著者

Kanako Tokuda Shiou-Ling Lu Zhang Zidi Yumiko Kato Siyu Chen Kazuya Noda Katsutoshi Hirose Yu Usami Narikazu Uzawa Shinya Murakami Satoru Toyosawa Mitsunori Fukuda Ge-Hong Sun-Wada Yoh Wada Takeshi Noda

出版者

Japan Society for Cell Biology

雑誌

Cell Structure and Function (ISSN:03867196)

巻号頁・発行日

pp.23061, (Released:2023-10-04)

被引用文献数

1

---

Osteoclasts play a crucial role in bone homeostasis by forming resorption pits on bone surfaces, resulting in bone resorption. The osteoclast expression of Rab38 protein is highly induced during differentiation from macrophages. Here we generated mice with double knockout (DKO) of Rab38 and its paralogue, Rab32, to investigate the roles of these proteins in osteoclasts. Bone marrow–derived macrophages from Rab32/38 DKO mice differentiated normally into osteoclasts in vitro. However, DKO osteoclasts showed reduced bone resorption activity. These osteoclasts also demonstrated defective secretion of tartrate-resistant acid phosphatase and cathepsin K into culture medium. Furthermore, the plasma membrane localization of a3, an osteoclast-specific a subunit of V-ATPase, was abrogated in DKO mice, substantiating the reduced resorption activity. In vivo, Rab32- and Rab38-positive cells were attached to the bone surface. Eight-week-old DKO mice showed significantly thickened trabecular bones in micro-CT and histomorphometry analysis, as well as reduced serum levels of cross-linked C-telopeptide of type I collagen, indicating diminished bone resorption in vivo. In DKO male mice over 10 weeks of age, hyperostosis appeared at the talofibular syndesmosis, the distal junction of the tibia and fibula. Furthermore, middle-aged mice (10 to 12 months of age) exhibited kyphosis, which is not usually observed in wild-type male mice until around 24 months of age. These results indicate that Rab32 and Rab38 contribute to osteoclast function by supporting intracellular traffic, thereby maintaining normal bone homeostasis.Keywords: Rab32, Rab38, osteoclast, lysosome-related organelle, secretory lysosome

著者

Masamitsu FUTAI Ge-Hong SUN-WADA Yoh WADA Naomi MATSUMOTO Mayumi NAKANISHI-MATSUI

出版者

The Japan Academy

雑誌

Proceedings of the Japan Academy, Series B (ISSN:03862208)

巻号頁・発行日

vol.95, no.6, pp.261-277, 2019-06-11 (Released:2019-06-11)

参考文献数

87

被引用文献数

64

---

Vacuolar-type ATPase (V-ATPase), initially identified in yeast and plant vacuoles, pumps protons into the lumen of organelles coupled with ATP hydrolysis. The mammalian counterpart is found ubiquitously in endomembrane organelles and the plasma membrane of specialized cells such as osteoclasts. V-ATPase is also present in unique organelles such as insulin secretory granules, neural synaptic vesicles, and acrosomes of spermatozoa. Consistent with its diverse physiological roles and unique localization, the seven subunits of V-ATPase have 2–4 isoforms that are organelle- or cell-specific. Subunits of the enzyme function in trafficking organelles and vesicles by interacting with small molecule GTPases. During osteoclast differentiation, one of the four isoforms of subunit a, a3, is indispensable for secretory lysosome trafficking to the plasma membrane. Diseases such as osteopetrosis, renal acidosis, and hearing loss are related to V-ATPase isoforms. In addition to its role as an enzyme, V-ATPase has versatile physiological roles in eukaryotic cells.