Cystic Fibrosis Bone Disease: The Interplay between CFTR Dysfunction and Chronic Inflammation

Abstract

Cystic fibrosis is a monogenic disease with a multisystemic phenotype, ranging from predisposition to chronic lung infection and inflammation to reduced bone mass. The exact mechanisms unbalancing the maintenance of an optimal bone mass in cystic fibrosis patients remain unknown. Multiple factors may contribute to severe bone mass reduction that, in turn, have devastating consequences in the patients' quality of life and longevity. Here, we will review the existing evidence linking the CFTR dysfunction and cell-intrinsic bone defects. Additionally, we will also address how the proinflammatory environment due to CFTR dysfunction in immune cells and chronic infection impairs the maintenance of an adequate bone mass in CF patients.

Keywords: CFTR; bone; cystic fibrosis related bone disease; osteoporosis.

Figure 1

Classification and effects of CFTR mutations and approved CFTR function-restoring pharmacological interventions. Class I mutations result in the premature termination of CFTR transcription and in the absence of a functional CFTR. Class II mutations lead to the misfolding of CFTR protein and aberrant trafficking of the protein. Class III mutations are gating mutations causing ineffective chloride/bicarbonate transport. Mutations belonging to class IV decrease the conduction of ions through the channel. Class III and IV mutations lead to normal levels of CFTR expressed at the cell surface but a reduced CFTR function. Splicing and missense mutations belong to class V and cause reduced CFTR synthesis. Class VI mutations reduce CFTR stability of the cell membrane due to increased CFTR recycling. Thus far, the CFTR modulators in the clinic target class II, class III and IV mutations. Image created using Biorender.com (www.biorender.com; access on 22 November 2022).

Figure 2

Cystic fibrosis bone disease is a multifactorial disease due to chronic organ involvement, the direct impact of CFTR dysfunction and long-term therapeutical approaches. Scheme was created using Biorender.com (www.biorender.com; access on 22 November 2022).

Figure 3

Defects in CFTR function hamper osteoblast maturation. Scheme was created using Biorender.com (www.biorender.com; access on 6 December 2022).

Figure 4

CFTR dysfunction and recurrent pro-inflammatory environment potentiates osteoclast formation and activity, contributing to bone loss and higher risk of fractures. Scheme was created using Biorender.com (www.biorender.com; access on 9 December 2022).