Mitogen-Activated Protein Kinases as Therapeutic Targets for Rheumatoid Arthritis

Paunović, Verica; Harnett, Margaret M.

doi:10.1007/s40265-013-0014-6

Cited by 55 publications

(41 citation statements)

References 146 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MAPK pathway plays a pivotal role in the development of inflammation and tissue destruction in RA [8, 9]. Western blot analysis revealed activation of MAPK signaling in hind paws of arthritic rats as seen by increased phosphorylation of p38MAPK, ERK1/2 and JNK1/2 proteins, compared to control rats (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In fact, the three MAPKs have been identified to play a key role in the regulation of cytokine, chemokine and prostaglandin synthesis. Dysregulated activation of MAPKs has been implicated in RA pathogenesis, so, MAPKs can serve as pivotal molecular targets for therapeutic intervention [8, 9]. Activation of p38 MAPK contributes to RA pathogenesis via driving the expression of adhesion proteins in inflammatory cells and through generation of TNF-α [9].…”

Section: Discussionmentioning

confidence: 99%

“…Activation of p38 MAPK contributes to RA pathogenesis via driving the expression of adhesion proteins in inflammatory cells and through generation of TNF-α [9]. The ERK family is involved in macrophage generation of TNF-α and COX-2-dependent production of PGE 2 in RA human fibroblast like synoviocytes [8]. A crucial role of JNK in RA pathogenesis is through matrix metalloproteinases(MMPs)-mediated cartilage degradation [8, 9].…”

Section: Discussionmentioning

confidence: 99%

“…The ERK family is involved in macrophage generation of TNF-α and COX-2-dependent production of PGE 2 in RA human fibroblast like synoviocytes [8]. A crucial role of JNK in RA pathogenesis is through matrix metalloproteinases(MMPs)-mediated cartilage degradation [8, 9]. Interestingly, administration of CM attenuated the activation of the three MAPKs.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, proinflammatory cytokines can activate several inflammatory transduction pathways, including mitogen activated protein kinase (MAPK). The MAPK family includes p38MAPK, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), which have been reported to be activated in the synovium of RA patients [8, 9]. …”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Camel Milk Attenuates Rheumatoid Arthritis Via Inhibition of Mitogen Activated Protein Kinase Pathway

Arab

Salama²,

Abdelghany

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Camel milk (CM) has shown beneficial anti-inflammatory actions in several experimental and clinical settings. So far, its effect on rheumatoid arthritis (RA) has not been previously explored. Thus, the current work aimed to evaluate the effects of CM in Adjuvant-induced arthritis and air pouch edema models in rats, which mimic human RA. Methods: CM was administered at 10 ml/kg orally for 3 weeks starting on the day of Freund’s adjuvant paw inoculation. The levels of TNF-α and IL-10 were measured by ELISA while the protein expression of NF-κBp65, COX-2 and iNOS was detected by immunohistochemistry. The expression of MAPK target proteins was assessed by Western blotting. Results: CM attenuated paw edema, arthritic index and gait score along with dorsal pouch inflammatory cell migration. CM lowered the TNF-α and augmented the anti-inflammatory IL-10 levels in sera and exudates of arthritic rats. It also attenuated the expression of activated NF-κBp65, COX-2 and iNOS in the lining of the dorsal pouch. Notably, CM inhibited the MAPK pathway signal transduction via lowering the phosphorylation of p38 MAPK, ERK1/2 and JNK1/2 in rat hind paws. Additionally, CM administration lowered the lipid peroxide and nitric oxide levels and boosted glutathione and total anti-oxidant capacity in sera and exudates of animals. Conclusion: The observed CM downregulation of the arthritic process may support the interest of CM consumption as an adjunct approach for the management of RA.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Camel Milk Attenuates Rheumatoid Arthritis Via Inhibition of Mitogen Activated Protein Kinase Pathway

Arab

Salama²,

Abdelghany

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

Ras Guanine Nucleotide–Releasing Protein 4 Is Aberrantly Expressed in the Fibroblast‐like Synoviocytes of Patients With Rheumatoid Arthritis and Controls Their Proliferation

