Osteoclastogenesis and sphingosine-1-phosphate secretion from human osteoclast precursor monocytes are modulated by the cystic fibrosis transmembrane conductance regulator

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1867

Article

Jourdain, Marie-Laure^1,2  Sergheraert, Johan^1,2  Braux, Julien^1,2  Guillaume, Christine¹  Gangloff, Sophie C.¹  Hubert, Dominique³  Velard, Frederic¹  Jacquot, Jacky¹ 

[1] Univ Reims, BIOS EA Biomat & Inflammat Site Osseux 4691, F-51097 Reims, France

[2] CHU Reims, Pole Med Bucco Dent, F-51100 Reims, France

[3] Hop Cochin, Serv Pneumol, Adult Cyst Fibrosis Ctr, F-75012 Paris, France

关键词: Cystic fibrosis;    Bone disease;    Osteoclastogenesis;    F508del-CFTR;    sip;   

DOI  :  10.1016/j.bbadis.2020.166010

来源: Elsevier

【 摘 要 】

Osteopenia and increased fracture rates are well-recognized in patients with cystic fibrosis (CF) disease. In CF pathology, F508del is the most common CFTR mutation, with more than 85% of patients carrying it on at least one allele. The underlying molecular defect in CFTR caused by the F508del-CFTR mutation in osteoclastogenesis, i.e., on the generation and bone-resorption activity of osteoclasts (OCs) from peripheral blood-derived monocytes (PBMCs) remained unexplored. We therefore investigated whether the F508del mutation could affect the osteoclastogenic capacity of PBMCs collected from 15 adult patients bearing the F508de1-CFTR mutation, to modulate their bone-resorptive abilities and the level of sphingosine-1 -phosphate (S1P) produced by OCs, a key factor in the bone mineral density and formation. In the present study, a severe, defective differentiation of CF-F508del PBMCs to CF-F508del OCs without any significant difference in nuclei number per OC was found compared to non-CF healthy PBMCs from 13 subjects after 7-14-days culture periods. We observed a reduced number of formed non-CF healthy OCs in the presence of a selective inhibitor of CFTR chloride conductance (CFTR-Inh(172)). Our data regarding OCs resorptive capabilites revealed that a loss of CFTR chloride activity in OCs led to a marked reduction in their trench-resorption mode. A 7-fold increase of the SlP release by CF-F508del OCs was found compared to non-CF healthy OCs after a 21-days culture period. We hypothesize that defective maturation of F508del-OCs precursor monocytes associated with high S1 P production in the bone environment might contribute to low bone mineral density observed in the CF population.

【 授权许可】

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