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A3665 - Cystic Fibrosis Related Bone Disease - Alterations in Blood Monocytes of G551D-Bearing Cystic Fibrosis Patients Undergoing Treatment with Ivacaftor
Author Block: J. Jacquot1, D. Abdallah1, M. Jourdain1, C. Guillaume1, N. Ronan2, Y. McCarthy3, E. Flanagan3, B. Plant3, F. Velard1; 1University Reims Champagne Ardenne, EA4691, BIOS, Reims, France, 2Respiratory, Cork Cystic Fibrosis Centre, Cork University Hospital, University College Cork, Ireland, Cork, Ireland, 3Cork Cystic Fibrosis Centre, Cork University Hospital, University College Cork, Ireland, Cork, Ireland.
Rationale: Bone fragility and low bone mineral density often affect children and young adults with cystic fibrosis (CF) disease and is associated with significant morbidity due to vertebral fractures and decreased lung function (Jacquot J et al., Osteoporos Int, 2016). We recently reported that bone demineralization is improved by the CFTR potentiator ivacaftor in young patients carrying the G551-D CFTR mutation (Sermet-Gaudelus I et al., J Cystic Fibros, 2016). Due to the presence of CFTR in monocytes, we hypothesized that ivacaftor may impact monocyte differentiation and activation. Monocyte osteoclast precursors fuse and differentiate to form bone-resorbing multinuclear osteoclasts upon stimulation by two essential factors, the monocyte/macrophage colony stimulating factor (M-CSF) and the receptor activator of NF-kB ligand (RANKL). Methods: We examined the expression level of M-CSFR and RANK receptors on blood monocytes from G551-D CF patients by flow cytometry, prior to and at six and nine months after receiving CFTR potentiator ivacaftor. Results: Compared to healthy controls, our first set of data demonstrates higher level of a double M-CSFRhigh/RANKhigh subpopulation on monocyte of G551-D CF patients, which was reduced by in vivo ivacaftor treatment. In addition, expression of both M-CSFR and RANK receptors (more predominantly for the RANK receptor) reported by unit of monocytic cells was markedly decreased by in vivo ivacaftor treatment. Moreover, we examined ex vivo differentiation and activation of healthy monocytes into osteoclasts for a 14-days period with/or without the addition of Inh-172 drug, an inhibitor of CFTR chloride channel activity. Interestingly, multinuclear osteoclasts derived from Inh172-treated healthy monocytes were largest, more adherent, and were prone to generate large pits and trenches of dentin resorption. In addition, multinuclear osteoclasts derived Inh172-treated healthy monocytes released a very low level of bioactive lipid mediator sphingosine 1-phosphate (S1P), a key mediator in the directed migration of osteoblast/osteoclast precursors attached to the bone surface. Conclusion: Altogether, these data highlight the critical regulatory role of CFTR in M-CSFR and RANK receptors expression in monocytes, and suggest CF bone disease as a new, cell-type-monocyte dysfunction disease, providing new insights into the pathogenesis of CF bone disease. D. A. is a postdoctoral fellow of French Association Vaincre la Mucoviscidose, Paris, France; Vaincre la Mucoviscidose and Vertex Inc. provided funding supports.