Treadmill Running Ameliorates Destruction of Articular Cartilage and Subchondral Bone, Not Only Synovitis, in a Rheumatoid Arthritis Rat Model

Shimomura, Seiji; Inoue, Hiroaki; Nakagawa, Shuji; Fujii, Yuta; Kishida, Tsunao; Ichimaru, S.; Tsuchida, Shinji; Shirai, Toshiharu; Ikoma, Kazuya; Mazda, Osam; Kubo, Toshikazu

doi:10.3390/ijms19061653

Cited by 22 publications

(12 citation statements)

References 35 publications

(35 reference statements)

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“…In experimental models of arthritis, it has been confirmed that mechanical stress increase joint inflammation, stimulate the progression and chronicity of arthritis and structural damage [16,17,48]; besides, the mechanical stress decrease the bone quality [16]. In contrast to our findings, other studies in the AIA model have shown an anti-inflammatory effect of PE in some parameters such as synovial hyperplasia [49,50], and joint destruction [51].…”

Section: Discussionsupporting

confidence: 54%

Exercise Exacerbates the Transcriptional Profile of Hypoxia, Oxidative Stress and Inflammation in Rats with Adjuvant-Induced Arthritis

González-Chávez

Quiñonez-Flores

Espino-Solís

et al. 2019

Cells

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Physical exercise (PE) is recommended for Rheumatoid Arthritis (RA), but the molecular and biological mechanisms that impact the inflammatory process and joint destruction in RA remain unknown. The objective of this study was to evaluate the effect of PE on the histological and transcriptional changes in the joints of adjuvant-induced arthritis (AIA) rat model. AIA rats were subjected to PE on a treadmill for eight weeks. The joints were subjected to histological and microarray analysis. The differentially expressed genes (DEGs) by PE in the arthritic rats were obtained from the microarray. The bioinformatic analysis allowed the association of these genes in biological processes and signaling pathways. PE induced the differential expression of 719 genes. The DEGs were significantly associated with pathogenic mechanisms in RA, including HIF-1, VEGF, PI3-Akt, and Jak-STAT signaling pathways, as well as response to oxidative stress and inflammatory response. At a histological level, PE exacerbated joint inflammatory infiltrate and tissue destruction. The PE exacerbated the stressed joint environment aggravating the inflammatory process, the hypoxia, and the oxidative stress, conditions described as detrimental in the RA joints. Research on the effect of PE on the pathogenesis process of RA is still necessary for animal models and human.

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Section: Discussionsupporting

confidence: 54%

Exercise Exacerbates the Transcriptional Profile of Hypoxia, Oxidative Stress and Inflammation in Rats with Adjuvant-Induced Arthritis

González-Chávez

Quiñonez-Flores

Espino-Solís

et al. 2019

Cells

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“…Following past reports, we conducted immunostaining for TNF-α and Cx43 [17]. TNF-α expression was aggravated throughout the synovial membranes, but the level of staining was significantly lower for the T group than for the control group (Figure 3A,C).…”

Section: Resultsmentioning

confidence: 76%

“…We also analyzed the role of Cx43 as a key gene in synovial membrane inflammation in RA. Studies have shown that, in collagen-induced arthritis (CIA) rats, Cx43 induces joint destruction through pro-inflammatory cytokines such as TNF-α and IL-6, and that joint destruction is suppressed not only if Cx43 expression is suppressed in small interfering ribonucleic acid, but also by suppressing Cx43 expression through treadmill running as well [17,23,24]. Cx43 expression changes with mechanical stress such as stretching stimuli and shearing forces in cardiomyocytes and osteocytes [25,26]; therefore, it may also change due to the addition of mechanical stress to the synovial membranes by treadmill running.…”

Section: Discussionmentioning

confidence: 99%

“…Exercise therapy for RA is strongly recommended by a Cochrane review [14], and it has been reported to improve bodily functions and ADL, clinical indicators of joint symptoms, muscle strength, and cardio-pulmonary function [15,16]. In recent years, treadmill running in rat RA models was reported to inhibit the production of connexin 43 (Cx43) and TNF-α in the synovial membranes, as well as prevent the degeneration of articular cartilage and subchondral bone [17]. It was also revealed that exercise therapy inhibits joint destruction through bio-molecular mechanisms by suppressing pro-inflammatory cytokines.…”

