Mitogen-activated protein kinases as therapeutic targets in osteoarthritis

Abstract

Purpose of review: The mitogen-activated protein (MAP) kinases are intracellular signaling proteins which play a central role in controlling the activity of pathways that regulate production and activity of multiple mediators of joint tissue destruction. The therapeutic potential of MAP kinase inhibition in osteoarthritis was reviewed.

Recent findings: Results from basic research studies support the role of MAP kinases as central mediators that regulate expression of proinflammatory cytokines and metalloproteinases but also as potential pain mediators as well. Cell culture and animal model studies suggest that inhibition of MAP kinases might slow progression of osteoarthritis but trials of MAP kinase inhibitors in humans with osteoarthritis have not yet been reported. Safety concerns of the currently available inhibitors have limited their initial use to trials in conditions considered more severe than osteoarthritis.

Summary: MAP kinase inhibition has the potential to slow disease progression in osteoarthritis and also might reduce pain; however, safety concerns have limited the use of general MAP kinase inhibitors in humans. Further understanding of the function of specific isoforms of the MAP kinases as well as upstream and downstream effectors may lead to the development of more specific inhibitors with less toxicity that could eventually be used as structure-modifying drugs for osteoarthritis.

Figure 1. MAP kinase signaling pathways

A diverse array of receptors, including growth factor, cytokine, and integrin receptors, activate signaling pathways which lead to the activation of the MAP kinase pathways. MAP kinase kinase kinases (MAPKKKs) activate MAP kinase kinases (MKKs; MAP and ERK kinase or MEK), which in turn activate the MAP kinases (p38, ERK1/2, and JNK). The MAP kinases activate other kinases, such as p90RSK, and transcription factors that regulate gene transcription including Elk-1, MEF2, ATF2, c-Myc, Ets-1, and c-Jun. In this way, all three MAP kinases are involved in the expression of matrix metalloproteinases (MMPs) and other mediators involved in the development of OA.