Fgf9 Negatively Regulates Bone Mass by Inhibiting Osteogenesis and Promoting Osteoclastogenesis Via MAPK and PI3K/AKT Signaling
Fgf9 Negatively Regulates Bone Mass by Inhibiting Osteogenesis and Promoting Osteoclastogenesis Via MAPK and PI3K/AKT Signaling
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Fgf9 通过 MAPK 和 PI3K/AKT 信号传导抑制成骨并促进破骨细胞生成，从而负向调节骨量。
DOI：
10.1002/jbmr.4230
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发表时间：
2021-01-23
影响因子：
6.2
通讯作者：
Wang, Zhugang
中科院分区：
文献类型：
--
作者：
Tang, Lingyun;Wu, Min;Wang, Zhugang
成纤维细胞生长因子9（Fgf 9）是一种众所周知的调节骨发育的因子;然而，其在骨稳态中的功能仍然未知。以前，我们确定了FGF 9基因的点突变（p.Ser99Asn，S99 N），并产生了一个同基因敲入小鼠模型，这表明，这种功能丧失突变损害早期关节形成，并负责人类多发性骨结合综合征3（SYNS 3）。此外，新生和成年S99 N突变小鼠表现出显著增加的骨量，表明Fgf 9也参与骨稳态。纯合子新生儿和杂合子成人的组织形态学、断层扫描和血清学分析表明，Fgf 9（S99 N）突变极大地增加了围产期和成人骨骼中的骨量和骨形成，并减少了成人骨骼中的破骨细胞生成。体外分化试验进一步表明，S99 N突变通过促进骨髓间充质干细胞（BMSC）的成骨和矿化以及减弱骨髓单核细胞（BMMs）的破骨细胞生成来增强骨形成。考虑到S99 N突变的功能丧失效应，我们假设Fgf 9本身抑制骨生成并促进破骨细胞生成。体外分化试验表明，Fgf 9显着抑制BMSC成骨分化和矿化，并首次表明，Fgf 9促进破骨细胞生成，通过增强前破骨细胞聚集和细胞-细胞融合。此外，使用特异性抑制剂和体外分化测定，并显示Fgf 9主要通过MEK/ERK途径和部分通过PI 3 K/AKT途径抑制BMSC成骨。Fgf 9还作为潜在的共刺激因子与巨噬细胞集落刺激因子（M-CSF）和NF-κ B配体受体激活剂（RANKL）通过共激活MAPK和PI 3 K/AKT信号通路促进破骨细胞生成。综上所述，我们的研究表明，Fgf 9是通过调节骨生成和破骨细胞生成的骨稳态的负调节剂，并为骨退行性疾病提供了潜在的治疗靶点。(c)2020年美国骨与矿物质研究学会（ASBMR）。
Fibroblast growth factor 9 (Fgf9) is a well-known factor that regulates bone development; however, its function in bone homeostasis is still unknown. Previously, we identified a point mutation in the FGF9 gene (p.Ser99Asn, S99N) and generated an isogeneic knock-in mouse model, which revealed that this loss-of-function mutation impaired early joint formation and was responsible for human multiple synostosis syndrome 3 (SYNS3). Moreover, newborn and adult S99N mutant mice exhibited significantly increased bone mass, suggesting that Fgf9 also participated in bone homeostasis. Histomorphology, tomography, and serological analysis of homozygous newborns and heterozygous adults showed that the Fgf9(S99N) mutation immensely increased bone mass and bone formation in perinatal and adult bones and decreased osteoclastogenesis in adult bone. An in vitro differentiation assay further revealed that the S99N mutation enhanced bone formation by promoting osteogenesis and mineralization of bone marrow mesenchymal stem cells (BMSCs) and attenuating osteoclastogenesis of bone marrow monocytes (BMMs). Considering the loss-of-function effect of the S99N mutation, we hypothesized that Fgf9 itself inhibits osteogenesis and promotes osteoclastogenesis. An in vitro differentiation assay revealed that Fgf9 prominently inhibited BMSC osteogenic differentiation and mineralization and showed for the first time that Fgf9 promoted osteoclastogenesis by enhancing preosteoclast aggregation and cell-cell fusion. Furthermore, specific inhibitors and in vitro differentiation assays were used and showed that Fgf9 inhibited BMSC osteogenesis mainly via the MEK/ERK pathway and partially via the PI3K/AKT pathway. Fgf9 also promoted osteoclastogenesis as a potential costimulatory factor with macrophage colony-stimating factor (M-CSF) and receptor activator of NF-kappa B ligand (RANKL) by coactivating the MAPK and PI3K/AKT signaling pathways. Taken together, our study demonstrated that Fgf9 is a negative regulator of bone homeostasis by regulating osteogenesis and osteoclastogenesis and provides a potential therapeutic target for bone degenerative diseases. (c) 2020 American Society for Bone and Mineral Research (ASBMR).