CFTR mutation is associated with bone differentiation abnormalities in cystic fibrosis.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: This is the first study of its kind, clearly demonstrating a role for CFTR mutation in delaying osteoblast differentiation and/or regeneration.