Abstract
Fibroblast growth factor signaling is essential for mammalian bone morphogenesis and growth, involving membranous ossification and endochondral ossification. FGF9 has been shown to be an important regulator of endochondral ossification; however, its role in the early differentiation of chondrocytes remains unknown. Therefore, in this study, we aimed to determine the role of FGF9 in the early differentiation of chondrogenesis. We found an increase in FGF9 expression during proliferating chondrocyte hypertrophy in the mouse growth plate. Silencing of FGF9 promotes the growth of ATDC5 cells and promotes insulin-induced differentiation of ATDC5 chondrocytes, which is due to increased cartilage matrix formation and type II collagen (col2a1) and X (col10a1), Acan, Ihh, Mmp13 gene expression. Then, we evaluated the effects of AKT, GSK-3β, and mTOR. Inhibition of FGF9 significantly inhibits phosphorylation of AKT and GSK-3β, but does not affected the activation of mTOR. Furthermore, phosphorylation of inhibited AKT and GSK-3β was compensated using the AKT activator SC79, and differentiation of ATDC5 cells was inhibited. In conclusion, our results indicate that FGF9 acts as an important regulator of early chondrogenesis partly through the AKT/GSK-3β pathway.
Highlights
In mammals, endochondral ossification begins with the formation of cartilage from undifferentiated mesenchymal cells, involving multiple steps, including proliferation and hypertrophy of chondrocytes [1]
We examined the phosphorylation of AKT, Glycogen synthase kinase (GSK)-3β, mammalian Target of Rapamycin (mTOR) to explore the underlying regulation mechanism of Fibroblast growth factor 9 (FGF9)
We showed that FGF9, a member of FGFs, acted as a regulator of early chondrogenic differentiation partly by modulating the phosphorylation of AKT and GSK-3β
Summary
Endochondral ossification begins with the formation of cartilage from undifferentiated mesenchymal cells, involving multiple steps, including proliferation and hypertrophy of chondrocytes [1]. The production and maturation of chondrocytes is sequentially and tempo-spatially controlled by multitude of systemic and local factors, among which several growth factors and cytokines such as fibroblast growth factor (FGFs), as well as the intracellular signaling pathways play a key role [3]. Fibroblast growth factor signaling is essential for the mammalian skeleton morphogenesis and growth, involved in both membranous ossification and endochondral ossification [6]. Mice lacking FGF9 exhibit a disproportionate shortening of proximal skeletal elements, a prominent defect observed in patients afflicted with FGFR3-induced chondrodysplasia syndromes [8]
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