Rab32和Rab38通过调节破骨细胞中的细胞内交通来维持骨稳态。

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS ACS Applied Bio Materials Pub Date : 2023-11-17 Epub Date: 2023-11-10 DOI:10.1247/csf.23061
Kanako Tokuda, Shiou-Ling Lu, Zidi Zhang, 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
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引用次数: 0

摘要

破骨细胞通过在骨表面形成吸收坑,导致骨吸收,在骨稳态中发挥着至关重要的作用。Rab38蛋白在破骨细胞从巨噬细胞分化过程中被高度诱导表达。在这里,我们产生了Rab38及其同源物Rab32的双敲除(DKO)小鼠,以研究这些蛋白质在破骨细胞中的作用。来自Rab32/38 DKO小鼠的骨髓源性巨噬细胞在体外正常分化为破骨细胞。然而,DKO破骨细胞的骨吸收活性降低。这些破骨细胞还表现出向培养基中分泌抗酒石酸酸性磷酸酶和组织蛋白酶K的缺陷。此外,在DKO小鼠中,破骨细胞特异性V-ATP酶亚基a3的质膜定位被消除,证实了吸收活性的降低。在体内,Rab32-和Rab38阳性细胞附着在骨表面。在显微CT和组织形态计量学分析中,8周龄的DKO小鼠显示骨小梁显著增厚,血清I型胶原交联C-末端肽水平降低,表明体内骨吸收减少。在10周龄以上的DKO雄性小鼠中,距腓联合(胫骨和腓骨的远端连接处)出现骨质增生。此外,中年小鼠(10至12个月大)表现出后凸,这通常在野生型雄性小鼠中直到24个月大左右才观察到。这些结果表明,Rab32和Rab38通过支持细胞内交通来促进破骨细胞功能,从而维持正常的骨稳态。关键词:Rab32,Rab38,破骨细胞,溶酶体相关细胞器,分泌性溶酶体。
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Rab32 and Rab38 maintain bone homeostasis by regulating intracellular traffic in osteoclasts.

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.Key words: Rab32, Rab38, osteoclast, lysosome-related organelle, secretory lysosome.

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来源期刊
ACS Applied Bio Materials
ACS Applied Bio Materials Chemistry-Chemistry (all)
CiteScore
9.40
自引率
2.10%
发文量
464
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