Role of lysosomal channel protein TPC2 in osteoclast differentiation and bone remodeling under normal and low-magnesium conditions.

The bone is the main storage site for Ca and Mg ions in the mammalian body. Although investigations into Ca signaling have progressed rapidly and led to better understanding of bone biology, the Mg signaling pathway and associated molecules remain to be elucidated. Here, we investigated the role of a potential Mg signaling-related lysosomal molecule, two-pore channel subtype 2 (TPC2), in osteoclast differentiation and bone remodeling. Previously, we found that under normal Mg conditions, TPC2 promotes osteoclastogenesis. We observed that under low-Mg conditions, TPC2 inhibited, rather than promoted, the osteoclast differentiation and that the phosphatidylinositol 3,5-bisphosphate (PI(3,5)P) signaling pathway played a role in the TPC2 activation under low-Mg conditions. Furthermore, PI(3,5)P depolarized the membrane potential by increasing the intracellular Na levels. To investigate how membrane depolarization affects osteoclast differentiation, we generated a light-sensitive cell line and developed a system for the light-stimulated depolarization of the membrane potential. The light-induced depolarization inhibited the osteoclast differentiation. We then tested the effect of -inositol supplementation, which increased the PI(3,5)P levels in mice fed a low-Mg diet. The -inositol supplementation rescued the low-Mg diet-induced trabecular bone loss, which was accompanied by the inhibition of osteoclastogenesis. These results indicate that low-Mg-induced osteoclastogenesis involves changes in the role of TPC2, which are mediated through the PI(3,5)P pathway. Our findings also suggest that -inositol consumption might provide beneficial effects in Mg deficiency-induced skeletal diseases.