The Unit on Skeletal Genomics (USG) has three main goals: 1) conduct a natural history study to uncover the clinical spectrum of selected skeletal dysplasias and identify new gene-disease associations; 2) understand their pathomechanisms via cell and animal models; and 3) develop mechanistically informed treatments. The group focuses on skeletal disorders affecting the FGF23/phosphate axis or those with an unknown cause.

FGF23 is a hormone made by bone cells that increases urinary phosphate excretion and decreases intestinal absorption, thus lowering phosphate levels. Elevated levels of FGF23 have been associated with left ventricular hypertrophy and cardiovascular mortality (Gutiérrez et al. Circulation, 2009; Faul et al. JCI, 2011; Sharma et al. Journal of the American Geriatric Society, 2021). Abnormal phosphate levels also have important health implications: hyperphosphatemia is associated with arterial calcification, cardiovascular disease and all-cause mortality (Kendrick et al. Advances in Chronic Kidney Disease, 2011; Campos-Obando et al. European Journal of Epidemiology, 2018), while hypophosphatemia is associated with neurotoxicity from cancer immunotherapy (Tang et al. Cancer Immunology Research, 2022). Abnormal phosphate concentrations also influence the risk of various types of cancers (Wulaningsih et al. BMC Cancer, 2013). Since FGF23 and/or phosphate dysregulation have been associated with cardiovascular mortality and response to cancer drugs, an improved understanding of the FGFR1-FGF23-phosphate axis has the potential for clinical repercussions beyond the skeleton.

The identification of new genes associated with skeletal disease will inform development, allow an improved understanding of bone and cartilage biology, and potentially lead to the use of targeted therapeutic strategies. The USG seeks to leverage clinical and/or pathomechanistic insights in order to uncover new pathways involved in skeletal disease, open new avenues of research in skeletal growth and physiology, and improve precision medicine. We use genomic approaches to identify and characterize the molecular bases of genetic skeletal disorders.