Mucosa-associated lymphoid tissue lymphoma translocation 1 as a novel therapeutic target for rheumatoid arthritis

Chang Hoon Lee,Su Jeong Bae,Miok Kim

doi:10.1038/s41598-017-12349-9

Abstract

Emerging evidence suggests that mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) is a key regulator of inflammatory diseases; however, the pathological role of MALT1 in rheumatoid arthritis (RA) is not well understood. Consequently, this protein has not been therapeutically targeted for the treatment of RA. MALT1 plays a role in the paracaspase pathway, has proteolytic activity and is involved in the regulation of inflammatory responses. In this study, we found that the MALT1-targeting inhibitory small molecule, MALT1 selective inhibitor 2-chloro-N-[4-[5-(3,4-dichlorophenyl)-3-(2-methoxyethoxy)-1H-1,2,4-triazol-1-yl]phenylacetamide (MI-2) strongly suppresses the differentiation of monocytes into osteoclasts in the absence or presence of the inflammatory cytokine tumour necrosis factor α. Furthermore, MI-2 ameliorates pathologic bone erosion and synovitis in an in vivo mouse model of collagen-induced arthritis. Mechanistically, MI-2 blocked expression of the master osteoclast regulator – nuclear factor of activated T cells 1 (NFATc1) – by inhibiting nuclear factor κB (NF-κB), which is a critical regulator of NFATc1. These findings highlight the important regulatory role of MALT1 in the NF-κB–NFATc1-signalling axis during osteoclastogenesis and suggest that targeting MALT1 is a promising treatment option for rheumatoid arthritis.

Highlights

Rheumatoid arthritis (RA) is a chronic inflammatory disease that is characterised by joint destruction caused by infiltrating leukocytes, such as monocytes
mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) is a part of the paracaspase pathway and has proteolytic activity[9,10]
Because many MALT1 substrates are involved in regulating inflammatory responses, the protease activity of MALT1 has emerged as an interesting therapeutic target

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disease that is characterised by joint destruction caused by infiltrating leukocytes, such as monocytes. The cause of RA is not clear; the aggravation of RA symptoms is currently thought to be caused by an increased number of osteoclasts in the joints of RA patients, which may be due to the differentiation of infiltrating monocytes[4,5]. Blocking the differentiation of monocytes into osteoclasts could represent a novel effective therapeutic approach for RA. The effects of a selective MALT1 inhibitor, on the differentiation of monocytes into osteoclasts was evaluated to assess the role of MALT1 in RA. ABC-DLBCL cell lines in vitro and xeno-transplanted ABC-DLBCL tumours in vivo Those effects are thought to be caused by the irreversible inhibited cleavage of MALT1 substrates[11]. The findings of this study provide important insights into the potential of MALT1 as a novel therapeutic target and the applicability of MI-2 or other selective MALT1 inhibitors for treating RA

Methods

Results

Conclusion