Background/Purpose: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction. Filgotinib is a selective small molecule inhibitor of JAK 1 enzymes, and is currently in clinical development for the treatment of rheumatoid arthritis (RA). However, a direct role of filgotinib for osteogenesis has not been demonstrated. Here, we examined filgotinib inhibited monocyte differentiation and proinflammatoly cytokine production in osteoblasts.

Methods: To determine if the JAK-STAT enzyme was expressed in RA osteoblasts and MG63 (human osteosarcoma cell line), we performed immunohistochemistry. In order to confirm that filgotinib inhibited STAT signaling phosphorylation, interleukin (IL)-6 and IL-6 receptor (IL-6R) stimulated MG63 was used for western blotting. To determine whether filgotinib was involved in proinflammatoly cytokine production, monocyte chemotactic protein-1(MCP-1)/CCL2, IL-8/CXCL8, receptor activator for nuclear factor -κB ligand (RANKL) and CXCL16 in filgotinib treated MG63 conditioned medium was measured using enzyme-linked immunosorbent assay (ELISA). Finally, to confirm if monocyte was differentiated with filgotinib, THP-1 (human acute monocytic leukemia cell line) was cultured with filgotinib treated MG63 conditioned medium.

Results: JAK1, 2 and 3 was expressed in osteoblast and MG63. We found that phosphorylated STAT1 and STAT3 signaling in IL-6 and IL-6R stimulated filgotinib treated MG63 was significantly decreased at 10 minutes compared to nontreated MG63. MCP-1/CCL2 in filgotinib treated MG63 conditioned medium was significantly decreased compared with in nontreated MG63 conditioned medium (12.8 ± 0.6 pg/ml and 41.6 ± 0.0 pg/ml, p< 0.05, respectively). CXCL16 in in filgotinib treated MG63 conditioned medium was also significantly decreased compared with in nontreated MG63 conditioned medium (12.8 ± 0.6 pg/ml and 41.6 ± 0.0 pg/ml, p< 0.05, respectively). Additionally, THP-1 with IL-6 and IL-6R treated MG63 conditioned medium differentiated into multinuclear cells. On the other hand, THP-1 with filgotinib treated MG63 conditioned medium did not differentiate into multinuclear cells.

Conclusion: Filgotinib inhibited proinflammatory cytokine production and monocyte differentiation. These data indicate that filgotinib acts on bone metabolism, suggesting that filgotinib may prevent bone destruction.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/filgotinib-inhibits-monocyte-differentiation-and-pro-inflammatoly-cytokine-production-in-osteoblasts/