Nuclear Factor-kappa B / metabolism
  • Signal Transduction / drug effects
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism
  • Vitamin D / analogs & derivatives*
  • Vitamin D / pharmacology

Substances

  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • TNF Receptor-Associated Factor 6
  • TRAF6 protein, mouse
  • Tnfrsf11a protein, mouse
  • Tnfsf11 protein, mouse
  • dihydroxy-vitamin D3
  • Vitamin D