Kelly, Madison M.Sharma, KaranWright, Christian S.Yi, XinReyes Fernandez, Perla C.Gegg, Aaron T.Gorrell, Taylor A.Noonan, Megan L.Baghdady, AhmedSieger, Jacob A.Dolphin, Annette C.Warden, Stuart J.Deosthale, PadminiPlotkin, Lilian I.Sankar, UmaHum, Julia M.Robling, Alexander G.Farach-Carson, Mary C.Thompson, William R.2024-06-242024-06-242024-01-10Kelly MM, Sharma K, Wright CS, et al. Loss of the auxiliary α2δ1 voltage-sensitive calcium channel subunit impairs bone formation and anabolic responses to mechanical loading. JBMR Plus. 2024;8(2):ziad008. Published 2024 Jan 10. doi:10.1093/jbmrpl/ziad008https://hdl.handle.net/1805/41798Voltage-sensitive calcium channels (VSCCs) influence bone structure and function, including anabolic responses to mechanical loading. While the pore-forming (α1) subunit of VSCCs allows Ca2+ influx, auxiliary subunits regulate the biophysical properties of the pore. The α2δ1 subunit influences gating kinetics of the α1 pore and enables mechanically induced signaling in osteocytes; however, the skeletal function of α2δ1 in vivo remains unknown. In this work, we examined the skeletal consequences of deleting Cacna2d1, the gene encoding α2δ1. Dual-energy X-ray absorptiometry and microcomputed tomography imaging demonstrated that deletion of α2δ1 diminished bone mineral content and density in both male and female C57BL/6 mice. Structural differences manifested in both trabecular and cortical bone for males, while the absence of α2δ1 affected only cortical bone in female mice. Deletion of α2δ1 impaired skeletal mechanical properties in both sexes, as measured by three-point bending to failure. While no changes in osteoblast number or activity were found for either sex, male mice displayed a significant increase in osteoclast number, accompanied by increased eroded bone surface and upregulation of genes that regulate osteoclast differentiation. Deletion of α2δ1 also rendered the skeleton insensitive to exogenous mechanical loading in males. While previous work demonstrates that VSCCs are essential for anabolic responses to mechanical loading, the mechanism by which these channels sense and respond to force remained unclear. Our data demonstrate that the α2δ1 auxiliary VSCC subunit functions to maintain baseline bone mass and strength through regulation of osteoclast activity and also provides skeletal mechanotransduction in male mice. These data reveal a molecular player in our understanding of the mechanisms by which VSCCs influence skeletal adaptation.en-USAttribution-NonCommercial 4.0 InternationalBone formationLoadingMechanotransductionVoltage-sensitive calcium channelα2δ1 subunitArticle