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Cross-Talk between the Interleukin-6 and Prostaglandin E₂ Signaling Systems Results in Enhancement of Osteoclastogenesis through Effects on the Osteoprotegerin/Receptor Activator of Nuclear Factor-B (RANK) Ligand/RANK System

Departments of Medicine (X.-H.L., S.Y., A.C.L.) and Urology (A.K.), Mount Sinai School of Medicine, New York, New York 10029

Address all correspondence and requests for reprints to: Xin-Hua Liu, Ph.D., Department of Medicine, Box 1055, Annenberg Building, Room 23-78, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029. E-mail: liu.xinhua{at}mssm.edu.

The osteoprotegerin (OPG)/receptor activator of nuclear factor-B ligand (RANKL)/receptor activator of nuclear factor-B (RANK) system is the dominant and final mediator of osteoclastogenesis. Abnormalities of this system have been implicated in the pathogenesis of many skeletal diseases. Cyclooxygenase (COX)-2 and prostaglandin (PG)E₂, a major eicosanoid product of the COX-2-catalyzed pathway, play key roles in normal bone tissue remodeling. PGE₂ exerts its actions by binding and activating the E series of prostaglandin (EP) receptor. Activation of EP₂ and EP₄ receptors is associated with PGE₂-induced osteoclast differentiation. IL-6, a major proinflammatory cytokine, has also been reported to induce osteoclast differentiation. Although interactions between the COX-2/PGE₂ and IL-6 systems have been described in bone cells, the mechanisms underlying these cooperative signaling pathways and the possible involvement of the OPG/RANKL/RANK system have not been fully elucidated. We demonstrate that COX-2, PGE₂, and IL-6 stimulate osteoblast growth and osteoclast differentiation. Effects on osteoclast differentiation, particularly with IL-6, were most marked when osteoclast precursor cells were grown in coculture with osteoblasts, indicating a possible role of the RANK/RANKL/OPG system. COX-2 and PGE₂ stimulated osteoclastogenesis through inhibition of OPG secretion, stimulation of RANKL production by osteoblasts, and up-regulation of RANK expression in osteoclasts. PGE₂ stimulated IL-6 secretion by bone cells, whereas COX-2 inhibitors decreased this same parameter. IL-6, in turn, increased PGE₂ secretion, COX-2, and EP receptor subtype expression in bone cells. Finally, IL-6 was the mediator of PGE₂-induced suppression of OPG production by osteoblasts. These findings provide evidence for cross-talk between the PGE₂ and IL-6 signaling enhance osteoclast differentiation via effects on the OPG/RANKL/RANK system in bone cells.

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