Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis

Badger, Alison M.; Griswold, Don E.; Kapadia, Rasesh; Blake, S; Swift, Brandon; Hoffman, Sandy J.; Stroup, George B.; Webb, Edward F.; Rieman, David J.; Gowen, Maxine; Boehm, Jeffrey C.; Adams, Jerry L.; Lee, John C.

doi:10.1002/1529-0131(200001)43:1<175::aid-anr22>3.0.co;2-s

Cited by 212 publications

(123 citation statements)

References 31 publications

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“…High levels of activated MKKs were confirmed by Western blot analysis, with increases in both phospho-MKK3 and -MKK6. Because p38 activation contributes to bone destruction and synovial inflammation in animal models of arthritis, 37 one can infer that similar pathways might be relevant in RA. If so, MKK3 and MKK6 are potential gateways to p38 activation in rheumatoid synovium and could enhance cytokine and protease production.…”

Section: Discussionmentioning

confidence: 70%

Expression and Activation of Mitogen-Activated Protein Kinase Kinases-3 and -6 in Rheumatoid Arthritis

Chabaud-Riou¹,

Firestein²

2004

The American Journal of Pathology

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The p38 mitogen-activated protein (MAP) kinase signal transduction pathway regulates the production of interleukin-1 and tumor necrosis factor-␣. p38 kinase inhibitors are effective in animal models of arthritis and are currently being developed in rheumatoid arthritis (RA). However, little is known about the upstream kinases that control the activation of p38 in RA synovium. In vitro studies previously identified the MAP kinase kinases (MAPKKs) MKK3 and MKK6 as the primary regulators of p38 phosphorylation and activation. To investigate a potential role for MKK3 and MKK6 in RA, we evaluated their expression and regulation in RA synovium and cultured fibroblastlike synoviocytes (FLS). Immunohistochemistry demonstrated that MKK3 and MKK6 are expressed in RA and osteoarthritis (OA) synovium. Digital image analysis showed no significant differences between OA and RA with regard to expression or distribution. However, phosphorylated MKK3/6 expression was significantly higher in RA synovium and was localized to the sublining mononuclear cells and the intimal lining. Actin-normalized Western blot analysis of synovial tissue lysates confirmed the increased expression of phosphorylated MKK3/6 in RA. Western blot analysis demonstrated constitutive expression of MKK3 and MKK6 in RA and OA FLS. Phospho-MKK3 levels were low in medium-treated FLS, but were rapidly increased by interleukin-1 and tumor necrosis factor-␣, although phospho-MKK6 levels only modestly increased. p38 co-immunoprecipitated with MKK3 and MKK6 from cytokine-stimulated FLS and the complex phosphorylated activating transcription factor-2 in an in vitro kinase assay. These data are the first documentation of MKK3 and MKK6 activation in human inflammatory disease. By forming a complex with p38 in synovial tissue and FLS, these kinases can potentially be targeted to regulate the production of proinflammatory cytokine production in inflamed synovium. (Am J Pathol 2004, 164:177-184) Mitogen-activated protein (MAP) kinases are a family of serine/threonine kinases that mediate signal transduction and orchestrate an appropriate cellular response to environmental stress. In mammalian cells, three principle MAP kinase pathways have been identified, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. 1 Multiple MAP kinase pathways can be simultaneously activated and the relative balance is determined by the parallel upstream kinase cascades known as MAP kinase kinases (MAPKKs) and MAP kinase kinase kinases (MAP3Ks). 2 The p38 MAP kinase is of particular interest in inflammatory diseases such as rheumatoid arthritis (RA) because it regulates the production of pathogenic cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-␣. 3,4 p38 is expressed and activated in RA synovium 5 and blockade using selective inhibitors decreases inflammation and bone destruction animal models of arthritis. 6 However, little is known about the upstream kinases that can activate this pathway in joint tissues. Of the MAPKKs, MKK3 a...

