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Blood, 15 August 2005, Vol. 106, No. 4, pp. 1144-1145. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Olmsted-Davis, E. Search for Related Content PubMed Articles by Olmsted-Davis, E. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Cox-2 RANKs high in osteoclastogenesis Elizabeth Olmsted-Davis BAYLOR COLLEGE OF MEDICINE In this issue of Blood, Han and colleagues are the first to report a novel role for cyclooxygenase inhibitor-2 in osteoclastogenesis as an intermediate in the RANKL-induced differentiation of monocytes to osteoclasts. Cyclooxygenase 2 (Cox-2), which catalyzes the generation of prostaglandins to further modulate the inflammatory response, is best known as a longstanding target to alleviate pain. For diseases such as rheumatoid arthritis, in which the inflammatory response aids in the destruction of the articular cartilage and results in significant pain, inhibition of Cox-2 seems a logical target.1 However, after years of developing molecules to block its actions, we have yet to unravel all of its functions. View larger version (36K): [in this window] [in a new window]   Regulation of osteoclastogenesis by RANKL involves synthesis of Cox-2.   Here, Han and colleagues show a novel functional role for Cox-2 in the differentiation of monocyte precursors into osteoclasts. The authors demonstrate a mechanism in which Cox-2 is an essential mediator for receptor activator of nuclear factor (NF)–B ligand (RANKL)–induced osteoclastogenesis via a transient increase in Cox-2 expression in a monocytic cell line, after stimulation with RANKL. This enhanced Cox-2 expression was absent in RANKL-stimulated monocytic cells that possessed a dominant-negative form of Rac1, suggesting that this up-regulation was Rac1 dependent. The authors identified a small 27-bp region of the Cox-2 promoter that was essential for RANKL-induced activity. This region was found to have an NF-B binding site that when mutated completely abolished RANKL-induced NF-B DNA binding. Collectively, the data suggest a mechanism by which RANKL binds RANK on the monocyte/preosteoclast surface, thereby stimulating the guanosine triphosphatase (GTPase) Rac1 to induce NF-B binding to the Cox-2 promoter, resulting in a rapid but transient increase in Cox-2 expression.2 Further, with induction of Cox-2, the prostaglandin (PG) E2 is rapidly synthesized, which the authors demonstrate leads to osteoclast differentiation (see figure). In these studies, RANKL-induced osteoclastogenesis in bone marrow–derived monocyte/macrophage precursors could be completely abolished by addition of the Cox-2 inhibitor celecoxib, but restored by inclusion of exogenous PGE2, demonstrating for the first time a physiologic role for Cox-2 in osteoclastogenesis. The authors suggest that this may be in part what leads to inflammatory bone destruction in rheumatoid arthritis and other bone diseases; however, more importantly, it provides another link between bone formation and resorption. With identification of a key role for Cox-2 in the generation of osteoclasts, another missing link to understanding bone formation and repair is now found. Taken together, the data provide a new model by which inflammatory responses generated during bone injury may lead to PGE2-stimulated angiogenesis,3 chondrogenesis,4 osteogenesis,4 and now osteoclastogenesis via differentiation of resident monocytic precursors. Since osteoclasts are essential factors in the transition of cartilage to bone, this may be the key to understanding how this process is coordinately regulated. Thus, the study by Han et al provides significant insights to our understanding of bone tissue engineering. Footnotes Comment on Han et al, page 1240 References Martel-Pelletier J, Pelletier JP, Fahmi H. Cyclooxygenase-2 and prostaglandins in articular tissues. Semin Arthritis Rheum. 2003;33: 155-167.[CrossRef][Medline] [Order article via Infotrieve] Benitah SA, Valeron PF, Lacal JC. ROCK and nuclear factor-kappaB-dependent activation of cyclooxygenase-2 by Rho GTPases: effects on tumor growth and therapeutic consequences. Mol Biol Cell. 2003;14: 3041-3054.[Abstract/Free Full Text] Tsujii M, Kawano S, Tsuhii S, et al. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell. 1998;94: 705-716. Simons AM, Manigrasso MB, O'Connor JP. Cyclooxygenase 2 function is essential for bone fracture healing. J Bone Miner Res. 2002;17: 963-976.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Transcriptional induction of cyclooxygenase-2 in osteoclast precursors is involved in RANKL-induced osteoclastogenesis Song Yi Han, Na Kyung Lee, Kyung Hee Kim, In Whan Jang, Mijung Yim, Jae Hong Kim, Won Jae Lee, and Soo Young Lee Blood 2005 106: 1240-1245. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Olmsted-Davis, E. Search for Related Content PubMed Articles by Olmsted-Davis, E. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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