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Map kinase c‐Jun N‐terminal kinase mediates PMMA induction of osteoclasts
Author(s) -
Yamanaka Y.,
AbuAmer Y.,
Faccio R.,
Clohisy J.C.
Publication year - 2006
Publication title -
journal of orthopaedic research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.041
H-Index - 155
eISSN - 1554-527X
pISSN - 0736-0266
DOI - 10.1002/jor.20199
Subject(s) - rankl , osteoclast , p38 mitogen activated protein kinases , kinase , osteolysis , mapk/erk pathway , chemistry , microbiology and biotechnology , mitogen activated protein kinase , c jun , nf κb , tumor necrosis factor alpha , cancer research , signal transduction , transcription factor , medicine , biology , activator (genetics) , biochemistry , dentistry , receptor , gene
Abstract Erosive osteolysis induced by implant‐derived wear debris is mediated by recruitment and activation of osteoclasts in a pro‐inflammatory microenvironment that is enriched with osteoclastogenic and pro‐inflammatory cytokines such as RANKL and tumor necrosis factor α (TNF‐α). These cytokines activate the transcription factor NF‐κB and MAP kinases, including c‐Jun, Erks, and p38, all known to be essential for the development of osteoclasts. We have recently documented that TNF and RANKL play a pivotal role in the development of inflammatory osteolysis. We have also found that polymethyl methacrylate (PMMA) particles stimulate osteoclastogenesis, at least in part, by induction of RANKL, TNF, and by activation of NF‐κB and MAP kinases. More importantly, our data indicate that inhibitors of NF‐κB and the MAP kinases p38 and ERK abrogate particle‐induced osteoclastogenesis. In the current study, we investigated if inhibition of c‐Jun N‐Terminal kinase (JNK) pathway alters PMMA‐induced osteoclastogenesis. Our findings point out that PMMA particles activate the JNK pathway in wild‐type and TLR4‐null (endotoxin‐resistant) osteoclast precursors. This activation was selectively blocked in a dose‐dependent fashion by the JNK inhibitor SP600125. Most importantly, we provide evidence that SP600125 inhibits osteoclast formation in a reversible manner. Collectively, our findings demonstrate that activation of the JNK pathway is essential for basal and PMMA‐stimulated osteoclastogenesis, and buttress the potential significance of targeting the JNK pathway to inhibit osteolysis. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 24:1349–1357, 2006