Wednesday, April 2, 2025
4/2/2025
FGFR3 Activities in the Control of Skeletal Growth - PROJECT SUMMARY Skeletal growth occurs during development in cartilage growth plates, bone template regions wherein chondrocytes actively proliferate, follow a stepwise maturation program, and produce an abundant extracellular matrix. Their activities are tightly regulated by numerous factors, including the fibroblast growth factor receptor- 3 (FGFR3), whose importance in humans is illustrated by the fact that FGFR3 gain-of-function variants (FGFR3Ach) cause achondroplasia (ACH), the most frequent form of short stature. The disorder markedly affects the appendicular skeleton (short limbs), axial skeleton (vertebral stenosis and lordosis) and craniofacial skeleton (frontal bossing and flat face) and also results in a large spectrum of neurologic issues. Various types of surgical and pharmacological treatments have been proposed and approved for this condition, but none addresses all clinical issues, and long-term outcomes are unknown. There is thus an urgent clinical need to develop new, safe and efficient treatments for ACH. We propose to help address this need by deepening our current understanding of the pathways acting upstream and downstream of FGFR3 in growth plate chondrocytes (GPCs) and by testing in preclinical models if targeting newly identified pathways may provide successful treatments. Aim 1 will test the hypothesis that the expression of FGFR3 is controlled by several cis-acting regulatory elements (CREs) and that the inactivation of key CREs could safely and effectively lessen the severity of ACH. This hypothesis and our research strategy rely on a solid scientific premise constituted by published and pilot data. We will create and analyze CRE reporter transgenic mice to determine to which extent individual CREs reproduce the expression pattern of Fgfr3. We will also determine which CREs most significantly contribute to Fgfr3 expression in mice by deleting the most likely ones in the Fgfr3 wild-type and ACH alleles and assessing phenotypic consequences. Aim 2 will test the hypothesis that FGFR3Ach perturbs a pathway critical to ensure the high-energy demands of GPC activities and whose link to FGFR3Ach was uncovered in pilot studies. We will analyze to which extent this pathway is perturbed and affects GPC activities in ACH. Further, we will use transgenic approaches to test if normalizing this pathway may safely and effectively lessen ACH features. This project is highly significant and innovative considering on the one hand the prevalence and severity of ACH and the current lack of fully satisfying treatments, and considering on the other hand that it will push forward the frontiers of scientific knowledge to propose novel, potentially life-changing strategies to treat people with ACH, and may also suggest novel mechanisms and treatments for other chondrodysplasias and still poorly treatable FGFR3-related cancers.
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