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

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. 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.

The ciliary protein C2cd3 is required for mandibular musculoskeletal tissue patterning

“…Previous reports from our lab and others have documented the craniofacial and skeletal phenotypes present in ta 2 embryos (Abbott et al, 1960(Abbott et al, , 1959Bonatto Paese et al, 2022, 2021b, 2021aBrooks et al, 2021;Brugmann et al, 2010;Caruccio et al, 1999;Chang et al, 2014;Dvorak and Fallon, 1991;Harris et al, 2006;Schneider et al, 1999;Schock et al, 2015). To better understand the molecular etiology of these phenotypes, we performed a temporal analysis of mandibular development, initially focused on Meckel's cartilage.…”

“…4J-N) (Bonatto Paese et al, 2021a). In addition to the lower jaw phenotypes, ta 2 embryos also present with palatal clefting and hypoplastic palatine bones (Bonatto Paese et al, 2022; Chang et al, 2014; Schock et al, 2015). Indeed, C2cd3 ex4-5fl/fl ; AP2-Cre embryos presented with palatal clefting characterized by hypoplastic maxillary, premaxillary, and palatine bones as well as an absent palatine process and a dysmorphic pterygoid process (Fig.…”

“…To study the molecular etiologies of phenotypes associated with human OFD14, we utilized the talpid 2 (ta 2 ). The ta 2 is a naturally occurring avian mutant that is characterized by its numerous craniofacial phenotypes as well as its polydactylous limbs (Abbott et al, 1960(Abbott et al, , 1959Bonatto Paese et al, 2022, 2021aBrugmann et al, 2010;Caruccio et al, 1999;Chang et al, 2014;Schock et al, 2015). We previously reported that the ta 2 phenotype was the result of a 19 bp deletion in C2CD3 (Chang et al, 2014).…”

Sox10 is required for systemic initiation of bone mineralization

“…For Von Kossa staining, fixed embryos were rinsed with deionized water and stained with 2.5% silver nitrate solution (Abcam ab150687) under a light source for 20 minutes. The reaction was stopped with 5% sodium thiosulfate to prevent overstaining, and larvae were imaged immediately 106,107 . For the Osteoimage TM Mineralization Assay (Lonza PA-1503), we followed the manufacturer's protocol after fixing.…”