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Published on: December 18, 2019
Fibroblast Growth Factor 19 Disrupts Cartilage Development Via the FGFR4/β-catenin Axis
Hao Chen1, Yujia Cui1, Jiazhou Li1
1State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
Abstract:
Fibroblast growth factor 19 (FGF19) has received increasing attention in metabolic disorders of the skeletal system, but its role in cartilage development is poorly understood. In the present study, we used ex vivo metatarsal organ model for nascent cartilage and an AAV-FGF19 overexpression model for adolescent growth plates to demonstrate the influence of FGF19 on cartilage development. We found that FGF19 could impair chondrocyte maturation at the neonatal stage and decrease growth plate thickness at the adolescent stage. FGF19 reduces chondrogenic differentiation of mesenchymal stem cells and the chondrocyte maturation via downregulation of Wnt/β-catenin signalling. FGF19-mediated chondrocyte maturation and cartilage differentiation require the participation of FGFR4 with the aid of β-klotho (KLB). FGF19 signalling entered the cytoplasm through FGFR4, activated the expression of SFRP1, WIF1 and DKK2, which are antagonists of β-catenin signalling, and hindered chondrocyte proliferation and cartilage growth. This study demonstrates for the first time that FGF19 inhibits cartilage development through the FGFR4/β-catenin axis, providing evidence for the vital role of FGF19 in growth plate chondrogenesis and endochondral ossification.
Insights
Fibroblast growth factor 19 (FGF19) impairs cartilage development by inhibiting chondrocyte maturation and growth plate thickness. This occurs through the FGFR4/β-catenin pathway, affecting skeletal growth.
Area of Science:
- Skeletal Biology
- Endocrinology
- Developmental Biology
Background:
- Fibroblast growth factor 19 (FGF19) is implicated in skeletal metabolic disorders.
- The specific role of FGF19 in cartilage development remains unclear.
Purpose of the Study:
- To investigate the influence of FGF19 on cartilage development and chondrogenesis.
- To elucidate the molecular mechanisms underlying FGF19's effects on growth plate chondrocytes.
Main Methods:
- Utilized an ex vivo metatarsal organ model for neonatal cartilage.
- Employed an adeno-associated virus (AAV)-FGF19 overexpression model in adolescent growth plates.
- Assessed chondrocyte differentiation, maturation, and proliferation markers.
Main Results:
- FGF19 impaired chondrocyte maturation in neonatal models and reduced growth plate thickness in adolescent models.
- FGF19 decreased mesenchymal stem cell chondrogenic differentiation and chondrocyte maturation by downregulating Wnt/β-catenin signaling.
- FGF19 signaling, via FGFR4 and β-klotho (KLB), activated Wnt antagonists (SFRP1, WIF1, DKK2), inhibiting chondrocyte proliferation and cartilage growth.
Conclusions:
- FGF19 inhibits cartilage development and growth plate chondrogenesis through the FGFR4/β-catenin axis.
- This study provides novel insights into the role of FGF19 in endochondral ossification and skeletal development.
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