Involvement of Siglec-15 in regulating RAP1/RAC signaling in cytoskeletal remodeling in osteoclasts mediated by macrophage colony-stimulating factor

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING
Hideyuki Kobayashi, M. Alaa Terkawi, Masahiro Ota, Tomoka Hasegawa, Tomomaya Yamamoto, Tomohiro Shimizu, Dai Sato, Ryo Fujita, Toshifumi Murakami, Norio Amizuka, Norimasa Iwasaki, Masahiko Takahata
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引用次数: 0

Abstract

DNAX-associated protein 12 kD size (DAP12) is a dominant immunoreceptor tyrosine-based activation motif (ITAM)-signaling adaptor that activates costimulatory signals essential for osteoclastogenesis. Although several DAP12-associated receptors (DARs) have been identified in osteoclasts, including triggering receptor expressed on myeloid cells 2 (TREM-2), C-type lectin member 5 A (CLEC5A), and sialic acid-binding Ig-like lectin (Siglec)-15, their precise role in the development of osteoclasts and bone remodeling remain poorly understood. In this study, mice deficient in Trem-2, Clec5a, Siglec-15 were generated. In addition, mice double deficient in these DAR genes and FcεRI gamma chain (FcR)γ, an alternative ITAM adaptor to DAP12, were generated. Bone mass analysis was conducted on all mice. Notably, Siglec-15 deficient mice and Siglec-15/FcRγ double deficient mice exhibited mild and severe osteopetrosis respectively. In contrast, other DAR deficient mice showed normal bone phenotype. Likewise, osteoclasts from Siglec-15 deficient mice failed to form an actin ring, suggesting that Siglec-15 promotes bone resorption principally by modulating the cytoskeletal organization of osteoclasts. Furthermore, biochemical analysis revealed that Sigelc-15 activates macrophage colony-stimulating factor (M-CSF)-induced Ras-associated protein-1 (RAP1)/Ras-related C3 botulinum toxin substrate 1 (Rac1) pathway through formation of a complex with p130CAS and CrkII, leading to cytoskeletal remodeling of osteoclasts. Our data provide genetic and biochemical evidence that Siglec-15 facilitates M-CSF-induced cytoskeletal remodeling of the osteoclasts.

Abstract Image

Siglec-15 参与调节巨噬细胞集落刺激因子介导的破骨细胞细胞骨架重塑过程中的 RAP1/RAC 信号传导
DNAX 相关蛋白 12 kD 大小(DAP12)是一种优势免疫受体酪氨酸基激活基序(ITAM)信号适配体,可激活破骨细胞生成所必需的成本刺激信号。虽然已在破骨细胞中发现了几种 DAP12 相关受体(DAR),包括髓系细胞上表达的触发受体 2(TREM-2)、C 型凝集素成员 5 A(CLEC5A)和唾液酸结合 Ig 样凝集素(Siglec)-15,但它们在破骨细胞的发育和骨重塑中的确切作用仍鲜为人知。在这项研究中,我们培育出了缺乏 Trem-2、Clec5a 和 Siglec-15 的小鼠。此外,还产生了这些 DAR 基因和 FcεRI γ 链(FcR)γ(DAP12 的另一种 ITAM 适配体)双重缺失的小鼠。对所有小鼠进行了骨量分析。值得注意的是,Siglec-15缺陷小鼠和Siglec-15/FcRγ双缺陷小鼠分别表现出轻度和重度骨质疏松。相比之下,其他 DAR 缺陷小鼠则表现出正常的骨表型。同样,Siglec-15缺陷小鼠的破骨细胞也不能形成肌动蛋白环,这表明Siglec-15主要通过调节破骨细胞的细胞骨架组织来促进骨吸收。此外,生化分析表明,Sigelc-15 通过与 p130CAS 和 CrkII 形成复合物,激活巨噬细胞集落刺激因子(M-CSF)诱导的 Ras 相关蛋白-1(RAP1)/Ras 相关 C3 肉毒毒素底物 1(Rac1)通路,从而导致破骨细胞的细胞骨架重塑。我们的数据提供了遗传和生化证据,证明 Siglec-15 可促进 M-CSF 诱导的破骨细胞细胞骨架重塑。
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来源期刊
Bone Research
Bone Research CELL & TISSUE ENGINEERING-
CiteScore
20.00
自引率
4.70%
发文量
289
审稿时长
20 weeks
期刊介绍: Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.
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