Fibroblast Growth Factor Receptor Inhibitors Reduce Adipogenesis of Orbital Fibroblasts and Enhance Myofibroblastic Differentiation in Graves’ Orbitopathy

ABSTRACT

Purpose: Orbital fibroblasts are involved in pathogenesis of Graves’ orbitopathy (GO). Fibroblast growth factor (FGF) affects fibroblasts of GO. This study aims to investigate the roles of FGF and FGF receptor (FGFR) in GO.

Methods: Serum FGF proteins and orbital fibroblast FGFR proteins and mRNAs were measured in GO patients and controls. Orbital fibroblasts of GO were cultured and accessed for changes in proliferation (by nuclei number and MTT), myofibroblastic differentiation (by α-SMA), and adipogenesis (by oil droplets using Oil Red O stain) under FGF1 with or without FGFR inhibitors (FGFRi).

Results: Serum FGF1 and FGF2 were increased in GO patients. FGFR1 was the most abundantly expressed FGFR in GO orbital fibroblasts. FGF1 increased GO fibroblast proliferation/adipogenesis and suppressed myofibroblastic differentiation, while FGFRi reversed these effects.

Conclusion: FGF signaling may be involved in GO pathogenesis. Manipulation of FGF-FGFR pathway for GO treatment is worthy of further investigation.

Registration number on Clinicaltrials.gov: NCT03324022.

Keywords:

• Adipogenesis
• fibroblast growth factor receptors
• fibroblast growth factors
• Graves’ orbitopathy
• myofibroblast

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Correction

Acknowledgments

The authors thank the staff of the Eighth Core Lab in the Department of Medical Research of the National Taiwan University Hospital for technical support during the study. The authors also thank Professor Tien-Shang Huang for the support funding, and Mr. Hung-Mu Wei for the laboratory works.

Declaration of interest statement

The authors report no conflict of interest.

Supplementary material

Supplemental data for this article can be accessed here.

Precis

Serum FGF1 and FGF2 concentrations were elevated in GO patients. FGFR1 was the most abundantly expressed FGFR in orbital fibroblasts. FGFR inhibitors suppressed fibroblast proliferation & adipogenesis and enhanced myofibroblastic differentiation in GO.

Additional information

Funding

This work was supported by Ministry of Science and Technology, Taiwan (grand number: MOST 106-2314-B-002-144-, MOST 103-2320-B-002-058-, MOST 107-2320-B-002-038-MY3), National Health Research Institute (NHRI-EX108-108088C), Liver Disease Prevention and Treatment Research Foundation, Taiwan.