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 Ca2+ and Mg2+ ions in the mammalian body. Although investigations into Ca2+ signaling have progressed rapidly and led to better understanding of bone biology, the Mg2+ signaling pathway and associated molecules remain to be elucidated. Here, we investigated the role of a potential Mg2+ signaling-related lysosomal molecule, two-pore channel subtype 2 (TPC2), in osteoclast differentiation and bone remodeling. Previously, we found that under normal Mg2+ conditions, TPC2 promotes osteoclastogenesis. We observed that under low-Mg2+ 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-Mg2+ 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-Mg2+ diet. The myo-inositol supplementation rescued the low-Mg2+ diet-induced trabecular bone loss, which was accompanied by the inhibition of osteoclastogenesis. These results indicate that low-Mg2+-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 Mg2+ deficiency-induced skeletal diseases.
['Notomi|Takuya|T|', 'Kuno|Miyuki|M|', 'Hiyama|Akiko|A|', 'Nozaki|Tadashige|T|', 'Ohura|Kiyoshi|K|', 'Ezura|Yoichi|Y|', 'Noda|Masaki|M|']
D000818:Animals D016723:Bone Remodeling D001862:Bone Resorption D015220:Calcium Channels D020013:Calcium Signaling D002454:Cell Differentiation D007294:Inositol D008247:Lysosomes D008274:Magnesium D008275:Magnesium Deficiency D008297:Male D008564:Membrane Potentials D051379:Mice D008810:Mice, Inbred C57BL D010010:Osteoclasts D010012:Osteogenesis D018129:Phosphatidylinositol Phosphates D000067996:RAW 264.7 Cells D012964:Sodium
lysosome osteoclast ion channel magnesium optogenetics phosphatidylinositol phosphatase plasma membrane