PT  - JOURNAL ARTICLE
AU  - Christian Louis Bonatto Paese
AU  - Ching-Fang Chang
AU  - Daniela Kristeková
AU  - Samantha A. Brugmann
TI  - Pharmacological intervention of the FGF-PTH axis as a potential therapeutic for craniofacial ciliopathies
AID  - 10.1101/2022.04.21.489105
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.04.21.489105
4099  - http://biorxiv.org/content/early/2022/04/22/2022.04.21.489105.short
4100  - http://biorxiv.org/content/early/2022/04/22/2022.04.21.489105.full
AB  - 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 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. While pharmacological intervention with the FDA-approved pan-FGFR inhibitor AZD4547 alone rescued expression of the FGF target Sprouty2, 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 a 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.Summary Statement Treatment options for ciliopathic phenotypes are very limited. Using an avian model, we report a novel molecular mechanism and potential therapeutic treatment for ciliopathic micrognathia.Competing Interest StatementThe authors have declared no competing interest.