SAT0005 INHIBITION OF HEPATOCYTE GROWTH FACTOR/C-MET SIGNALING ABROGATES JOINT DESTRUCTION BY SUPPRESSING MIGRATION OF MONOCYTES TO SYNOVIUM IN RHEUMATOID ARTHRITIS
Authors: M. Hosonuma, N. Sakai, H. Furuya, Y. Tsubokura, S. Nishimi, Y. Ikari, S. Ishii, A. Maeoka, T. Tokunaga, K. Wakabayashi, T. Kasama, M. Takami, T. Isozaki
Journal: Annals of the Rheumatic Diseases (2020)

Background: Hepatocyte growth factor (HGF), originally discovered as a mitogen of hepatocytes, binds to receptor-tyrosine kinase c-Met and has been shown to be a multi-functional cytokine that promotes processes such as cell proliferation, survival, differentiation, migration, and angiogenesis 1 . Since HGF/c-Met signaling also leads to tumorigenesis and cancer invasion, that has recently attracted attention as a target for anticancer agents 2 . However, in reports of rheumatoid arthritis (RA), though anti-inflammatory and antiangiogenic mechanisms related to HGF/c-Met signal inhibition have been reported, the role of HGF in RA bone destruction through monocyte migration remains unclear 3 . Objectives: To determine the expression of HGF in RA biological fluids, the role it plays in monocyte migration and the therapeutic effect of a savolitinib, a specific c-Met inhibitor, in arthritis model mice. Methods: HGF/c-Met expression in serum, synovial fluid (SF), and synovial tissues (STs) obtained from RA patients and control subjects, as well as RA fibroblast-like synoviocytes (FLSs) was evaluated by ELISA and immunostaining. To determine the function of HGF in RA SFs, we preincubated RA SFs with a neutralizing anti-HGF antibody and measured the ability of these SFs to induce the human acute monocytic leukemia cell line (THP-1) chemotaxis. Additionally, examinations of SKG mice treated with savolitinib (2.5 mg/kg/day) for 4 weeks were conducted. Results: HGF level in serum from RA patients was significantly higher as compared to the controls (930 ± 97 vs. 476 ± 97 pg/mL, p &lt;0.01) and decreased by drug treatment for 24 weeks (1147 ± 284 vs. 539 ± 160 pg/mL, p &lt;0.05). Additionally, HGF level in SF from RA patients was higher as compared to SF from osteoarthritis patients (1632 ± 366 vs. 566 ± 140 pg/mL, p &lt;0.05). HGF and c-Met expressions were also noted in RA STs. Stimulation of RA-FLS with TNF-α increased HGF/c-Met expression in a concentration-dependent manner, and c-Met signal inhibition by SU11274 suppressed production of fractalkine/CX3CL1, CXCL16, and MIP-1α/CCL3 (mean 50%, 56%, 90%, respectively). When HGF was removed by immunoprecipitation, migration of THP-1 in RA-SF was suppressed (mean 23%). In SKG mice, savolitinib significantly suppressed ankle bone damage on µCT, with an associated reduction in number of tartrate-resistant acid phosphatase-positive osteoclasts. Conclusion: HGF is produced by inflammation in synovium associated with RA, and then activates monocyte migration to synovium tissue and promotes bone destruction through its own chemotactic effect as well as enhanced chemokine production. These results indicate that a strategy that targets c-Met signaling may be important for resolving bone destruction in RA. References: [1] Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A, Tashiro K, Shimizu S. Molecular cloning and expression of human hepatocyte growth factor. Nature. 1989 Nov 23;342(6248):440-3 [2] Lee D, Sung ES, Ahn JH, An S, Huh J, You WK. Development of antibody-based c-Met inhibitors for targeted cancer therapy. Immunotargets Ther. 2015 Feb 9;4:35-44. [3] Koch AE, Halloran MM, Hosaka S, Shah MR, Haskell CJ, Baker SK, Panos RJ, Haines GK, Bennett GL, Pope RM, Ferrara N. Hepatocyte growth factor. A cytokine mediating endothelial migration in inflammatory arthritis. Arthritis Rheum. 1996 Sep;39(9):1566-75 Disclosure of Interests: None declared