POS1042 JANUS KINASE INHIBITOR SUPPRESSES THE DIFFERENTIATION AND FUNCTION OF TUMOR NECROSIS FACTOR-ALPHA AND INTERLEUKIN-6- INDUCED OSTEOCLASTS IN PERIPHERAL BLOOD MONOCYTES FROM PATIENTS WITH RHEUMATOID ARTHRITIS

Abstract

BackgroundWe have previously reported that stimulation of mouse bone marrow–derived macrophages with tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) induces differentiation of osteoclast-like cells having bone resorption ability[1]. Recently, we have shown that the combination of TNF-α and IL-6 can induce osteoclasts (OCs) from human peripheral blood mononuclear cells (PBMCs) via receptor activator of nuclear factor kappa-B ligand (RANKL)-independent pathways, and that there are functional differences between TNF-α and IL-6-induced OCs and RANKL-induced OCs. In particular, the number of TNF-α and IL-6-induced OCs differentiated from PBMCs in patients with rheumatoid arthritis (RA) positively correlated with the modified total Sharp score (mTSS). On the other hands, no such correlation was observed between the number of RANKL-induced OCs from RA PBMCs and mTSS[2].ObjectivesWe undertook this study to clarify whether Janus kinase (JAK) inhibitors, a new class of disease modifying anti-rheumatic drugs, could inhibit the differentiation and function of TNF-α and IL-6-induced OCs using peripheral blood monocytes (PBMs) derived from patients with RA.MethodsPBMs derived from RA patients and healthy donors were stimulated by TNF-α and IL-6 or RANKL with or without 10-1000 nM filgotinib, a JAK inhibitor. The number of tartrate-resistant acid phosphatase-positive multinucleated cells induced by TNF-α and IL-6 or RANKL and bone resorption activity using a pit formation assay were assessed. The examination was the number of TNF-α and IL-6-induced or RANKL-induced OCs differentiated from PBMs in RA patients before and 6 months after treatment with filgotinib.ResultsThe number of TNF-α and IL-6–induced OCs and RANKL-induced OCs derived from PBMs in patients with RA was significantly increased compared to that derived from PBMCs in healthy donors (n = 5 each). Addition of filgotinibin vitrosignificantly inhibited the differentiation of TNF-α and IL-6-induced OCs derived from PBMs of RA patients in a dose-dependent manner. The same concentrations of filgotinib did not inhibit osteoclastogenesis induce by RANKL. Stimulation of RA PBMs by TNF-α and IL-6 in the presence of filgotinib significantly inhibited generation of resorption pits on dentin slices compared to findings in those PBMs in the absence of filgotinib. In contrast, stimulation of RA PBMs by RANKL with filgotinib showed generation of resorption pits in a manner similar to those generated by RANKL without filgotinib. Six months after treatment with filgotinib, the number of TNF-α and IL-6-induced OCs differentiated from PBMs was significantly decreased compared with those of before the treatment, whereas no significant change in the number of RANKL-induced OCs was observed in the same patients (Figure 1).ConclusionOur results suggest that the prevention effect of progressive bone destruction by JAK inhibitor in RA patients may involve inhibition of TNF-α and IL-6-induced OC differentiation, as well as suppression of osteoclastic bone resorption activity.