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.
All Science Journal Classification (ASJC) codes
- Endocrinology, Diabetes and Metabolism
- Orthopedics and Sports Medicine