Increased Ca2+ signaling through CaV1.2 promotes bone formation and prevents estrogen deficiency-induced bone loss

Chike Cao, Yinshi Ren, Adam S. Barnett, Anthony J. Mirando, Douglas Rouse, Se Hwan Mun, Kyung Hyun Park-Min, Amy L. McNulty, Farshid Guilak, Courtney M. Karner, Matthew J. Hilton, Geoffrey S. Pitt

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

While the prevalence of osteoporosis is growing rapidly with population aging, therapeutic options remain limited. Here, we identify potentially novel roles for CaV1.2 L-type voltage-gated Ca2+ channels in osteogenesis and exploit a transgenic gain-of-function mutant CaV1.2 to stem bone loss in ovariectomized female mice. We show that endogenous CaV1.2 is expressed in developing bone within proliferating chondrocytes and osteoblasts. Using primary BM stromal cell (BMSC) cultures, we found that Ca2+ influx through CaV1.2 activates osteogenic transcriptional programs and promotes mineralization. We used Prx1-, Col2a1-, or Col1a1-Cre drivers to express an inactivation-deficient CaV1.2 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 CaV1.2 mutant in osteoblasts at the time of ovariectomy stemmed bone loss. Together, these data highlight roles for CaV1.2 in bone and demonstrate the potential dual anabolic and anticatabolic therapeutic actions of tissue-specific CaV1.2 activation in osteoblasts.

Original languageEnglish (US)
JournalJCI Insight
Volume2
Issue number22
DOIs
StatePublished - Nov 16 2017

Keywords

  • Bone Biology
  • Bone development
  • Calcium channels
  • Osteoclast/osteoblast biology

ASJC Scopus subject areas

  • Medicine(all)

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    Cao, C., Ren, Y., Barnett, A. S., Mirando, A. J., Rouse, D., Mun, S. H., Park-Min, K. H., McNulty, A. L., Guilak, F., Karner, C. M., Hilton, M. J., & Pitt, G. S. (2017). Increased Ca2+ signaling through CaV1.2 promotes bone formation and prevents estrogen deficiency-induced bone loss. JCI Insight, 2(22). https://doi.org/10.1172/jci.insight.95512