Calcium Channel TRPV6 is a Novel Regulator in RANKL-induced Osteoclastic Differentiation and Activity through the IGF–PI3K–AKT Pathway

Abstract Background: Calcium ion signals are important for osteoclast differentiation. Transient receptor potential vanilloid 6 (TRPV6) is a novel regulator of bone homeostasis. However, it is unclear whether TRPV6 was involved in the process of osteoclast formation.Results: In the present study, we found that knockout of the TRPV6 gene induced osteoporosis in mice, and depletion of TRPV6 did not affect bone formation but significantly enhanced bone resorption. Further studies showed that TRPV6, distributed on the cell membrane of osteoclasts, was a negative regulator of osteoclast differentiation and function. Mechanistically, TRPV6 suppressed osteoclastogenesis by decreasing the production the IGF1R and AKT ligands to inhibit the IGF–PI3K–AKT signaling pathway. Blocking the IGF–PI3K–AKT pathway significantly reduced the effect of TRPV6 on osteoclasts.Conclusion: Our study confirmed the important role of TPRV6 in bone metabolism and clarified its regulatory role on osteoclasts at the cellular level, which may provide a new strategy for the treatment of osteoporosis.