Open AccessPharmacological intervention of the FGF–PTH axis as a potential therapeutic for craniofacial ciliopathies
Author(s) -
Christian Louis Bonatto Paese,
Che Shoa Chang,
Daniela Kristeková,
Samantha A. Brugmann
Publication year - 2022
Publication title -
disease models and mechanisms
Language(s) - English
Resource type - Journals
eISSN - 1754-8411
pISSN - 1754-8403
DOI - 10.1242/dmm.049611
Subject(s) - ciliopathies , craniofacial , fibroblast growth factor , intervention (counseling) , medicine , cilium , biology , endocrinology , neuroscience , microbiology and biotechnology , phenotype , genetics , psychiatry , receptor , gene
Ciliopathies represent a disease class characterized by a broad range of phenotypes including polycystic kidneys and skeletal anomalies. Ciliopathic skeletal phenotypes are among the most common and most difficult to treat due to a poor understanding of the pathological mechanisms leading to disease. Using an avian model (talpid2) for a human ciliopathy with both kidney and skeletal anomalies (orofaciodigital syndrome 14), we identified disruptions in the FGF23-PTH axis that resulted in reduced calcium uptake in the developing mandible and subsequent micrognathia. Although pharmacological intervention with the U.S. Food and Drug Administration (FDA)-approved pan-FGFR inhibitor AZD4547 alone rescued expression of the FGF target SPRY2, it did not significantly rescue micrognathia. In contrast, treatment with a cocktail of AZD4547 and teriparatide acetate, a PTH agonist and FDA-approved treatment for osteoporosis, resulted in molecular, cellular and phenotypic rescue of ciliopathic micrognathia in talpid2 mutants. Together, these data provide novel insight into pathological molecular mechanisms associated with ciliopathic skeletal phenotypes and a potential therapeutic strategy for a pleiotropic disease class with limited to no treatment options.