Alteration of RANKL‐Induced Osteoclastogenesis in Primary Cultured Osteoclasts From SERCA2 +/− Mice

RANKL is essential for the terminal differentiation of monocytes/marcrophages 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 type2 (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.