Enhanced bone repair with FGFR antagonists in a model of hypochondroplasia

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Hypochondroplasia (HCH) belongs to the group of osteochondrodysplasias, genetic disorders that impair bone development and formation, thereby affecting growth. HCH is a rare form of dwarfism, linked to so-called “gain-of-function” mutations in the FGFR3 (Fibroblast Growth Factor Receptor 3) gene. Patients with these mutations have growth defects of the long bones, skull and face. These growth defects of the face and skull are at the origin of craniomaxillofacial anomalies that may require maxillofacial bone surgeries.
FGFRs are major genes for bone formation and repair. Despite advances in medical research, the impact of these mutations on bone repair has never been studied in the craniofacial skeleton. Through their work, the results of which have just been published in the journal Bone Research, researchers at Institut Imagine have shed light on the cellular mechanisms involved in the various stages of mandibular (lower jaw) bone repair.

Maxillofacial surgeon Dr. Anne Morice, under the supervision of Dr. Laurence Legeai-Mallet (Institut Imagine, Inserm, AP-HP, Université Paris Cité) recently studied mandibular bone repair in a mouse model of hypochondroplasia. Anne Morice's work has shown that HCH mice exhibit defective mandibular repair, characterized by poor bone mineralization, impaired cartilage cell differentiation and pseudarthrosis (lack of consolidation of bone fractures). The team also showed in a mouse model of Crouzon, a form of syndromic craniosynostosis (premature fusion of cranial sutures) linked to a FGFR2 mutation, that bone repair was conversely accompanied by excessively high bone mineralization in fractured bone areas.

The team then explored the potential of FGFR3 antagonists, which block the action of the FGFR3 receptor overactivated by the mutation, in an attempt to restore defective mandibular bone repair. Two FGFR3 antagonist molecules were tested during bone repair in this mouse model: infigratinib and vosoritide, two treatments administered to patients with achondroplasia (a more severe form of dwarfism also linked to a mutation in the FGFR3 gene) to increase bone growth. 

Infigratinib or vosoritide administered during bone repair are highly effective, restoring a normal bone repair process in HCH mice. These treatments enhanced bone formation and mineralization of bone repair calluses by blocking FGFR3 overactivity. This finding highlights the critical role of FGFR3 in regulating bone repair, and suggests that FGFR antagonists could become a transformative therapeutic approach for treating bone repair defects associated with FGFR3 mutations.

Laurence Legeai-Mallet explains: “Our results highlight the crucial role of FGFR3 in bone repair processes. The beneficial effect of FGFR antagonists in our mice models provides a compelling argument for the development of targeted therapies to treat skeletal defects in patients with FGFR3-related diseases.”

The use of FGFR antagonists could revolutionize the treatment of defects in bone consolidation after fractures or bone surgery, as well as the treatment of craniofacial anomalies in patients with osteochondrodysplasias.

Anne Morice's recent work has been published in the scientific journal Bone Research. 

This project is supported by the AXA Mutuals' Philanthropy Department as part of the Head and Heart Chair at Institut Imagine.

 

Reference:

FGFR antagonists restore defective mandibular bone repair in a mouse model of osteochondrodysplasia 

Morice et al, Bone Research, 2025

DOI 10.1038/s41413-024-00385-x