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

View ORCID ProfileChristian Louis Bonatto Paese, View ORCID ProfileChing-Fang Chang, View ORCID ProfileDaniela Kristeková, View ORCID ProfileSamantha A. Brugmann
doi: https://doi.org/10.1101/2022.04.21.489105
Christian Louis Bonatto Paese
1Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
3Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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  • For correspondence: samantha.brugmann@cchmc.org christian.bonattopaese@cchmc.org
Ching-Fang Chang
1Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
3Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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Daniela Kristeková
4Laboratory of Molecular Morphogenesis, Institute of Animal Physiology and Genetics, v.v.i., Czech Academy of Sciences, Brno 602 00, Czech Republic
5Department of Experimental Biology, Faculty of Science, Masaryk University, Brno 625 00, Czech Republic
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Samantha A. Brugmann
1Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
2Division of Plastic Surgery, Department of Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
3Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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  • For correspondence: samantha.brugmann@cchmc.org christian.bonattopaese@cchmc.org
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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 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 Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 22, 2022.
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Pharmacological intervention of the FGF-PTH axis as a potential therapeutic for craniofacial ciliopathies
Christian Louis Bonatto Paese, Ching-Fang Chang, Daniela Kristeková, Samantha A. Brugmann
bioRxiv 2022.04.21.489105; doi: https://doi.org/10.1101/2022.04.21.489105
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Pharmacological intervention of the FGF-PTH axis as a potential therapeutic for craniofacial ciliopathies
Christian Louis Bonatto Paese, Ching-Fang Chang, Daniela Kristeková, Samantha A. Brugmann
bioRxiv 2022.04.21.489105; doi: https://doi.org/10.1101/2022.04.21.489105

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