Work

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

Year: 2017

Type: article

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

Source: Journal of Biological Chemistry

DOI: 10.1074/jbc.m117.780072