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.

患有囊性纤维化（CF）病的患者公认骨质减少和骨折率增加。在CF病理学中，F508del是最常见的CFTR突变，超过85％的患者至少将其携带一个等位基因。CFTR的潜在分子缺陷是由破骨细胞形成过程中的F508del-CFTR突变引起的，也就是来自外周血单核细胞（PBMC）的破骨细胞（OCs）的产生和骨吸收活性。因此，我们调查了F508del突变是否会影响从15名患有F508del-CFTR突变的成年患者收集的PBMC的破骨细胞能力，以调节其骨吸收能力和OCs产生的鞘氨醇-1-磷酸（S1P）的水平，骨矿物质密度和形成的关键因素。在本研究中，与7-14天培养期后的13名受试者的非CF健康PBMC相比，发现CF-F508del PBMCs向CF-F508del OCs的缺陷分化，每个OC的核数没有任何显着差异。我们观察到在存在CFTR氯化物电导选择性抑制剂（CFTR-Inh）的情况下形成的非CF健康OC的数量减少了₁₇₂）。我们有关OCs吸收性功能的数据表明，OCs中CFTR氯化物活性的丧失导致其沟槽吸收模式显着降低。培养21天后，与非CF健康OC相比，CF-F508del OC的S1P释放增加了7倍。我们假设在骨骼环境中与高S1P产生相关的F508del-OCs前体单核细胞的成熟缺陷可能会导致CF人群中骨矿物质密度降低。