Abstract
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.
Highlights
The bone is the main storage site for Ca2؉ and Mg2؉ ions in the mammalian body
With regard to osteoclastic molecules associated with the [Ca2ϩ]i pathway, we have previously reported that a lysosomal Ca2ϩ channel, two-pore channel subtype 2 (TPC2), functions in osteoclastogenesis [10]
In the low-Mg2ϩ culture medium, osteoclast differentiation was promoted in stromal cell-free bone marrow (BM) and RAW 264.7 mouse osteoclast precursor-like cells (RAW) (Fig. 1, B versus D and G, and supplemental Fig. S1F)
Summary
Received for publication, February 15, 2017, and in revised form, September 25, 2017 Published, Papers in Press, October 30, 2017, DOI 10.1074/jbc.M117.780072 Takuya Notomi‡§¶1, Miyuki Kunoʈ, Akiko Hiyama¶, Tadashige Nozaki¶, Kiyoshi Ohura¶, Yoichi Ezura‡, and Masaki Noda‡§**2 From the ‡Department of Molecular Pharmacology, Medical Research Institute and the §Global Center of Excellence Program for Molecular Science for Tooth and Bone Diseases, Tokyo Medical and Dental University, Bunkyo 113-8510, Tokyo, Japan, the ¶Department of Pharmacology, Osaka Dental University, Hirakata, Osaka 573-1121, Japan, the ʈDepartment of Physiology, Graduate School of Medicine, Osaka City University, Abeno, Osaka 545-8585, Japan, and the **Yokohama City Minato Red Cross Hospital, Yokohama, Kanagawa 231-8682, Japan
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