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Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18
Zhonghao Liu1, Jingsong Xu, Jennifer S Colvin
1Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, Missouri 63110, USA.
Abstract:
Gain of function mutations in fibroblast growth factor (FGF) receptors cause chondrodysplasia and craniosynostosis syndromes. The ligands interacting with FGF receptors (FGFRs) in developing bone have remained elusive, and the mechanisms by which FGF signaling regulates endochondral, periosteal, and intramembranous bone growth are not known. Here we show that Fgf18 is expressed in the perichondrium and that mice homozygous for a targeted disruption of Fgf18 exhibit a growth plate phenotype similar to that observed in mice lacking Fgfr3 and an ossification defect at sites that express Fgfr2. Mice lacking either Fgf18 or Fgfr3 exhibited expanded zones of proliferating and hypertrophic chondrocytes and increased chondrocyte proliferation, differentiation, and Indian hedgehog signaling. These data suggest that FGF18 acts as a physiological ligand for FGFR3. In addition, mice lacking Fgf18 display delayed ossification and decreased expression of osteogenic markers, phenotypes not seen in mice lacking Fgfr3. These data demonstrate that FGF18 signals through another FGFR to regulate osteoblast growth. Signaling to multiple FGFRs positions FGF18 to coordinate chondrogenesis in the growth plate with osteogenesis in cortical and trabecular bone.
Insights
Fibroblast growth factor 18 (FGF18) acts as a key signaling molecule in bone development. FGF18 regulates both cartilage formation and bone ossification by interacting with multiple fibroblast growth factor receptors (FGFRs).
Area of Science:
- Molecular Biology
- Developmental Biology
- Skeletal Biology
Background:
- Gain-of-function mutations in fibroblast growth factor (FGF) receptors lead to skeletal disorders like chondrodysplasia and craniosynostosis.
- The specific FGF ligands and signaling mechanisms regulating bone development, including endochondral, periosteal, and intramembranous ossification, are not fully understood.
- Identifying FGF ligands is crucial for understanding FGF receptor (FGFR) signaling in skeletal development.
Purpose of the Study:
- To identify the physiological ligands for FGFRs involved in bone development.
- To elucidate the mechanisms by which FGF signaling regulates chondrogenesis and osteogenesis.
- To investigate the role of FGF18 in skeletal development and its interactions with FGFRs.
Main Methods:
- Analysis of Fgf18 expression in developing bone tissues.
- Generation and phenotypic analysis of mice with targeted disruption of Fgf18.
- Comparison of Fgf18-deficient mice with Fgfr3-deficient mice to assess signaling pathways.
- Assessment of chondrocyte proliferation, differentiation, and Indian hedgehog signaling.
- Evaluation of ossification defects and expression of osteogenic markers.
Main Results:
- Fgf18 is expressed in the perichondrium, a key site for bone development.
- Mice lacking Fgf18 exhibit growth plate abnormalities similar to Fgfr3-deficient mice, including expanded chondrocyte zones and increased proliferation.
- FGF18 acts as a physiological ligand for FGFR3, regulating chondrocyte proliferation and differentiation.
- FGF18 also signals through other FGFRs to regulate osteoblast growth, evidenced by delayed ossification and reduced osteogenic markers in Fgf18-deficient mice.
- These findings indicate FGF18 coordinates chondrogenesis and osteogenesis through interactions with multiple FGFRs.
Conclusions:
- FGF18 is a critical signaling molecule in skeletal development, acting through both FGFR3 and other FGFRs.
- FGF18 signaling is essential for regulating chondrogenesis in the growth plate and osteogenesis in developing bone.
- The dual role of FGF18 in signaling through multiple FGFRs highlights its importance in coordinating complex skeletal development processes.