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Section: Discussionmentioning

confidence: 70%

Expression and Activation of Mitogen-Activated Protein Kinase Kinases-3 and -6 in Rheumatoid Arthritis

Chabaud-Riou¹,

Firestein²

2004

The American Journal of Pathology

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“…This finding suggests potential therapeutic targets for combating PGE 2 -related inflammation in cartilage, most notably, ERK-1/2 and p38 MAPKs. MAPK activation may be involved in inflammatory and degenerative arthropathies (44,45), and several therapeutic trials have indicated that p38 MAPK inhibitors can halt joint disease (46)(47)(48). However, the use of MAPK inhibitors in clinical practice is limited by the ability of these compounds to block overall MAPK activity.…”

Section: Discussionmentioning

confidence: 83%

Up‐regulation of microsomal prostaglandin E synthase 1 in osteoarthritic human cartilage: Critical roles of the ERK‐1/2 and p38 signaling pathways

Masuko

Bérenbaum

Humbert

et al. 2004

Arthritis & Rheumatism

118

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Objective. Microsomal prostaglandin E synthase 1 (mPGES-1) is the final enzyme of the cascade that produces prostaglandin E 2 (PGE 2 ), a key actor in arthritis. To study mPGES-1 synthesis in human cartilage and its regulation by interleukin-1␤ (IL-1␤), we used human cartilage and an immortalized human chondrocyte cell line. Furthermore, we investigated the signaling pathways involved in mPGES-1 expression.Methods. We used real-time quantitative reverse transcription-polymerase chain reaction, Northern blotting, and Western blotting to measure mPGES-1 messenger RNA (mRNA) and protein expression in human chondrocytes. PGE 2 production was measured by enzyme-linked immunosorbent assay.Results. Cartilage specimens from osteoarthritis (OA) patients contained far greater amounts of mPGES-1 and cyclooxygenase 2 (COX-2) mRNA than did normal cartilage. Incubation with IL-1␤ markedly increased mPGES-1 mRNA and protein in a dosedependent and time-dependent manner, in parallel with an increase in PGE 2 levels. Both PD98059, an ERK pathway inhibitor, and SB203580, a p38␣/␤ MAPK inhibitor, abolished the increases in mPGES-1 mRNA and protein in response to IL-1␤. The specific p38␣ MAPK inhibitor SC906 suppressed IL-1␤-induced COX-2 expression but not IL-1␤-induced mPGES-1 expression, suggesting preferential involvement of p38␤ MAPK in IL-1␤-induced mPGES-1 expression.Conclusion. This study is the first to show that mPGES-1 is stimulated in human chondrocytes by the proinflammatory cytokine IL-1␤ via activation of both ERK-1/2 and p38 MAPK in an isoform-specific manner. We postulate that mPGES-1 may be a novel target for OA therapy.Prostaglandin E 2 (PGE 2 ) plays an important role in cartilage metabolism. Its many effects on chondrocytes (for review, see ref. 1) include enhanced production of matrix metalloproteinase 3 (2), modulation of proteoglycan and collagen synthesis (2,3), and stimulation of chondrocyte apoptosis (4,5). The synovial fluid of patients with osteoarthritis (OA) and rheumatoid arthritis contains high concentrations of PGE 2 (4), and cartilage and chondrocytes from OA patients spontaneously release more PGE 2 than does normal cartilage (2,6,7). These results suggest that PGE 2 may be actively involved in cartilage breakdown in OA patients. PGE 2 is synthesized by the isoenzymes cyclooxygenase 1 (COX-1) and COX-2, both of which act on arachidonic acid to form the prostaglandin endoperoxide H 2 (PGH 2 ). The prostanoid synthase prostaglandin E synthase (PGES) produces PGE 2 from PGH 2 . Three

