Plasma membrane calcium ATPase regulates bone mass by fine-tuning osteoclast differentiation and survival

Hyung Joon Kim, Vikram Prasad, Seok Won Hyung, Zang Hee Lee, Sang Won Lee, Aditi Bhargava, David Pearce, Youngkyun Lee, Hong Hee Kim

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40 Citations (Scopus)

Abstract

The precise regulation of Ca2+ dynamics is crucial for proper differentiation and function of osteoclasts. Here we show the involvement of plasma membrane Ca2+ ATPase (PMCA) isoforms 1 and 4 in osteoclastogenesis. In immature/undifferentiated cells, PMCAs inhibited receptor activator of NF-κB ligand-induced Ca2+ oscillations and osteoclast differentiation in vitro. Interestingly, nuclear factor of activated T cell c1 (NFATc1) directly stimulated PMCA transcription, whereas the PMCA-mediated Ca2+ efflux prevented NFATc1 activation, forming a negative regulatory loop. PMCA4 also had an anti-osteoclastogenic effect by reducing NO, which facilitates preosteoclast fusion. In addition to their role in immature cells, increased expression of PMCAs in mature osteoclasts prevented osteoclast apoptosis both in vitro and in vivo. Mice heterozygous for PMCA1 or null for PMCA4 showed an osteopenic phenotype with more osteoclasts on bone surface. Furthermore, PMCA4 expression levels correlated with peak bone mass in premenopausal women. Thus, our results suggest that PMCAs play important roles for the regulation of bone homeostasis in both mice and humans by modulating Ca2+ signaling in osteoclasts.

Original languageEnglish
Pages (from-to)1145-1158
Number of pages14
JournalJournal of Cell Biology
Volume199
Issue number7
DOIs
Publication statusPublished - 2012 Dec

ASJC Scopus subject areas

  • Cell Biology

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    Kim, H. J., Prasad, V., Hyung, S. W., Lee, Z. H., Lee, S. W., Bhargava, A., Pearce, D., Lee, Y., & Kim, H. H. (2012). Plasma membrane calcium ATPase regulates bone mass by fine-tuning osteoclast differentiation and survival. Journal of Cell Biology, 199(7), 1145-1158. https://doi.org/10.1083/jcb.201204067