P38 MAP kinase inhibitors as potential therapeutics for the treatment of joint degeneration and pain associated with osteoarthritis

Brown, Kimberly K.; Heitmeyer, S.A.; Hookfin, E.B.; Hsieh, Lily C.; Buchalova, Maria; Taiwo, Yetunde O.; Janusz, Michael J.

doi:10.1186/1476-9255-5-22

Cited by 61 publications

(52 citation statements)

References 43 publications

(47 reference statements)

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“…Previously published IC 50 values of 136 nM for SB 203580 (Brown et al) [36], 14 nM for Pamapimod (Hill et al) [14] and 20 nM for BIRB-796 (Ross et al) [37] are in the range with our results. In addition Hill et al [14] reported an IC 50 of 400 nM for the inhibition of TNF-α from whole blood by Pamapimod, which is in line with our results demonstrating the validity of our assay.…”

Section: Discussionsupporting

confidence: 80%

Impact of p38 MAP Kinase Inhibitors on LPS-Induced Release of TNF-α in Whole Blood and Primary Cells from Different Species

Fehr

Unger²,

Schaeffeler

et al. 2015

Cell Physiol Biochem

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Background/Aims: Inhibition of p38 mitogen-activated protein kinase (p38 MAPK) is promising for the treatment of inflammatory disorders, however, the efficacy of p38 MAPK inhibitors in clinical trials is limited so far. Since functional sensitivity of p38 MAPK is commonly predicted by preclinical species, we systematically investigated interspecies differences including human tissue. Methods: Ex vivo test models were established using whole blood and primary cells from different species such as mice, rats, pigs and humans to compare LPS-induced TNF-α inhibition of four different p38 MAPK reference inhibitors SB 203580, BIRB-796, Pamapimod, and a Losmapimod analogue as well as a proprietary imidazole-based p38 MAPK Inhibitor. Results: All analysed p38 MAPK inhibitors resulted in significant inhibition of LPS-induced TNF-α release but with high interspecies differences for dose sensitivity. IC₅₀ values from human whole blood and PBMC showed significant higher sensitivity towards p38 MAPK inhibition compared with data from pig and rat. Conclusion: Inhibition of TNF-α release by p38 MAPK inhibitors can be reliably identified in well-established laboratory species such as rat or mouse. However, our data indicate that animal models appear to be limited for valid prediction of the inhibitory potential for TNF-α release in humans. Thus, human tissues should be considered early in the drug development process of p38 MAPK inhibitors.

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Section: Discussionsupporting

confidence: 80%

Impact of p38 MAP Kinase Inhibitors on LPS-Induced Release of TNF-α in Whole Blood and Primary Cells from Different Species

Fehr

Unger²,

Schaeffeler

et al. 2015

Cell Physiol Biochem

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“…One of the relevant signaling pathways is that of MAPK (mitogen-activated protein kinase), especially the p38MAPK pathway, as it plays a pivotal role in the inflammatory processes in joint destruction. Inhibition of the p38MAPK by the inhibitor SB203580 was previously shown to reduce PGE2 and NO-release of chondrocytes in an in vitro inflammation model (17) and demonstrated an attenuation of cartilage degradation in vivo (18). Furthermore, p38MAPK is thought to be a key player in mechanical stressinduced signaling as activation of p38MAPK by mechanical stress was observed in bovine cartilage and human chondrocytes (19,20).…”

Section: Introductionmentioning

confidence: 99%

Single impact trauma in human early-stage osteoarthritic cartilage: Implication of prostaglandin D2 but no additive effect of IL-1β on cell survival

Joos

Hogrefe²,

Rieger³

et al. 2011

Int J Mol Med

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Abstract. Injury to articular cartilage is often associated with an inflammatory reaction and frequently results in the development of post-traumatic osteoarthritis (post-traumatic OA). Cell death, inflammation and loss of proteoglycans participate in these mechanisms with p38MAPK being one of the pivotal signaling kinases. Therefore, the interaction of trauma and of the pro-inflammatory cytokine IL-1β was investigated in an in vitro tissue model of human osteoarthritic cartilage. Trauma was induced by impacting cartilage explants with a drop-tower system and its effect was measured in terms of cell survival, gene expression and the release of mediators. In addition, the effect of concomitant IL-1β stimulation and p38MAPK inhibition by SB203580 was investigated. We found a significant decrease in chondrocyte viability after trauma, but no additional effect of IL-1β stimulation. SB203580 had a tendency to improve cell survival suggesting a role for p38 signaling in cell viability after impact in an inflammatory environment. We showed that various mediators are released in response to trauma with or without IL-1β stimulation, differing in composition and time response. Trauma resulted in an increased release of IL-6, whereas TNF-α and IL-1β release was unaffected. Prostaglandin (PG) and NO synthesis pathways were both affected by trauma and/ or IL-1β. We demonstrate for the first time an elevated release of prostaglandin D2 (PGD2) by human articular cartilage in response to a single mechanical impact. The up-regulation of mediators was time-dependent, with a more early increase of PGD2 compared to prostaglandin E2 (PGE2) and a late induction of NO by co-stimulation with IL-1β between 6 and 24 h.

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“…For instance, inhibition of the p38 MAPK signaling pathway with SB203580 showed antiinflammatory effects in both cartilage explants 75 and animal models. 76 However, there is a conflicting report showing that inhibition of the p38 MAPK pathway using SB203580 leads to OA-like changes in a rat animal model. 77 Similarly, the JNKs are activated in macrophages after stimulation with lipopolysaccharides.…”

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confidence: 99%

Anti-Inflammatory Strategies in Cartilage Repair

Zhang

Pizzute

Pei

2014

Tissue Engineering Part B: Reviews

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P38 MAP kinase inhibitors as potential therapeutics for the treatment of joint degeneration and pain associated with osteoarthritis

Abstract: Background: Evaluate the potential role of p38 inhibitors for the treatment of osteoarthritis using an animal model of joint degeneration (iodoacetate-induced arthritis) and a pain model (Hargraeves assay).

Cited by 61 publications

References 43 publications

Impact of p38 MAP Kinase Inhibitors on LPS-Induced Release of TNF-α in Whole Blood and Primary Cells from Different Species

Impact of p38 MAP Kinase Inhibitors on LPS-Induced Release of TNF-α in Whole Blood and Primary Cells from Different Species

Single impact trauma in human early-stage osteoarthritic cartilage: Implication of prostaglandin D2 but no additive effect of IL-1β on cell survival

Anti-Inflammatory Strategies in Cartilage Repair

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