title: Plasma membrane calcium ATPase regulates bone mass by fine-tuning osteoclast differentiation and survival.
abstract: The precise regulation of Ca(2+) dynamics is crucial for proper differentiation and function of osteoclasts. Here we show the involvement of plasma membrane Ca(2+) ATPase (PMCA) isoforms 1 and 4 in osteoclastogenesis. In immature/undifferentiated cells, PMCAs inhibited receptor activator of NF-κB ligand-induced Ca(2+) oscillations and osteoclast differentiation in vitro. Interestingly, nuclear factor of activated T cell c1 (NFATc1) directly stimulated PMCA transcription, whereas the PMCA-mediated Ca(2+) 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 Ca(2+) signaling in osteoclasts.
authors.affiliation: Department of Cell and Developmental Biology, BK21 Program and Dental Research Institute, Seoul National University, Seoul 110-749, Korea.
authors.forename: Hyung Joon
authors.initials: HJ
authors.lastname: Kim
authors.forename: Vikram
authors.initials: V
authors.lastname: Prasad
authors.forename: Seok-Won
authors.initials: SW
authors.lastname: Hyung
authors.forename: Zang Hee
authors.initials: ZH
authors.lastname: Lee
authors.forename: Sang-Won
authors.initials: SW
authors.lastname: Lee
authors.forename: Aditi
authors.initials: A
authors.lastname: Bhargava
authors.forename: David
authors.initials: D
authors.lastname: Pearce
authors.forename: Youngkyun
authors.initials: Y
authors.lastname: Lee
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Kim
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D015519:Bone Density; D020013:Calcium Signaling; D002454:Cell Differentiation; D002459:Cell Fusion; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D005269:Femur / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008813:Mice, Inbred ICR; D008875:Middle Aged; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010010:Osteoclasts / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D021381:Protein Transport; D053245:RANK Ligand / Q000502:physiology; D051381:Rats; D018709:Statistics, Nonparametric; D015533:Transcriptional Activation; D055815:Young Adult
chemical_list: C506952:ATP2B1 protein, human; D050778:NFATC Transcription Factors; D020033:Protein Isoforms; D053245:RANK Ligand; D009569:Nitric Oxide; C507517:ATP2B4 protein, human; D053499:Plasma Membrane Calcium-Transporting ATPases