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  • Title: Osteoclastogenesis and sphingosine-1-phosphate secretion from human osteoclast precursor monocytes are modulated by the cystic fibrosis transmembrane conductance regulator.
    Author: Jourdain ML, Sergheraert J, Braux J, Guillaume C, Gangloff SC, Hubert D, Velard F, Jacquot J.
    Journal: Biochim Biophys Acta Mol Basis Dis; 2021 Mar 01; 1867(3):166010. PubMed ID: 33188942.
    Abstract:
    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 F508del-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-Inh172). 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 S1P 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 S1P production in the bone environment might contribute to low bone mineral density observed in the CF population.
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