Mutant hFGF23(A12D) stimulates osteoblast differentiation through FGFR3

Area of Science:

• Endocrinology
• Cell Biology
• Genetics

Background:

• Fibroblast growth factor (FGF) 23 is crucial for bone development, interacting with FGF receptors (FGFRs).
• A previously identified mutant human FGF23 (hFGF23(A12D)) was found in a mandibular prognathism pedigree, but its function in bone formation is unknown.

Purpose of the Study:

• To elucidate the specific function and mechanism of the mutant hFGF23(A12D) in bone formation.

Main Methods:

• Isolated rat calvaria (RC) cells were infected with lentivirus carrying mutant hFGF23(A12D) or wild-type hFGF23.
• Real-time PCR, western blot, ELISA, CCK-8 assay, alkaline phosphatase staining, RNA sequencing, co-immunoprecipitation, and immunofluorescence staining were employed.

Main Results:

• hFGF23(A12D) exhibited impaired secretion.
• The mutant inhibited RC cell proliferation while stimulating osteoblast differentiation.
• Increased FGFR3 expression was observed, and hFGF23(A12D) activated the MAPK signaling pathway via interaction with FGFR3's intracellular domain.

Conclusions:

• hFGF23(A12D) impairs secretion but promotes osteoblast differentiation and bone formation through specific interactions with FGFR3.
• This study clarifies the molecular mechanisms underlying hFGF23(A12D)'s role in osteoblastogenesis.