Defects in Fibroblast Growth Factor Receptor 3 (FGFR3) signaling are responsible for the most common form of dwarfism achondroplasia (ACH) and the less severe form of dwarfism hypochondroplasia (HCH). These rhizomelic dwarfisms are characterized by short stature, lordosis and lumbar spinal stenosis. Impaired growth of long bones due to excessive activation of FGFR3 signaling are well studied, but not for spinal defects such as intervertebral disc (IVD) changes and vertebral canal stenosis.
FGFR3 is widely expressed not only in the vertebral bodies but also in the cartilage endplates, nucleus pulposus and annulus fibrosus that formed the integral compartments of the IVD unit in the spine. Recently, we identified defects in the structure of the vertebral bodies and intervertebral discs (IVD) in our mouse models for ACH and HCH. A specific and noticeable abnormality is in the organization of the annulus fibrosus that correlated well with our novel findings that chondrocytes from the endplate cartilage contributes to the maintenance of the inner annulus fibrosus for IVD homeostasis. We showed a cellular differentiation and transition processes within and between IVD structures, and we hypothesize abnormal FGFR3 signaling has a role in this specific process leading to the observed IVD changes that we will assess in the current proposal.
The goal of our project “understanding FGF signaling to treat spinal defects” (FANTASIA) is to provide an in-depth understanding of FGFR3 function in axial skeleton formation with a focus in deciphering the pathogenic mechanism resulting from a gain-of-function outcome in the IVD defects. Our objectives will be 1) to characterize the cellular defects in the spine of mouse models for ACH and HCH; 2) to decipher the regulatory network of FGFR3 function in the spine in health and disease; 3) to determine the role of endplate hypertrophic chondrocytes in intervertebral disc pathogenesis for ACH and HCH patients; and 4) to perform preclinical studies of drug efficacy for treating spine defects in Ach and Hch mouse models.
The major outcomes of FANTASIA will provide critical insights into the molecular and cellular changes in the development and maintenance of the spine, and its response to changes in mechanical loading in the progression and pathogenesis in patients with ACH and HCH. Our approach of combining phosphoproteome and single-cell transcriptome will provide key insights into the role of FGF signaling in the axial skeleton, and in FGFR3-related disorders, by defining the cellular crosstalks between cartilage, bone and IVD in lumbar vertebrae. Importantly, the availability of Ach and Hch mouse data will guild the studies in preclinical assessment of the efficacy of drug treatments on the axial skeleton. This proposal will specifically test a tyrosine kinase inhibitor to modulate FGF signaling to resolve not only for long bone growth abnormalities, but also the spine, benefiting ACH and HCH patients.
The current proposal takes advantage of the combined synergistic expertise, using start-of-the art technologies such as single cell RNA sequencing and high-resolution episcopic microscopy. This is make possible with the unique Ach and Hch mouse models from the principal investigators, to address this knowledge gap in axial skeleton. The Hong Kong and Paris teams have the combined synergistic expertise in the scientific fields covered within this project and unique resources in realizing the goal of FANTASIA.
Madame Laurence LEGEAI-MALLET (IHU IMAGINE - INSTITUT DES MALADIES GÉNÉTIQUES)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
UMR_S 1163 IHU IMAGINE - INSTITUT DES MALADIES GÉNÉTIQUES
School of Biomedical Sciences, LKS Faculty of Medicine / The Hong Kong University
Help of the ANR 643,864 euros
Beginning and duration of the scientific project: February 2020 - 36 Months