3 years ago

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

Kiyoshi Ohura, Yoichi Ezura, Tadashige Nozaki, Takuya Notomi, Akiko Hiyama, Miyuki Kuno, Masaki Noda
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 have 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)P2] signaling pathway played a role in the TPC2 activation under low-Mg(2+) conditions. Furthermore, PI(3,5)P2 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)P2 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)P2 pathway. Our findings also suggest that myo-inositol consumption might provide beneficial effects in Mg(2+) deficiency-induced skeletal diseases.

Publisher URL: http://doi.org/10.1074/jbc.M117.780072

DOI: 10.1074/jbc.M117.780072

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