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

Christian Louis Bonatto Paese1,2, Ching-Fang Chang1,2, Daniela Kristeková3,4

  • 1Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

Disease Models & Mechanisms
|July 12, 2022
PubMed

Insights

Ciliopathies cause skeletal issues like micrognathia. Combining FGFR inhibitor AZD4547 with teriparatide acetate effectively treated this ciliopathic skeletal defect in a model, offering a new therapeutic approach.

Area of Science:

  • Genetics
  • Developmental Biology
  • Pharmacology

Background:

  • Ciliopathies are genetic disorders impacting multiple organs, often causing difficult-to-treat skeletal anomalies.
  • The underlying molecular mechanisms of ciliopathic skeletal phenotypes remain poorly understood.
  • Orofaciogital syndrome 14 (OFD14) is a human ciliopathy with kidney and skeletal defects.

Purpose of the Study:

  • To investigate the pathological mechanisms of ciliopathic micrognathia using an avian model.
  • To identify potential therapeutic strategies for ciliopathic skeletal disorders.

Main Methods:

  • Utilized the avian talpid2 mutant model, a model for OFD14.
  • Analyzed disruptions in the FGF23-PTH axis.
  • Administered pharmacological interventions including AZD4547 (pan-FGFR inhibitor) and teriparatide acetate (PTH agonist).

Main Results:

  • Identified FGF23-PTH axis disruption leading to reduced mandibular calcium uptake and micrognathia in talpid2 mutants.
  • AZD4547 alone partially restored FGF pathway signaling but did not rescue micrognathia.
  • A combination of AZD4547 and teriparatide acetate achieved molecular, cellular, and phenotypic rescue of micrognathia.

Conclusions:

  • Disruptions in the FGF23-PTH axis are implicated in ciliopathic micrognathia.
  • Combined pharmacological treatment with AZD4547 and teriparatide acetate shows promise for treating ciliopathic skeletal anomalies.
  • This study offers novel insights into ciliopathy pathogenesis and potential therapeutic avenues for a class of diseases with limited treatment options.
Keywords:
talpid2C2CD3CiliopathiesFGFMicrognathiaPrimary cilia

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