ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2132

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

Wataru Fujii1, Eishi Ashihara2, Hidetake Nagahara3, Yuji Kukida1, Takahiro Seno1,4, Aihiro Yamamoto1, Masataka Kohno1, Ryo Oda5, Daigo Taniguchi6, Hiroyoshi Fujiwara5, Tsunao Kishida7, Osam Mazda7 and Yutaka Kawahito1, 1Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan, 2Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto, Japan, 3Department of Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan, 4Department of Rheumatic Diseases and Joint Function, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan, 5Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, kyoto, Japan, 6Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan, 7Department of Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords:

Session Information

Date: Monday, November 9, 2015

Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis II

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Synovial fluid pH is decreased in patients with rheumatoid
arthritis (RA); however, the underlying mechanisms are unclear. Here, we examined the mechanism by which synovial fluid pH is regulated and explore the
therapeutic strategy by manipulating this mechanism.

Methods: The pH and lactate concentration in synovial fluid
from RA and osteoarthritis (OA) patients were determined. Cultured synovial
fibroblasts (SFs) from the inflamed joints of patients with RA (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 electro-transfer of MCT4-specific siRNA into the articular synovium
of collagen-induced
arthritis (CIA) mice.

Results: The synovial fluid from RA patients had significantly lower pH
(p < 0.01) and higher lactate values (p < 0.05),
respectively, than the
synovial fluid from
OA patients (Figure 1A). Synovial fluid pH correlated inversely with both the patient
disease activity score (DAS)-28 CRP (r = -0.51, p < 0.05, Figure 1B) and synovial fluid lactate levels (r =
-0.71, p < 0.01, Figure 1C). RASFs exhibited up-regulated transcription of monocarboxylate transporter (MCT) 4 mRNA. MCT4 exports
intracellular lactate into the extracellular space. RASFs had significantly higher MCT4 protein
levels than osteoarthritis synovial
fibroblasts. Knockdown of MCT4
induced RASF apoptosis (Figure
2), thereby inhibiting their proliferation. Moreover, electro-transfer of MCT4-specific siRNA into the articular synovium of CIA mice significantly reduced the
severity of arthritis (p
< 0.05, Figure 3).

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.

Figure 1


Figure 2


Figure 3


Disclosure: W. Fujii, None; E. Ashihara, None; H. Nagahara, None; Y. Kukida, None; T. Seno, None; A. Yamamoto, None; M. Kohno, None; R. Oda, None; D. Taniguchi, None; H. Fujiwara, None; T. Kishida, None; O. Mazda, None; Y. Kawahito, None.

To cite this abstract in AMA style:

Fujii W, Ashihara E, Nagahara H, Kukida Y, Seno T, Yamamoto A, Kohno M, Oda R, Taniguchi D, Fujiwara H, Kishida T, Mazda O, Kawahito Y. Monocarboxylate Transporter 4, Associated with the Acidification of Synovial Fluid, Is a Novel Therapeutic Target for Inflammatory Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/monocarboxylate-transporter-4-associated-with-the-acidification-of-synovial-fluid-is-a-novel-therapeutic-target-for-inflammatory-arthritis/. Accessed .

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