Mitogen-activated protein kinases as therapeutic targets in osteoarthritis.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Loeser
Richard F
RF
Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. rloeser@wfubmc.edu
Erickson
Elizabeth A
EA
Long
David L
DL
D000818:Animals; D002358:Cartilage, Articular / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010003:Osteoarthritis / Q000188:drug therapy* / Q000378:metabolism*
D004791:Enzyme Inhibitors; D020928:Mitogen-Activated Protein Kinases