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

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 ?. 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 ?B (NF-?B), which is a critical regulator of NFATc1. These findings highlight the important regulatory role of MALT1 in the NF-?B-NFATc1-signalling axis during osteoclastogenesis and suggest that targeting MALT1 is a promising treatment option for rheumatoid arthritis.

SUBMITTER: Lee CH

PROVIDER: S-EPMC5605699 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Lee Chang Hoon CH Bae Su Jeong SJ Kim Miok M

Scientific reports 20170919 1

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-t ...[more]

PMID: 28928392

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Project description:BackgroundMucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) correlates with treatment outcomes in inflammatory bowel disease and rheumatoid arthritis (RA). This study aimed to further evaluate the MALT1 longitudinal change and its relationship with tumor necrosis factor inhibitors (TNFi) response in RA patients.MethodsSeventy-one RA patients receiving TNFi [etanercept (n = 42) or adalimumab (n = 29)] were enrolled. MALT1 was detected by RT-qPCR in peripheral blood samples of RA patients before treatment (W0), at week (W)4, W12, and W24 after treatment. RA patients were divided into response/non-response, remission/non-remission patients according to their treatment outcome at W24. Meanwhile, MALT1 was also detected by RT-qPCR in 30 osteoarthritis patients and 30 healthy controls (HCs).ResultsMucosa-associated lymphoid tissue lymphoma translocation protein 1 was elevated in RA patients compared with HCs (Z=-6.392, p < 0.001) and osteoarthritis patients (Z = -5.020, p < 0.001). In RA patients, MALT1 was positively correlated with C-reactive protein (rs = 0.347, p = 0.003), but not other clinical characteristics, treatment history, or current TNFi category. Meanwhile, MALT1 decreased from W0 to W12 in total RA patients (x2 = 86.455, p < 0.001), etanercept subgroup (x2 = 46.636, p < 0.001), and adalimumab subgroup (x2 = 41.291, p < 0.001). Moreover, MALT1 at W24 (p = 0.012) was decreased in response patients compared with non-response patients; MALT1 at W12 (p = 0.027) and W24 (p = 0.010) were reduced in remission patients than non-remission patients. In etanercept subgroup, MALT1 at W24 (p = 0.013) was decreased in response patients compared with non-response patients. In adalimumab subgroup, MALT1 at W24 (p = 0.015) was lower in remission patients than non-remission patients.ConclusionMucosa-associated lymphoid tissue lymphoma translocation protein 1 reduction after treatment is associated with response and remission to TNFi in RA patients.

Project description:BackgroundMucosa-associated lymphoid tissue (MALT) lymphoma is an extranodal lymphoma with an indolent natural course. The thyroid gland is an uncommon site of involvement. We aimed to investigate serial ultrasound features and the disease progression during the clinical course of thyroid MALT lymphoma.MethodsWe searched our hospital's pathology database (5,418 patients with thyroid malignancy) between January 2000 and July 2022. The medical records and serial ultrasounds of 11 patients with 12 thyroid MALT lymphoma foci were analyzed retrospectively.ResultsAn enlarging neck mass, dyspnea, B symptoms, and neck lymphadenopathy were seen at diagnosis in 9 (9/11, 81.8%), 3 (3/11, 27.3%), 2 (2/11, 18.2%), and 9 (9/11, 81.8%) cases, respectively. Eleven cases were concomitant Hashimoto thyroiditis. Common ultrasound features included bilateral or unilateral asymmetric goiter or large, solid, and very hypoechoic nodules (11/12, 91.7%) interspersed with linear, reticular hyperechoic, and enhanced posterior echoes (11/12, 91.7%), and neck lymph node involvement (10/11, 90.9%). The Thyroid Imaging and Reporting Data System (TIRADS) categories showed higher diagnostic accuracy (11/12, 91.7%) than real-time ultrasound (2/12, 16.7%) in evaluating thyroid lesions for recommendation of fine-needle aspiration (FNA). Serial ultrasound showed self-limiting changes in three cases, relapse in three cases after subtotal thyroidectomy and chemotherapy, large cell transformation (LCT) in one case after left lobectomy, partial remission in one case, and complete remission after chemo/radiation in four cases; progression to enlarged thyroid nodules occurred in three cases without treatment, with no obvious change observed after diagnosis. Three patients died during follow-up.ConclusionOn sonograms, solid large thyroid nodules or goiter with very hypoechoic and enhanced posterior echoes in the setting of Hashimoto thyroiditis should raise suspicion for MALT lymphoma. TIRADS categories can improve the ultrasound diagnostic efficacy for malignancy. Serial ultrasound examinations demonstrated self-limiting and indolent natures of thyroid MALT lymphoma.

Dataset Information

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

Publications

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

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