Decipher the role and the therapeutic potential of FGFR3 signaling in age-related diseases – BonyBrain

In the recent years, it has been shown that musculoskeletal failure and brain cognitive deficits are symptoms that are often intertwined and occur at the same time during aging, suggesting alterations of common regulatory mechanisms and molecular pathways. This is particularly true for the Fibroblast Growth factor Receptor 3 (FGFR3)-associated disorders that exhibit phenotype of premature bone and brain aging characterized by a low bone mineral density associated with cognitive alterations in adult patients.

FGFR3 is a member of RTK (Receptor Tyrosine Kinase) involved in the control cellular proliferation and differentiation in many tissues. Gain-of-function mutations localized in FGFR3 are responsible for the two most common form of dwarfism: achondroplasia and hypochondroplasia, which display bone development defects and premature bone aging. Recent work performed by P1& P2 has provide a pioneer study demonstrating that gain-of-function mutation of FGFR3 (p.Ala391Glu) associated with FGFR3-related craniosynostoses, could be also associated to severe brain cognitive alterations characterized by memory impairments and intellectual disability. This study has identified FGFR3 signaling as a sharing pathway by bone and brain for the control of their physiological functions, but also advanced our understanding of the complexity of multi-systemic impairments observed in FGFR3-related disorders. Importantly, this association between bone and brain alterations seems to induce accelerated aging phenotype, which is also present in other FGFR3 gain-of-function associated-diseases. This is the case for the mild dwarf mouse model (Fgf3N534K/+) expressing a mutation of FGFR3 responsible for the most frequent human hypochondroplasia (60%). These mutant mice are characterized by a mild and progressive dwarf phenotype affecting long bones and skull. The bone mineral density is decreased in long bones and vertebrae, but also present hippocampal-dependent memory deficits (unpublished data). Therefore, a better understanding of rare diseases associated to FGFR3 gain-of-function mutations, in particular during adulthood, could provide novel insight in the mechanisms regulating bone and brain physiology, the identification of common mechanisms involved in premature aging and novel therapeutic approaches to treat multi-systemic deficits.
The overall objective of BonyBrain project is to determine the pathophysiological impact of the Fgfr3N534K/+ mutation in bone formation and repair, brain functions and premature aging. By combining the expertise of two teams, located on the campus Necker, working in FGFR3-related disorders, bone physiology and therapeutic approaches (P1), and neurobiology, cognition and brain aging (P2), we will tackle 3 major questions:

1) Characterize the effects of FGFR3 mutation in skeleton, bone repair and aging.
2) Determine the impact of FGFR3 mutation in hippocampal cognitive and neuronal functions.
3) Evaluate the therapeutic potential of FGFR3 antagonists in bone/brain disorders and premature aging.

BonyBrain is designed to provide an in-depth understanding of FGFR3 signaling and functions in bone and brain physiology and aging, to decipher the complexity of multi-systemic impairments in FGFR3-associated disorders, to advance our understanding of the common molecular pathways in genetic disorders of bone and brain that represent premature signature of common late onset aging diseases, and to develop innovative therapeutic approach to delay/treat premature aging, with their devastating complications and economic burden, which represent a major public health care challenge.