Activation of p38 MAPK is a key step in tumor necrosis factor-mediated inflammatory bone destruction.
OBJECTIVE
To investigate whether activation of p38 MAPK is a crucial signaling factor in inflammatory bone destruction mediated by tumor necrosis factor (TNF). Mice overexpressing TNF were treated with 2 different inhibitors of p38 MAPK, and the effect of this treatment on joint inflammation and structural damage was assessed.


METHODS
Human TNF-transgenic mice received systemic treatment with 2 different p38 MAPK inhibitors (RO4399247 and AVE8677). Treatment was started at the time of symptom onset and lasted for 6 weeks. Mice were assessed for clinical signs of arthritis, bone erosion, and cartilage damage. In addition, the effect of these inhibitors on osteoclast generation in vitro and in vivo was assessed.


RESULTS
Both p38 MAPK inhibitors significantly reduced clinical signs of TNF-mediated arthritis. This was attributable to reducing synovial inflammation by 50% without affecting the cellular composition of the infiltrate. Synovial expression of interleukin-1 and RANKL was reduced upon p38 MAPK blockade, and activation of the molecular target MAPK-activated protein kinase 2 (MAPKAP-2) was also inhibited. Proteoglycan loss of articular cartilage was reduced by 50%, although p38 MAPK inhibition did not change matrix molecule synthesis by cultivated chondrocytes. Importantly, bone loss was almost completely prevented by p38 MAPK inhibition. The numbers of synovial osteoclasts and precursors were dramatically reduced, and both p38 MAPK inhibitors also inhibited in vitro osteoclastogenesis at micromolar concentrations and blocked activation of MAPKAP-2 as well as differentiation markers in cultured osteoclast precursors.


CONCLUSIONS
These results suggest the major importance of p38 MAPK for TNF-mediated inflammatory bone destruction in arthritis and suggest that inhibition of p38 MAPK might be an important tool for reducing structural damage in rheumatoid arthritis.
Zwerina
Jochen
J
Medical University of Vienna, Vienna, Austria.
Hayer
Silvia
S
Redlich
Kurt
K
Bobacz
Klaus
K
Kollias
Giorgos
G
Smolen
Josef S
JS
Schett
Georg
G
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D001862:Bone Resorption / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013585:Synovitis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004338:Drug Combinations; D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases