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1. Efficacy of abatacept in patients with rheumatoid arthritis, as assessed by magnetic resonance imaging of bilateral hands

Author

Satoshi Morita, Hirotoshi Ito, Takahiro Seno, Y. Kukida, Masataka Kohno, Ken Murakami, Toshifumi Sugitani, Hiroyoshi Fujiwara, Amane Nakabayashi, Yutaka Kawahito, Takashi Kida, Hidetake Nagahara, Ryo Oda, Risa Sagawa, Akiko Kasahara, and Takuya Inoue

Subjects
Male, musculoskeletal diseases, 0301 basic medicine, medicine.medical_specialty, Time Factors, Hand Joints, Abatacept, Arthritis, Rheumatoid, Disability Evaluation, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Predictive Value of Tests, Synovitis, medicine, Clinical endpoint, Humans, In patient, Prospective Studies, Prospective cohort study, Osteitis, Aged, 030203 arthritis & rheumatology, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Surgery, Treatment Outcome, 030104 developmental biology, Antirheumatic Agents, Rheumatoid arthritis, Administration, Intravenous, Female, Radiology, business, medicine.drug
Abstract

Aim To examine the efficacy of abatacept in patients with rheumatoid arthritis (RA) using magnetic resonance imaging (MRI) of bilateral hands. Method This prospective study included 35 RA patients. MRI of bilateral hands was performed at baseline and after 12 months of treatment with intravenous abatacept. MRI images were scored for synovitis, osteitis, erosion and joint space narrowing (JSN) according to the RA MRI Scoring System (RAMRIS). The primary endpoint was the change in RAMRIS score from baseline. Repair of erosion was defined as a negative change in the erosion score that was greater than the smallest detectable changes (SDCs). Results Thirty-one patients completed the study. Median synovitis and osteitis scores showed statistically significant reductions at Month 12 when compared to baseline (synovitis score, −5.5 [P

Published
2017

2. Monocarboxylate Transporter 4, Associated With the Acidification of Synovial Fluid, Is a Novel Therapeutic Target for Inflammatory Arthritis

Author

Hidetake Nagahara, Ryo Oda, Osam Mazda, Eishi Ashihara, Akika Ejima, Wataru Fujii, Y. Kukida, Tsunao Kishida, Daigo Taniguchi, Yutaka Kawahito, Takahiro Seno, Hiroyoshi Fujiwara, Aihiro Yamamoto, and Masataka Kohno

Subjects
musculoskeletal diseases, Small interfering RNA, Gene knockdown, biology, Chemistry, Inflammatory arthritis, Immunology, Arthritis, Osteoarthritis, medicine.disease, Rheumatology, Monocarboxylate transporter 4, biology.protein, medicine, Cancer research, Extracellular, Immunology and Allergy, Synovial fluid
Abstract

Objective Synovial fluid pH is decreased in patients with rheumatoid arthritis (RA); however, the underlying mechanisms are unclear. We undertook this study to examine the mechanism by which synovial fluid pH is regulated and to explore the possibility of a therapeutic strategy by manipulating this mechanism. Methods We determined the pH and lactate concentration in synovial fluid from 16 RA patients. Cultured synovial fibroblasts (SFs) from the inflamed joints of 9 RA patients (RASFs) were examined for the expression of ion transporters that regulate intracellular and extracellular pH. The ion transporter up-regulated in RASF lines was then suppressed in RASFs by small interfering RNA (siRNA), and the effect of transfection on viability and proliferation was investigated. Finally, we examined the therapeutic effect of electrotransfer of monocarboxylate transporter 4 (MCT4)–specific siRNA into the articular synovium of mice with collagen-induced arthritis (CIA). Results Synovial fluid pH correlated inversely with both the Disease Activity Score in 28 joints using the C-reactive protein level and the synovial fluid lactate levels. RASFs exhibited up-regulated transcription of MCT4 messenger RNA. MCT4 exported intracellular lactate into the extracellular space. RASFs had significantly higher MCT4 protein levels than did SFs from patients with osteoarthritis. Knockdown of MCT4 induced intrinsic apoptosis of RASFs, thereby inhibiting their proliferation. Moreover, electrotransfer of MCT4-specific siRNA into the articular synovium of mice with CIA significantly reduced the severity of arthritis. Conclusion RA activity correlated with decreased synovial fluid pH. This may be due to increased MCT4 expression in RASFs. Silencing MCT4 induced apoptosis in RASFs and reduced the severity of CIA, suggesting that MCT4 is a potential therapeutic target for inflammatory arthritis.

Published
2015

3. Monocarboxylate transporter 4, associated with the acidification of synovial fluid, is a novel therapeutic target for inflammatory arthritis.

Author

Fujii W, Kawahito Y, Nagahara H, Kukida Y, Seno T, Yamamoto A, Kohno M, Oda R, Taniguchi D, Fujiwara H, Ejima A, Kishida T, Mazda O, and Ashihara E

Subjects
Aged, Animals, Apoptosis genetics, Arthritis, Experimental genetics, Arthritis, Rheumatoid drug therapy, Arthritis, Rheumatoid genetics, Cartilage, Articular metabolism, Female, Humans, Hydrogen-Ion Concentration, Lactic Acid metabolism, Male, Mice, Middle Aged, Monocarboxylic Acid Transporters genetics, Muscle Proteins genetics, RNA, Small Interfering, Signal Transduction genetics, Transfection, Arthritis, Experimental metabolism, Arthritis, Rheumatoid metabolism, Monocarboxylic Acid Transporters metabolism, Muscle Proteins metabolism, Synovial Fluid metabolism, Synovial Membrane metabolism
Abstract

Objective: Synovial fluid pH is decreased in patients with rheumatoid arthritis (RA); however, the underlying mechanisms are unclear. We undertook this study to examine the mechanism by which synovial fluid pH is regulated and to explore the possibility of a therapeutic strategy by manipulating this mechanism., Methods: We determined the pH and lactate concentration in synovial fluid from 16 RA patients. Cultured synovial fibroblasts (SFs) from the inflamed joints of 9 RA patients (RASFs) were examined for the expression of ion transporters that regulate intracellular and extracellular pH. The ion transporter up-regulated in RASF lines was then suppressed in RASFs by small interfering RNA (siRNA), and the effect of transfection on viability and proliferation was investigated. Finally, we examined the therapeutic effect of electrotransfer of monocarboxylate transporter 4 (MCT4)-specific siRNA into the articular synovium of mice with collagen-induced arthritis (CIA)., Results: Synovial fluid pH correlated inversely with both the Disease Activity Score in 28 joints using the C-reactive protein level and the synovial fluid lactate levels. RASFs exhibited up-regulated transcription of MCT4 messenger RNA. MCT4 exported intracellular lactate into the extracellular space. RASFs had significantly higher MCT4 protein levels than did SFs from patients with osteoarthritis. Knockdown of MCT4 induced intrinsic apoptosis of RASFs, thereby inhibiting their proliferation. Moreover, electrotransfer of MCT4-specific siRNA into the articular synovium of mice with CIA significantly reduced the severity of arthritis., Conclusion: RA activity correlated with decreased synovial fluid pH. This may be due to increased MCT4 expression in RASFs. Silencing MCT4 induced apoptosis in RASFs and reduced the severity of CIA, suggesting that MCT4 is a potential therapeutic target for inflammatory arthritis., (© 2015, American College of Rheumatology.)

Published
2015
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