JTE-952 Suppresses Bone Destruction in Collagen-Induced Arthritis in Mice by Inhibiting Colony Stimulating Factor 1 Receptor.

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and structural destruction of the joints. Bone damage occurs in an early stage after onset and osteoclast activation plays a substantial role in its progression. Colony stimulating factor 1 receptor (CSF1R) is a receptor protein tyrosine kinase specifically expressed in monocytic-lineage cells such as macrophages and osteoclasts. Here, we investigated the effect of JTE-952, a novel CSF1R tyrosine kinase inhibitor, on osteoclast formation in vitro and on bone destruction in a mouse model of collagen-induced arthritis. JTE-952 completely inhibited osteoclast differentiation from human monocytes, with an IC50 of 2.8 nmol/L, and reduced osteoclast formation from the synovial cells of RA patients. Detectable levels of colony stimulating factor 1 (CSF1), a ligand of CSF1R, were observed in the synovial tissues of the arthritis model, similar to those observed in the pathology of human RA. JTE-952 significantly suppressed increases in the bone destruction score, the number of tartrate-resistant-acid-phosphatase-positive cells, and the severity of arthritis in the model mice. We also examined the efficacy of JTE-952 combined with methotrexate. This combination therapy more effectively reduced the severity of bone destruction and arthritis than monotherapy with either agent alone. In summary, JTE-952 potently inhibited human osteoclast formation in vitro and suppressed bone destruction in an experimental arthritis model, especially when combined with methotrexate. These results indicate that JTE-952 should strongly inhibit bone destruction and joint inflammation in RA patients and effectively prevent the progression of the structural destruction of joints.

• Authors: Naofumi Uesato, Koji Inagaki, Naoki Miyagawa, Yoshihiro Kitagawa, Reina Kakefuda, Yushi Matsuo, Takayuki Yamaguchi, Takahiro Hata, Kazutaka Ikegashira, Mutsuyoshi Matsushita
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 43 Issue 12 Pg. 1884-1892 ( 2020) ISSN: 1347-5215 [Electronic] Japan
• PMID: 33268706 (Publication Type: Journal Article)

Chemical References

• Azetidines
• Csf1r protein, mouse
• JTE-952
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Animals
• Arthritis, Experimental (drug therapy, metabolism, pathology)
• Azetidines (pharmacology, therapeutic use)
• Bone Density (drug effects, physiology)
• Dose-Response Relationship, Drug
• Humans
• Male
• Mice
• Mice, Inbred DBA
• Osteoclasts (drug effects, metabolism, pathology)
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor (antagonists & inhibitors, metabolism)
• Synovial Membrane (drug effects, metabolism, pathology)