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Fibroblast Growth Factor 23 Stimulates Cardiac Fibroblast Activity through Phospholipase C-Mediated Calcium Signaling

Ting-Wei Lee1,2, Cheng-Chih Chung3,4,5, Ting-I Lee1,2,6

  • 1Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.

International Journal of Molecular Sciences
|January 11, 2022
PubMed

Insights

Fibroblast growth factor-23 (FGF-23) enhances human atrial fibroblast proliferation and migration by activating FGF receptor 1 and increasing calcium entry. This study reveals FGF-23

Area of Science:

  • Cardiovascular Biology
  • Fibroblast Biology
  • Calcium Signaling

Background:

  • Fibroblast growth factor-23 (FGF-23) is known to cause cardiomyocyte hypertrophy and calcium dysregulation, contributing to heart failure.
  • The specific impact of FGF-23 on cardiac fibrogenesis, the process of scar tissue formation in the heart, is not well understood.

Purpose of the Study:

  • To investigate the effects of FGF-23 on the activity of human atrial fibroblasts.
  • To elucidate the underlying molecular mechanisms by which FGF-23 influences fibroblast behavior, including proliferation and migration.

Main Methods:

  • Cell proliferation and migration assays (MTS, EdU, wound-healing) were performed on human atrial fibroblasts treated with varying concentrations of FGF-23.
  • Calcium (Ca2+) imaging, ELISA, and Western blot analysis were used to assess Ca2+ entry, intracellular signaling molecules (IP3), and ion channel expression (Orai1, TRPC1).
  • Gene expression (PCR) and pharmacological inhibition (EGTA, U73122, PD166866) were employed to confirm the roles of Ca2+ signaling and FGF receptor 1 (FGFR1).

Main Results:

  • FGF-23 significantly increased the proliferation and migration of human atrial fibroblasts at a concentration of 25 ng/mL.
  • FGF-23 treatment led to increased Ca2+ entry and intracellular inositol 1,4,5-trisphosphate (IP3) levels, associated with upregulated Orai1 and TRPC1 channel expression.
  • Inhibition of phospholipase C or Ca2+ entry, and antagonism of FGFR1, attenuated the pro-fibroblast effects of FGF-23, indicating a critical role for FGFR1 and Ca2+ signaling.

Conclusions:

  • FGF-23 promotes human atrial fibroblast activity, suggesting a potential role in cardiac fibrogenesis.
  • The mechanism involves FGF-23 activating FGFR1, subsequently activating the phospholipase C/IP3 pathway, leading to enhanced Orai1 and/or TRPC1-mediated Ca2+ influx.
  • These findings highlight a novel pathway through which FGF-23 can influence cardiac remodeling and disease progression.

Keywords:
calciumfibroblast growth factor 23fibrosisinositol 1,4,5-trisphosphatephospholipase c

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