Therapeutic and Preventive Effects of Methotrexate on Zymosan-Induced Arthritis in SKG Mice

Nagate, Toshiaki; Kawai, Junya; Nakayama, Jun

doi:10.1292/jvms.71.713

Cited by 7 publications

(8 citation statements)

References 17 publications

(24 reference statements)

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“…Third, TNF-α has been suggested to remain in synovial tissue such as synovial lining cells in the late phase of inflammation as previously described. 33 In the present study, we found a significant difference in synovial hyperplasia between the WT and LOX-1 KO mice at day 7. Proteolytic enzymes such as MMP-3 released from hyperplastic synovium might cause a significant difference in cartilage degeneration between the WT and LOX-1 KO mice.…”

Section: Discussionsupporting

confidence: 56%

LOX-1 deficient mice show resistance to zymosan-induced arthritis

et al. 2018

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Recent data suggest that the lectin-like oxidized low-density lipoprotein (ox-LDL) receptor-1 (LOX-1)/ox-LDL system may be involved in the pathogenesis of arthritis. We aimed to demonstrate the roles of the LOX- 1/ox-LDL system in arthritis development by using LOX-1 knockout (KO) mice. Arthritis was induced in the right knees of C57Bl/6 wild-type (WT) and LOX-1 KO mice via zymosan injection. Saline was injected in the left knees. Arthritis development was evaluated using inflammatory cell infiltration, synovial hyperplasia, and cartilage degeneration scores at 1, 3, and 7 days after administration. LOX-1, ox-LDL, and matrix metalloproteinase-3 (MMP-3) expression in the synovial cells and chondrocytes was evaluated by immunohistochemistry. The LOX-1, ox-LDL, and MMP-3 expression levels in synovial cells were scored on a grading scale. The positive cell rate of LOX-1, ox-LDL, and MMP-3 in chondrocytes was measured. The correlation between the positive cell rate of LOX-1 or ox-LDL and the cartilage degeneration score was also examined. Inflammatory cell infiltration, synovial hyperplasia, and cartilage degeneration were significantly reduced in the LOX-1 KOmice with zymosan-induced arthritis (ZIA) compared to WT mice with ZIA. In the saline-injected knees, no apparent arthritic changes were observed. LOX-1 and ox-LDL expression in synovial cells and chondrocytes were detected in the knees of WT mice with ZIA. No LOX-1 and ox-LDL expression was detected in the knees of LOX-1 KO mice with ZIA or the salineinjected knees of both mice. MMP-3 expression in the synovial cells and chondrocytes was also detected in knees of both mice with ZIA, and was significantly less in the LOX-1 KO mice than in WT mice. The positive cell rate of LOX-1 or ox-LDL and the cartilage degeneration score showed a positive correlation. Our data show the involvement of the LOX-1/ox-LDL system in murine ZIA development. LOX-1-positive synovial cells and chondrocytes are potential therapeutic targets for arthritis prevention.

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Section: Discussionsupporting

confidence: 56%

LOX-1 deficient mice show resistance to zymosan-induced arthritis

et al. 2018

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“…Thus, these spontaneously develop arthritis due to peripheral autoreactive T cells [17,18], which is clinically and immunologically akin to human RA, wherein autoreactivity also plays a key role [19,20]. This model sometimes is used in evaluation of therapies for human RA [21,22]. However, the effectiveness of MSC treatment in these mice has not been tried.…”

Section: Introductionmentioning

confidence: 99%

Paradoxical effects of human adipose tissue-derived mesenchymal stem cells on progression of experimental arthritis in SKG mice

Kim

Lee

et al. 2014

Cellular Immunology

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“…Naproxen was used at 10 mg/kg on a daily basis (which is comparable to the human dosage for JIA) 15 . MTX was used at 1 mg/kg/three times per week, which is at the upper limit of the human dosage used for JIA, 16,17 but within the range of effective arthritis treatment within various mouse models 18‐21 . Prolonged treatment of 5‐week‐old skeletally immature mice with naproxen or MTX for 10 weeks did not result in significant body weight changes as compared to their control placebo‐treated mice (Figure 2A).…”

Section: Resultsmentioning

confidence: 99%

“…Tibia and femur bone length are decreased in mice treated with naproxen or MTX Considering the profound consequences for ATDC5 chondrogenic differentiation after naproxen or MTX exposure, we subsequently evaluated whether these compounds also alter in vivo growth plate development in mice with consequences for skeletal development.Naproxen was used at 10 mg/kg on a daily basis (which is comparable to the human dosage for JIA) 15. MTX was used at 1 mg/kg/three times per week, which is at the upper limit of the human dosage used for JIA,16,17 but within the range of effective arthritis treatment within various mouse models [18][19][20][21]. Prolonged treatment of 5-week-old skeletally immature mice with naproxen or MTX for 10 weeks did not result in significant body weight changes as compared to their control placebo-treated mice(Figure 2A).…”

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confidence: 99%

Evaluation of impaired growth plate development of long bones in skeletally immature mice by antirheumatic agents

Caron

Rietbergen

Castermans

et al. 2020

Journal Orthopaedic Research

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Restriction of physical growth and development is a known problem in patients with juvenile idiopathic arthritis (JIA). However, the effect of medical treatment for JIA on skeletal growth in affected children has not been properly investigated. We, therefore, hypothesize that naproxen and methotrexate (MTX) affect endochondral ossification and will lead to reduced skeletal development. Treatment of ATDC5 cells, an in vitro model for endochondral ossification, with naproxen or MTX resulted in increased chondrogenic but decreased hypertrophic differentiation. In vivo, healthy growing C57BL/6 mice were treated with naproxen, MTX, or placebo for 10 weeks. At 15 weeks postnatal, both the length of the tibia and the length of the femur were significantly reduced in the naproxen‐ and MTX‐treated mice compared to their controls. Growth plate analysis revealed a significantly thicker proliferative zone, while the hypertrophic zone was significantly thinner in both experimental groups compared to their controls, comparable to the in vitro results. Micro‐computed tomography analysis of the subchondral bone region directly below the growth disc showed significantly altered bone microarchitecture in naproxen and MTX groups. In addition, the involvement of the PTHrP‐Ihh loop in naproxen‐ and MTX‐treated cells was shown. Overall, these results demonstrate that naproxen and MTX have a profound effect on endochondral ossification during growth plate development, abnormal subchondral bone morphology, and reduced bone length. A better understanding of how medication influences the development of the growth plate will improve understanding of endochondral ossification and reveal possibilities to improve the treatment of pediatric patients.

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Therapeutic and Preventive Effects of Methotrexate on Zymosan-Induced Arthritis in SKG Mice

Cited by 7 publications

References 17 publications

LOX-1 deficient mice show resistance to zymosan-induced arthritis

LOX-1 deficient mice show resistance to zymosan-induced arthritis

Paradoxical effects of human adipose tissue-derived mesenchymal stem cells on progression of experimental arthritis in SKG mice

Evaluation of impaired growth plate development of long bones in skeletally immature mice by antirheumatic agents

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