Alteration of RANKL-induced osteoclastogenesis in primary cultured osteoclasts from SERCA2+/- mice.
RANKL is essential for the terminal differentiation of monocytes/macrophages into osteoclasts. RANKL induces long-lasting oscillations in the intracellular concentration of Ca(2+) ([Ca(2+)](i)) only after 24 h of stimulation. These Ca(2+) oscillations play a switch-on role in NFATc1 expression and osteoclast differentiation. Which Ca(2+) transporting pathway is induced by RANKL to evoke the Ca(2+) oscillations and its specific role in RANKL-mediated osteoclast differentiation is not known. This study examined the effect of a partial loss of sarco/endoplasmic reticulum Ca(2+) ATPase type 2 (SERCA2) on osteoclast differentiation in SERCA2 heterozygote mice (SERCA2(+/-)). The BMD in the tibias of SERCA2(+/-) mice increased >1.5-fold compared with wildtype mice (WT). RANKL-induced [Ca(2+)](i) oscillations were generated 48 h after RANKL treatment in the WT mice but not in the SERCA2(+/-) bone marrow-derived macrophages (BMMs). Forty-eight hours after RANKL treatment, there was a lower level of NFATc1 protein expression and markedly reduced translocation of NFATc1 into the nucleus during osteoclastogenesis of the SERCA2(+/-) BMMs. In addition, RANKL treatment of SERCA2(+/-) BMMs incompletely induced formation of multinucleated cells, leading to reduced bone resorption activity. These results suggest that RANKL-mediated induction of SERCA2 plays a critical role in the RANKL-induced [Ca(2+)](i) oscillations that are essential for osteoclastogenesis.
Department of Oral Biology, Brain Korea 21 Project, Center for Natural Defense System, Seoul, Korea.
Yu-Mi
YM
Yang
Min Seuk
MS
Kim
Aran
A
Son
Jeong Hee
JH
Hong
Kyung-Ho
KH
Kim
Jeong Taeg
JT
Seo
Syng-Ill
SI
Lee
Dong Min
DM
Shin
D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects*; D010022:Osteopetrosis / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D021381:Protein Transport / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000172:deficiency* / Q000378:metabolism
D050778:NFATC Transcription Factors; D053245:RANK Ligand; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse