Fibronectin-LILRB4/gp49B interaction negatively regulates osteoclastogenesis through inhibition of RANKL-induced TRAF6/TAK1/NF?kB/MAPK signaling
Fibronectin-LILRB4/gp49B interaction negatively regulates osteoclastogenesis through inhibition of RANKL-induced TRAF6/TAK1/NF?kB/MAPK signaling
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纤连蛋白-LILRB4/gp49B 相互作用通过抑制 RANKL 诱导的 TRAF6/TAK1/NF?kB/MAPK 信号传导负向调节破骨细胞生成
DOI：
10.1093/intimm/dxac051
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发表时间：
2022
影响因子：
4.4
通讯作者：
Takai Toshiyuki
中科院分区：
文献类型：
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作者：
Su Mei-Tzu;Ono Karin;Kezuka Dai;Miyamoto Shotaro;Mori Yu;Takai Toshiyuki
破骨细胞（负责骨吸收的多核细胞）的调节异常导致几种退行性骨疾病。在此之前，我们发现阻断白细胞免疫球蛋白（IG）样受体B4（LILRB 4）可以促进破骨细胞的体外分化，LILRB 4是一种在免疫调节中起重要作用的抑制性受体。在这里，我们探讨了gp 49 B，小鼠的LILRB 4直系同源物，是否调节破骨细胞在体内，以及是否纤连蛋白（FN），LILRB 4/gp 49 B的配体，肯定有助于LILRB 4/gp 49 B介导的破骨细胞。与野生型小鼠相比，gp 49 B缺陷小鼠表现出骨小梁数量的减少和破骨细胞形成的增加。Gp 49 B基因敲除可通过增加破骨细胞的形成来提高小鼠Raw 264.7细胞来源的破骨细胞的骨吸收能力。我们进一步揭示了gp 49 B缺陷通过增加转化生长因子（TGF）活化激酶1（TAK 1）、NF-κB和丝裂原活化蛋白激酶（MAPK）的磷酸化而增加核因子（NF）-κB配体（RANKL）诱导的信号转导的受体活化剂。此外，FN的N-末端30 kDa蛋白水解片段通过增加含Src同源性-2的酪氨酸磷酸酶1（SHP-1）磷酸化和肿瘤坏死因子受体相关因子6（TRAF 6）-SHP-1的结合促进gp 49 B介导的破骨细胞生成抑制。总之，FN-LILRB 4/gp 49 B相互作用在破骨细胞生成中负性调节RANKL诱导的TRAF 6/TAK 1/NF-κB/MAPK信号传导。
Dysregulation of osteoclasts, the multinucleated cells responsible for bone resorption, contributes to several degenerative bone disorders. Previously, we showed that blocking the leukocyte immunoglobulin (Ig)-like receptor B4 (LILRB4), a kind of inhibitory receptor that plays an important role in immune regulation, promotes osteoclast differentiationin vitro. Here, we explored whether gp49B, the murine ortholog of LILRB4, regulates osteoclastogenesisin vivo,and whether fibronectin (FN), a ligand of LILRB4/gp49B, certainly contributes to LILRB4/gp49B-mediated osteoclastogenesis. In comparison with wild-type mice, gp49B deficiency mice exhibited a loss of trabecular bone number and an increase in osteoclast formation. Gp49B knockout improved the bone resorptive capacity of osteoclasts derived from murine Raw264.7 cells by increasing osteoclast formation. We further revealed that gp49B deficiency increased the receptor activator of nuclear factor (NF)-κB ligand (RANKL)-induced signaling transduction by increasing the phosphorylation of transforming growth factor (TGF)-activated kinase 1 (TAK1), NF-κB and mitogen-activated protein kinases (MAPKs). Furthermore, the N-terminal 30 kDa proteolytic fragments of FN promoted gp49B-mediated inhibition of osteoclastogenesis by increasing Src homology-2-containing tyrosine phosphatase 1 (SHP-1) phosphorylation and tumor necrosis factor receptor-associated factor 6 (TRAF6)-SHP-1 association. In summary, the FN-LILRB4/gp49B interaction negatively regulates RANKL-induced TRAF6/TAK1/NF-κB/MAPK signaling in osteoclastogenesis.