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Increased Ca2+ signaling through CaV1.2 promotes bone formation and prevents estrogen deficiency–induced bone loss
Chike Cao, … , Matthew J. Hilton, Geoffrey S. Pitt
Chike Cao, … , Matthew J. Hilton, Geoffrey S. Pitt
Published November 16, 2017
Citation Information: JCI Insight. 2017;2(22):e95512. https://doi.org/10.1172/jci.insight.95512.
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Research Article Bone biology

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

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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.

Authors

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

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Figure 1

Endogenous CaV1.2 is expressed during mouse endochondral ossification and in BMSCs, and pharmacological inhibition of CaV1.2 channel activity decreases osteoblast differentiation.

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Endogenous CaV1.2 is expressed during mouse endochondral ossification an...
(A) LacZ staining of CaV1.2+/lacZ femur at P10 at 5× magnification. (B–E) Boxed regions shown in A indicate the presence of lacZ+ cells in the resting (B) and proliferating (C) chondrocytes, in the perichondrium/periosteum (D), and in the lining cells of trabecular bones (E). (F) LacZ staining of CaV1.2+/lacZ tibia at P18, showing lacZ staining in the endosteum. (G) LacZ staining of CaV1.2+/lacZ BMSCs cultured for 6 days on coverslip in α-MEM (without ascorbic acid) plus 15% FBS and 1% penicillin/streptomycin. (H) von Kossa staining of WT BMSCs after 14 days of differentiation in the presence of the L-type Ca2+ channel–specific blockers diltiazem (10 μM) or nifedipine (10 μM), n ≥ 3. (I) Expression analysis of osteoblast markers by quantitative PCR of WT BMSCs after 9 days of differentiation in the absence and presence of diltiazem (10 μM). Bar values are normalized means (normalized to H2O group) ± SD (n = 3, **P < 0.01). Statistical analysis was performed by 2-tailed unpaired t test.

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