Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea.
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.
Sci Rep. 2017 Nov 14;7(1):15575. doi: 10.1038/s41598-017-15586-0.
Osteoclasts can be differentiated from bone marrow-derived macrophages (BMDM). They play a key role in bone resorption. Identifying novel molecules that can regulate osteoclastogenesis has been an important issue. In this study, we found that FAM19A5, a neurokine or brain-specific chemokine, strongly stimulated mouse BMDM, resulting in chemotactic migration and inhibition of RANKL-induced osteoclastogenesis. Expression levels of osteoclast-related genes such as RANK, TRAF6, OSCAR, TRAP, Blimp1, c-fos, and NFATc1 were markedly decreased by FAM19A5. However, negative regulators of osteoclastogenesis such as MafB and IRF-8 were upregulated by FAM19A5. FAM19A5 also downregulated expression levels of RANKL-induced fusogenic genes such as OC-STAMP, DC-STAMP, and Atp6v0d2. FAM19A5-induced inhibitory effect on osteoclastogenesis was significantly reversed by a formyl peptide receptor (FPR) 2 antagonist WRW4 or by FPR2-deficiency, suggesting a crucial role of FPR2 in the regulation of osteoclastogenesis. Collectively, our results suggest that FAM19A5 and its target receptor FPR2 can act as novel endogenous ligand/receptor to negatively regulate osteoclastogenesis. They might be regarded as potential targets to control osteoclast formation and bone disorders.
破骨细胞可以从骨髓来源的巨噬细胞 (BMDM) 中分化出来。它们在骨吸收中起关键作用。鉴定可以调节破骨细胞生成的新分子一直是一个重要问题。在这项研究中，我们发现 FAM19A5，一种神经肽或脑特异性趋化因子，强烈刺激小鼠 BMDM，导致趋化性迁移并抑制 RANKL 诱导的破骨细胞生成。FAM19A5 显著降低了破骨细胞相关基因如 RANK、TRAF6、OSCAR、TRAP、Blimp1、c-fos 和 NFATc1 的表达水平。然而，破骨细胞生成的负调节剂如 MafB 和 IRF-8 被 FAM19A5 上调。FAM19A5 还下调了 RANKL 诱导的融合基因如 OC-STAMP、DC-STAMP 和 Atp6v0d2 的表达水平。FAM19A5 对破骨细胞生成的抑制作用被甲酰肽受体 (FPR) 2 拮抗剂 WRW4 或 FPR2 缺陷显著逆转，表明 FPR2 在破骨细胞生成的调节中起关键作用。总之，我们的结果表明 FAM19A5 和其靶受体 FPR2 可以作为新型内源性配体/受体来负调控破骨细胞生成。它们可能被视为控制破骨细胞形成和骨骼疾病的潜在靶点。
