Work

Fibroblast growth factor receptor 3 mutation promotes HSPB6-mediated cuproptosis in hypochondroplasia by impairing chondrocyte autophagy

Year: 2025

Type: article

Abstract: Hypochondroplasia (HCH) is a prevalent form of dwarfism linked to mutations in the fibroblast growth factor receptor 3 ( FGFR3 ) gene, causing missense alterations. We previous report was the first to identify FGFR3 (G382D) gain-of-function variants with a positive family history as a novel cause of HCH. However, the precise contribution of FGFR3 to the pathogenesis of HCH remains elusive. We generated an Fgfr3 (V376D) mutation mouse model using CRISPR/Cas9 technology and performed proteomic analyses to investigate the molecular mechanisms and potential therapeutic targets of HCH. Radiography and micro-computed tomography were employed to assess the bone-specific phenotype in Fgfr3 (V376D) mutant mice. Immunofluorescence, western blotting, and flow cytometry were used to systematically investigate the underlying mechanisms and therapeutic targets. We observed that Fgfr3 (V376D) mutant mice exhibit a bone-specific phenotype, with symmetrically short limb bones, partially resembling the dwarfism phenotype of patients with HCH. We demonstrated that the mutant-activated FGFR3 promotes heat shock protein B 6 (HSPB6)-mediated cuproptosis by inhibiting chondrocyte autophagy both in vivo and in vitro . Additionally, we revealed that FGFR3 (G382D) mutation leads to enhanced ERK signaling, increased Drp1-mediated mitochondrial fission, and upregulated cuproptosis-related protein ferredoxin 1 (FDX1). Furthermore, genetic and pharmacological inhibition of the HSPB6-ERK-Drp1-FDX1 pathway partially alleviate the phenotypes of FGFR3 mutants. Our study provides the first evidence for the pathogenicity of a gain-of-function mutation in FGFR3 (G382D) using mouse and cell models, and it underscores the potential of targeting the HSPB6-ERK-Drp1-FDX1 axis as a novel therapeutic approach for HCH. We first demonstrate that impaired autophagy and enhanced cuproptosis are pivotal in the pathogenesis of HCH. This study not only enlarged the therapeutic potential of targeting cuproptosis for treating FGFR3 mutation-related HCH but also provided a novel perspective on the role of the HSPB6-ERK-Drp1-FDX1 signaling pathway in the development of HCH. Consequently, this article provides valuable insights into the mechanisms and treatment strategies for FGFR3 mutation-related chondrodysplasia.

Source: Journal of Orthopaedic Translation

DOI: 10.1016/j.jot.2025.01.011