Section: Introductionmentioning

confidence: 99%

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Treadmill Running in Established Phase Arthritis Inhibits Joint Destruction in Rat Rheumatoid Arthritis Models

Fujii

Inoue

Shimomura

et al. 2019

IJMS

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Exercise therapy inhibits joint destruction by suppressing pro-inflammatory cytokines. The efficacy of pharmacotherapy for rheumatoid arthritis differs depending on the phase of the disease, but that of exercise therapy for each phase is unknown. We assessed the differences in the efficacy of treadmill running on rheumatoid arthritis at various phases, using rat rheumatoid arthritis models. Rats with collagen-induced arthritis were used as rheumatoid arthritis models, and the phase after immunization was divided as pre-arthritis and established phases. Histologically, the groups with forced treadmill running in the established phase had significantly inhibited joint destruction compared with the other groups. The group with forced treadmill running in only the established phase had significantly better bone morphometry and reduced expression of connexin 43 and tumor necrosis factor α in the synovial membranes compared with the no treadmill group. Furthermore, few cells were positive for cathepsin K immunostaining in the groups with forced treadmill running in the established phase. Our results suggest that the efficacy of exercise therapy may differ depending on rheumatoid arthritis disease activity. Active exercise during phases of decreased disease activity may effectively inhibit arthritis and joint destruction.

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“…It is one of the world's refractory diseases. 1,2) Leflunomide (LEF), a new type of immunomodulator, has been commonly used alone or in combination with methotrexate for the treatment of RA as a kind of disease-modifying anti-rheumatic drugs (DMARDs). 3) LEF is a derivative of isoxazole, which is converted to teriflunomide (TEF, A771726) through the gastrointestinal tract and liver.…”

Section: Introductionmentioning

confidence: 99%

Development and Evaluation of a Water-in-oil Microemulsion Formulation for the Transdermal Drug Delivery of Teriflunomide (A771726)

et al. 2019

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Teriflunomide (TEF, A771726) is the active metabolite of leflunomide (LEF), a disease-modifying antirheumatic drug. The main purpose of this study was to develop and evaluate water-in-oil (W/O) microemulsion formulation of TEF. The W/O microemulsion was optimized formula is the physical and chemical stability of lecithin, ethanol, isopropyl myristate (IPM) and water (20.65/20.78/41.52/17.05 w/w) by using the pseudo-ternary phase diagram and the average droplet size is about 40 nm. The permeability of TEF microemulsion is about 6 times higher than control group in vitro penetration test. The results of antiinflammatory effect showed that compared with the control group, the external TEF microemulsion group could significantly inhibit swelling of paw in rats, and no significant difference compared with oral LEF group. The results of hepatotoxicity test show that there were normal content of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and no obvious inflammatory infiltration of TEF microemulsion group compared with LEF group. The plasma concentration curve showed that compared with LEF group, the peak concentration of TEF microemulsion group was decreased, the half-life (t 1/2) was prolonged, and the relative bioavailability of TEF microemulsion was 75.35%. These results suggest that TEF W/O microemulsion can be used as a promising preparation to play an anti-inflammatory role while significantly reducing hepatotoxicity.

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Treadmill Running Ameliorates Destruction of Articular Cartilage and Subchondral Bone, Not Only Synovitis, in a Rheumatoid Arthritis Rat Model

Cited by 22 publications

References 35 publications

Exercise Exacerbates the Transcriptional Profile of Hypoxia, Oxidative Stress and Inflammation in Rats with Adjuvant-Induced Arthritis

Exercise Exacerbates the Transcriptional Profile of Hypoxia, Oxidative Stress and Inflammation in Rats with Adjuvant-Induced Arthritis

Treadmill Running in Established Phase Arthritis Inhibits Joint Destruction in Rat Rheumatoid Arthritis Models

Development and Evaluation of a Water-in-oil Microemulsion Formulation for the Transdermal Drug Delivery of Teriflunomide (A771726)

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