Background/Purpose: Despite tumor necrosis factor (TNF) inhibitors and Jak kinase inhibitors (JKI) have shown a significant advance in the treatment of rheumatoid arthritis (RA) however, only 20 to 30% of patients experience remission. Recently, we identified that moart, whose expression is markedly elevated at a late phase of osteoclast differentiation, is a keymembrane organizer of osteoclast multinucleation. Knockout mice lacking the entire moart gene dramatically reduced a bone loss in an ovariectomized mouse model. In this study, we investigated the therapeutic effects of MP2021, a competitive inhibitor of MOART, in a mouse model of collagen-induced arthritis (CIA).

Methods: To induce CIA, DBA/1J mice (n = 10 per group) were immunized subcutaneously at the tail with chicken type II collagen on days 0 and 14. Mouse MP2021, human MP2021, control IgG-Fc or TNFR2-Fc fusion protein (etanercept) were injected subcutaneously twice a week after the onset of CIA (therapeutic treatment). Clinical arthritis scores were measured by summing the scores of all four paws. Disease progression was monitored daily, and cytokines and histologic analysis (synovial inflammation, joint damage, and bone loss) were measured by ELISA, IHC, and microCT at the end of the study.

Results: Clinical arthritis scores and morphological signs of bone destruction improved in the mMP2021-treated group compared to IgG-Fc. Expression levels of IL-1b, IL-6, TNFa, COMP, MMP-3, and MMP-13 were significantly reduced in the articular bones of mice treated with mMP2021. Histologic analysis also showed that mMP2021 inhibited bone damage by inhibiting synovitis, synovial formation, and chondrolysis, and significantly reduced the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts. hMP2021 administered subcutaneously to CIA mice also showed more inhibitory effects on clinical arthritis scores than etanercept. The hMP2021 showed equivalent effects when administered intravenously or subcutaneously, which is a promising result for the clinical application of this molecule.

Conclusion: We found that human MP2021 as well as mouse MP2021 significantly inhibited cartilage damage and bone erosion in established mouse CIA models, along with a reduction in multinucleated osteoclasts. These findings suggest that MP2021 has potential as a novel therapeutic agent that can be effectively applied to various bone and joint diseases, including rheumatoid arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-competitive-inhibitor-of-moart-showed-potent-therapeutic-effects-in-a-mouse-model-of-collagen-induced-arthritis/