Related Experiment Video

Updated: Sep 17, 2025

Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development
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Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development

Published on: June 15, 2017

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Protein kinase A is a dependent factor and therapeutic target in mouse models of fibrous dysplasia

Zhongyu Liu1, Lu Xing1, Wenlong Huang1

  • 1State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China.

Nature Communications
|July 2, 2025
PubMed

Insights

Protein kinase A (PKA) drives fibrous dysplasia by promoting abnormal bone cell activity. Inhibiting PKA effectively reduces disease lesions and improves bone structure in mouse models, highlighting PKA as a therapeutic target.

Area of Science:

  • Skeletal Biology
  • Molecular Genetics
  • Endocrinology

Background:

  • Fibrous dysplasia is a rare genetic bone disorder caused by Gαs mutations, leading to skeletal deformities and fractures.
  • Protein kinase A (PKA) is a key downstream effector of Gαs, involved in numerous cellular processes, but its role in fibrous dysplasia was previously unelucidated.

Purpose of the Study:

  • To investigate the role of Protein kinase A (PKA) in the pathogenesis of fibrous dysplasia.
  • To evaluate the therapeutic potential of targeting PKA in fibrous dysplasia.

Main Methods:

  • Generated a transgenic mouse model with activating PKA mutation in skeletal stem cells to mimic fibrous dysplasia.
  • Utilized genetic PKA inhibitor peptides and small-molecule inhibitors to downregulate PKA activity in mouse models.
  • Assessed bone structure and cellular differentiation markers in PKA-manipulated mice.

Main Results:

  • PKA activation in skeletal stem cells induced fibrous dysplasia-like bone lesions.
  • PKA promoted osteoclastogenesis and aberrant osteogenic differentiation/proliferation while impairing mineralization.
  • PKA inhibition ameliorated fibrous dysplasia lesions and increased trabecular bone volume in mouse models.

Conclusions:

  • PKA is a critical mediator in the initiation and progression of fibrous dysplasia.
  • Targeting PKA activity represents a promising therapeutic strategy for fibrous dysplasia.
  • Further investigation into long-term pharmacological PKA inhibition is warranted.

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