Increased Ca²⁺ signaling through Ca_V1.2 promotes bone formation and prevents estrogen deficiency–induced bone loss

While the prevalence of osteoporosis is growing rapidly with population aging, therapeutic options remain limited. Here, we identify potentially novel roles for Ca_V1.2 L-type voltage–gated Ca²⁺ channels in osteogenesis and exploit a transgenic gain-of-function mutant Ca_V1.2 to stem bone loss in ovariectomized female mice. We show that endogenous Ca_V1.2 is expressed in developing bone within proliferating chondrocytes and osteoblasts. Using primary BM stromal cell (BMSC) cultures, we found that Ca²⁺ influx through Ca_V1.2 activates osteogenic transcriptional programs and promotes mineralization. We used Prx1-, Col2a1-, or Col1a1-Cre drivers to express an inactivation-deficient Ca_V1.2 mutant in chondrogenic and/or osteogenic precursors in vivo and found that the resulting increased Ca²⁺ influx markedly thickened bone not only by promoting osteogenesis, but also by inhibiting osteoclast activity through increased osteoprotegerin secretion from osteoblasts. Activating the Ca_V1.2 mutant in osteoblasts at the time of ovariectomy stemmed bone loss. Together, these data highlight roles for Ca_V1.2 in bone and demonstrate the potential dual anabolic and anticatabolic therapeutic actions of tissue-specific Ca_V1.2 activation in osteoblasts.