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“…Our examination of p38 MAPK distribution in developing limbs revealed the presence of cells expressing constitutively active p38 MAPK at sites of joint cavity formation and is endorsed by our demonstration that cultured cells derived from these sites also conserve p38 MAPK in the active state. Increasing emphasis on use of p38 MAPK inhibitors as anti-inflammatory therapies for joint disorders may therefore require re-evaluation (38). Our findings show that p38 MAPK regulates mechanically induced changes in extracellular matrix formation and, therefore, have implications for use of p38 MAPK-targeted antiinflammatory drugs.…”

Section: Discussionmentioning

confidence: 99%

A Specific Mechanomodulatory Role for p38 MAPK in Embryonic Joint Articular Surface Cell MEK-ERK Pathway Regulation

Lewthwaite

Bastow

Lamb

et al. 2006

Journal of Biological Chemistry

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Mechanisms regulating cell behavior and extracellular matrix composition in response to mechanical stimuli remain unresolved. Our previous studies have established that the MEK-ERK cascade plays a specific role in the mechano-dependent joint formation process by promoting the assembly of pericellular matrices reliant upon hyaluronan (HA) for their integrity. Here we demonstrate: (i) novel cross-talk between p38 MAPK and MEK-ERK signaling pathways that is specific for mechanical stimuli and (ii) a role for p38 MAPK in facilitating HA production by cells derived from the articular surface of embryonic chick tibiotarsal joints. We find that p38 MAPK blockade restricts pericellular assembly of HA-rich matrices and reduces basal as well as mechanical strain-induced release of HA. p38 MAPK blockers potentiated early strain-induced increases but restricted sustained increases in MEK/ERK phosphorylation at later times; c-Fos hyperphosphorylation at threonine 325 was found to parallel this p38 MAPK-mediated modulation of ERK activation. In contrast, p38 MAPK inhibitors had no detectable effect on the ERK activation induced by fibroblast growth factor 2 or pervanadate, a phosphatase inhibitor, and MEK inhibitors did not influence p38 MAPK phosphorylation, confirming both the specificity and unidirectionality of p38 MAPK-ERK cross-talk. Immunochemical and immunoblotting studies revealed constitutive p38 MAPK activation in cells at, or derived from, developing articular joint surfaces. Unlike the MEK-ERK pathway, however, p38 MAPK was not further stimulated by mechanical stimulation in vitro. Thus, p38 MAPK specifically facilitates ERK activation and downstream signaling in response to mechanical stimuli. These results suggest that constitutively active p38 MAPK serves an essential, permissive role in mechanically induced changes in ERK activation and in the accumulation of HA-rich extracellular matrices that serve a key role in joint development.Mitogen-activated protein kinases (MAPKs) 3 are ubiquitous serine/ threonine kinases that are activated by diverse extracellular stimuli, including growth factors, cytokines, and physiological mechanical signals (1-3). MAPKs are essential for transducing signals from the cell surface that regulate diverse cellular behaviors, such as those coordinating development, proliferation, and differentiation. Much recent emphasis has been placed on members of three well characterized mammalian MAPK families, comprising extracellular signal-regulated kinases (ERKs), p38 MAPKs, and c-Jun N-terminal kinases (JNKs) (4 -6). Until relatively recently it was considered that these families were preferentially activated by certain types of signal: the ERK family by growth factors and the p38 MAPK and JNK families by cellular stress. It is now becoming increasingly clear, however, that the various MAPK pathways can also be co-activated by a single stimulus. The precise interaction between members of these distinct MAPK families and how they cooperate to control cell behavior are, however, ill-define...

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Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis

Cited by 212 publications

References 31 publications

Expression and Activation of Mitogen-Activated Protein Kinase Kinases-3 and -6 in Rheumatoid Arthritis

Expression and Activation of Mitogen-Activated Protein Kinase Kinases-3 and -6 in Rheumatoid Arthritis

Up‐regulation of microsomal prostaglandin E synthase 1 in osteoarthritic human cartilage: Critical roles of the ERK‐1/2 and p38 signaling pathways

A Specific Mechanomodulatory Role for p38 MAPK in Embryonic Joint Articular Surface Cell MEK-ERK Pathway Regulation

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