Kono

Yasuda

Stevens

et al. 2015

Arthritis & Rheumatology

View full text Add to dashboard Cite

Objective. Ras guanine nucleotide-releasing protein 4 (RasGRP-4) is a calcium-regulated guanine nucleotide exchange factor and diacylglycerol/phorbol ester receptor not normally expressed in fibroblasts. While RasGRP-4-null mice are resistant to arthritis induced by anti-glucose-6-phosphate isomerase autoantibodies, the relevance of these findings to humans is unknown. We undertook this study to evaluate the importance of RasGRP-4 in the pathogenesis of human and rat arthritis.Methods. Synovial tissue from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) were evaluated immunohistochemically for the presence of RasGRP-4 protein. Fibroblast-like synoviocytes (FLS) were isolated from synovial samples, and expression of RasGRP-4 was evaluated by real-time quantitative reverse transcription-polymerase chain reaction analyses. The proliferation potency of FLS was evaluated by exposing the cells to a RasGRP-4-specific small interfering RNA (siRNA). Finally, the ability of RasGRP-4-specific siRNAs to hinder type II collagen-induced arthritis in rats was evaluated to confirm the importance of the signaling protein in the disease.Results. Unexpectedly, RasGRP-4 protein was detected in the synovial hyperplastic lining, where proliferating FLS preferentially reside. FLS isolated from tissues obtained from a subpopulation of RA patients expressed much more RasGRP-4 than did FLS from examined OA patients. Moreover, the level of RasGRP-4 transcript was correlated with the FLS proliferation rate. The ability of cultured FLS to divide was diminished when they were treated with RasGRP-4-specific siRNAs. The intraarticular injection of RasGRP-4-specific siRNAs also dampened experimental arthritis in rats.Conclusion. RasGRP-4 is aberrantly expressed in FLS and helps regulate their growth. This intracellular signaling protein is therefore a candidate target for dampening proliferative synovitis and joint destruction.

show abstract

UCHL1 regulates inflammation via MAPK and NF‐κB pathways in LPS‐activated macrophages

Zhang

Liu

Chen

et al. 2021

Cell Biology International

View full text Add to dashboard Cite

Inflammation is a common pathophysiological process as well as a clinical threat that occurs in various diseases worldwide. It is well‐documented that nuclear factor‐κB (NF‐κB) and mitogen‐activated protein kinase pathways are involved in inflammatory reactions to microbial infections in lipopolysaccharide (LPS)‐activated macrophages. The deubiquitinase ubiquitin carboxyl‐terminal hydrolase‐L1 (UCHL1) has been reported as an oncoprotein to promote the growth and progression of cancer cells. However, the regulatory mechanism of UCHL1 in inflammation is currently unclear. Here, we aimed to assess the effects of UCHL1 on LPS‐associated inflammatory response in vitro and in vivo by enzyme‐linked immunosorbent assay, quantitative reverse‐transcription polymerase chain reaction, and western blot analysis. This study identified that inhibition or knockdown of UCHL1 decreased the amounts of the key pro‐inflammatory cytokines, including interleukin‐6 and tumor necrosis factor‐α in macrophages. Additionally, inhibition of UCHL1 suppressed LPS‐induced extracellular signal‑regulated protein kinase 1/2 phosphorylation and NF‐κB translocation by regulating the inhibitor of NF‐κB. Mechanically, UCHL1 interacts with IκBα protein in THP‐1. Meanwhile, inhibition of UCHL1 blocked the LPS‐induced degradation of IκBα through the ubiquitin‐proteasome system. Moreover, in vivo assay showed that suppression of UCHL1 notably reduced the LPS‐induced animal death and release of pro‐inflammatory cytokines. Overall, the current findings uncover that UCHL1 functions as a crucial regulator for inflammatory response via reversing the degradation of IκBα, representing a potential target for the treatment of inflammatory diseases.

show abstract

Mitogen-Activated Protein Kinases as Therapeutic Targets for Rheumatoid Arthritis

Cited by 55 publications

References 146 publications

Camel Milk Attenuates Rheumatoid Arthritis Via Inhibition of Mitogen Activated Protein Kinase Pathway

Camel Milk Attenuates Rheumatoid Arthritis Via Inhibition of Mitogen Activated Protein Kinase Pathway

Ras Guanine Nucleotide–Releasing Protein 4 Is Aberrantly Expressed in the Fibroblast‐like Synoviocytes of Patients With Rheumatoid Arthritis and Controls Their Proliferation

UCHL1 regulates inflammation via MAPK and NF‐κB pathways in LPS‐activated macrophages

Contact Info

Product

Resources

About