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-κB (RANK) ligand/RANK system

The osteoprotegerin ( OPG)/ receptor activator of nuclear factor- kappa B ligand ( RANKL)/ receptor activator of nuclear factor- kappa 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) E-2, a major eicosanoid product of the COX- 2- catalyzed pathway, play key roles in normal bone tissue remodeling. PGE(2) exerts its actions by binding and activating the E series of prostaglandin ( EP) receptor. Activation of EP2 and EP4 receptors is associated with PGE(2)- induced osteoclast differentiation. IL- 6, a major proinflammatory cytokine, has also been reported to induce osteoclast differentiation. Although interactions between the COX- 2/ PGE(2) 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, PGE(2), 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 PGE(2) stimulated osteoclastogenesis through inhibition of OPG secretion, stimulation of RANKL production by osteoblasts, and up- regulation of RANK expression in osteoclasts. PGE(2) stimulated IL- 6 secretion by bone cells, whereas COX- 2 inhibitors decreased this same parameter. IL- 6, in turn, increased PGE(2) secretion, COX- 2, and EP receptor subtype expression in bone cells. Finally, IL- 6 was the mediator of PGE(2)- induced suppression of OPG production by osteoblasts. These findings provide evidence for cross- talk between the PGE(2) and IL- 6 signaling enhance osteoclast differentiation via effects on the OPG/ RANKL/ RANK system in bone cells.