ESPE Abstracts (2022) 95 P1-226

ESPE2022 Poster Category 1 Bone, Growth Plate and Mineral Metabolism (46 abstracts)

FGFR3 gene mutation causes hypochondroplasia via autophagy inhibition

Lin Che 1,2 , Jinxia Wu 3 , Ren Xu 4 & Jing Chen 5

1State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China; 2Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China; 3Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen, China; 4Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, China; 5Department of Child Health, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, China

Background: Fibroblast growth factor receptor 3 (FGFR3) is a negative regulator of skeletal development. Gain-of-function point mutations in FGFR3 are responsible for hypochondroplasia (HCH), one of the most common forms of dwarfism in humans. Autophagy is an evolutionarily conserved catabolic process, which is indispensable for cell homeostasis maintenance and stress responses. Dysregulation at the level of autophagic activity consequently disturbs the chondrocyte viability in the growth plate and mediates the onset and progression of multiple bone diseases, including HCH. Objective: The role of autophagy in HCH and its underlying molecular mechanisms remain elusive. The study aimed to explore the potential role of FGFR3 gene mutation-regulated autophagic activity in the pathogenesis and treatment of HCH.

Methods: We describe a de novo mutation in FGFR3 (G382D) in a patient with HCH. We characterize the impact of the variant on autophagy signaling using a mouse model with the corresponding genome-edited variant FGFR3 (V376D) and support these findings using ATDC5-FGFR3(G382D) cell lines.

Results: We found that mutant activated FGFR3 inhibited the autophagic activity of chondrocytes both in vivo and in vitro. Proteomic analysis in the FGFR3 (V376D, corresponding to human source G382D) mouse model revealed significantly upregulation of HSPB6 expression. Furthermore, we found that HSPB6 inhibited autophagy via activating the ERK/p-ERK signaling pathway. Consistently, in vitro, we found that mutations are critical for ATDC5 cells proliferation and autophagy regulation. Transient transfection of HSPB6 and targeted inhibition of ERK partially rescued FGFR3-mediated inhibition of ATDC5 cells proliferation and autophagy, and the rescue effect was more pronounced by combined treatment.

Conclusions: Our findings reveal that mutant activated FGFR3 inhibits the autophagic activity through activating ERK/p-ERK signaling pathway by increasing the HSPB6 expression level, which may play an essential role in the pathogenesis and treatment of HCH.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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