Fgf9 Negatively Regulates Bone Mass by Inhibiting Osteogenesis and Promoting Osteoclastogenesis Via MAPK and PI3K/AKT Signaling

作者：Lingyun Tang, Min Wu, Shunyuan Lu, Hongxin Zhang, Yan Shen, Chunling Shen, Hui Liang, Haoyang Ge, Xiaoyi Ding, Zhugang Wang · 发表于：Journal of Bone and Mineral Research · 年份：2020 · DOI：10.1002/jbmr.4230 · 被引用次数：85 · 研究领域：Fibroblast Growth Factor Research、Genetic Syndromes and Imprinting、Bone Metabolism and Diseases

ABSTRACT 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 Fgf9S99N 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–c...