Pharmacological intervention of the FGF-PTH axis as a potential therapeutic for craniofacial ciliopathies

PAESE, Christian Louis Bonatto, Ching-Fang CHANG, Daniela KRISTEKOVÁ and Samantha A. BRUGMANN. Pharmacological intervention of the FGF-PTH axis as a potential therapeutic for craniofacial ciliopathies. DMM Disease Models and Mechanisms. Company of Biologists Ltd, 2022, vol. 15, No 8, p. 1-10. ISSN 1754-8403. Available from: https://dx.doi.org/10.1242/dmm.049611.

Basic information

• Original name: Pharmacological intervention of the FGF-PTH axis as a potential therapeutic for craniofacial ciliopathies
• Authors: PAESE, Christian Louis Bonatto, Ching-Fang CHANG, Daniela KRISTEKOVÁ (703 Slovakia, belonging to the institution) and Samantha A. BRUGMANN (guarantor).
• Edition: DMM Disease Models and Mechanisms, Company of Biologists Ltd, 2022, 1754-8403.

Other information

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 10600 1.6 Biological sciences
• Country of publisher: United Kingdom of Great Britain and Northern Ireland
• Confidentiality degree: is not subject to a state or trade secret
• WWW: URL
• Impact factor: Impact factor: 4.300
• RIV identification code: RIV/00216224:14310/22:00128055
• Organization unit: Faculty of Science
• Doi: http://dx.doi.org/10.1242/dmm.049611
• UT WoS: 000864078600001
• Keywords in English: Primary cilia; Ciliopathies; FGF; C2CD3; Micrognathia; talpid(2)
• Tags: rivok
• Tags: International impact, Reviewed

Abstract

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.