CFTR mutation is associated with bone differentiation abnormalities in cystic fibrosis

Claire Dumortier; Andrew Frauenpreis; Antony Hoarau; Amy L. Ryan; Sophie C. Gangloff; Soula Danopoulos; Frédéric Velard; Denise Al Alam

doi:10.1016/j.jcf.2025.01.005

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CFTR mutation is associated with bone differentiation abnormalities in cystic fibrosis

Journal article

Open access

Peer reviewed

CFTR mutation is associated with bone differentiation abnormalities in cystic fibrosis

Claire Dumortier, Andrew Frauenpreis, Antony Hoarau, Amy L. Ryan, Sophie C. Gangloff, Soula Danopoulos, Frédéric Velard and Denise Al Alam

Journal of cystic fibrosis, Vol.24(4), pp.741-748

07/2025

DOI: 10.1016/j.jcf.2025.01.005

PMCID: PMC12943080

PMID: 39800643

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Abstract

•RUNX2 osteoblastic transcription factor expression is reduced in CF-derived cells during differentiation.•OCT4, a marker of pluripotency, is substantially retained in CF-derived mesenchymal stem cells.•The RANKL/TNSFRF11B ratio, bone homeostasis marker, is increased in CF-derived osteoblasts.•Adipocyte transcription factor PPARG persists in CF cells when cultured under osteogenic conditions. Cystic Fibrosis-related Bone Disease is an emerging challenge faced by 50 % of adult people with cystic fibrosis (CF). The multifactorial causes of this comorbidity remain elusive. However, congenital bone defects have been observed in animal models with CFTR mutations, suggesting its importance. The role of CFTR in bone cells development is unknown. Studies from human cells remain somewhat controversial depending on the cells used and the disease state of the patients from which the cells derived. Therefore, we investigated the role of CFTR in osteoblast development using induced pluripotent stem cells generated from homozygous CF donors for F508del and non-CF controls. This approach allows for a clear understanding towards how the CFTR mutation may influence osteoblast differentiation independently from other confounding factors. We observed a lower capacity of differentiation in CF cells as compared to control, already from mesenchymal stem cells (MSC) stage, whereby they retained expression of the pluripotency marker OCT4. Furthermore, our results demonstrated a delayed osteoblast commitment and altered expression of specific markers, such as an increased RANKL/OPG ratio and decreased BMP2, suggesting a potentially perturbed bone homeostasis associated with CFTR mutation. This is the first study of its kind, clearly demonstrating a role for CFTR mutation in delaying osteoblast differentiation and/or regeneration.

Cell Differentiation

Cystic fibrosis-related bone disease

iPSCs

MSC

osteoblasts

Details

Title: Subtitle: CFTR mutation is associated with bone differentiation abnormalities in cystic fibrosis
Creators: Claire Dumortier - Université de Reims Champagne-Ardenne
Andrew Frauenpreis - UCLA Medical Center
Antony Hoarau - Harbor–UCLA Medical Center
Amy L. Ryan - University of Iowa
Sophie C. Gangloff - UCLA Medical Center
Soula Danopoulos - UCLA Medical Center
Frédéric Velard - Université de Reims Champagne-Ardenne
Denise Al Alam - UCLA Medical Center
Resource Type: Journal article
Publication Details: Journal of cystic fibrosis, Vol.24(4), pp.741-748
DOI: 10.1016/j.jcf.2025.01.005
PMID: 39800643
PMCID: PMC12943080
NLM abbreviation: J Cyst Fibros
ISSN: 1569-1993
eISSN: 1873-5010
Publisher: Elsevier B.V
Language: English
Electronic publication date: 01/11/2025
Date published: 07/2025
Academic Unit: Anatomy and Cell Biology
Record Identifier: 9984774236302771

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