Background/Purpose: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and joint destruction. Among the therapeutic strategies available, Janus kinase (JAK) inhibitors have emerged as an important class of targeted treatments. Currently, five JAK inhibitors are approved for RA treatment in Japan. While their immunomodulatory effects are well-established, their influence on bone metabolism, particularly osteoblast differentiation, remains unclear. This study investigates the effects of different JAK inhibitors on osteoblast differentiation using an in vitro model.

Methods: To assess the impact of JAK inhibitors on osteoblast differentiation, mouse MC3T3-E1 pre-osteoblast cells were cultured in the presence of various JAK inhibitors, specifically Baricitinib (Bari), Peficitinib (Pefi), and Filgotinib (Filgo). The degree of osteoblast maturation was evaluated using Alizarin Red S staining, which detects calcium deposits indicative of mineralized bone matrix, and alkaline phosphatase staining, a marker of osteogenic differentiation. Additionally, the expression of key osteoblast differentiation markers was analyzed to determine molecular correlations with differentiation patterns.

Results: The study revealed distinct effects of different JAK inhibitors on osteoblast differentiation. Bari and Pefi: Both exhibited inhibitory effects on osteoblast maturation, with Bari demonstrating a particularly strong suppression of differentiation. Cells treated with these inhibitors showed reduced mineralization in Alizarin Red S staining and lower alkaline phosphatase activity. Filgo: Unlike Bari and Pefi, Filgo did not inhibit osteoblast differentiation. Even at high concentrations, osteoblasts successfully matured, displaying significant mineralization. Expression of Osterix, a critical transcription factor for osteoblast differentiation, was notably observed in Filgo-treated cells, further supporting its lack of inhibitory effects. FOXM1 Expression: In Filgo-treated cells and control groups, FOXM1 expression increased, suggesting its potential role in osteoblast differentiation. Conversely, FOXM1 levels remained unchanged in cells exposed to Bari and Pefi, reinforcing the hypothesis that JAK signaling influences osteoblast maturation through FOXM1-mediated pathways.

Conclusion: These findings indicate that JAK inhibitors exert differential effects on osteoblast differentiation. Bari and Pefi demonstrated inhibitory activity, whereas Filgo did not affect osteoblast maturation. Furthermore, the regulation of FOXM1 expression by JAK signaling suggests a possible mechanistic link to osteoblast differentiation, warranting further investigation into its role in bone remodeling and therapeutic implications for RA treatment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effect-of-jak-inhibitors-on-osteoblast-differentiation/