Original Full Length ArticleProstaglandin D2 induces apoptosis of human osteoclasts by activating the CRTH2 receptor and the intrinsic apoptosis pathway

Prostaglandin D2 (PGD2) is a lipid mediator synthesized from arachidonic acid that directly activates two specific receptors, the D-type prostanoid (DP) receptor and chemoattractant receptor homologous molecule expressed on T-helper type 2 cells (CRTH2). PGD2 can affect bone metabolism by influencing both osteoblast and osteoclast (OC) functions, both cells involved in bone remodeling and in in vivo fracture repair as well. The objective of the present study was to determine the effects of PGD2, acting through its two specific receptors, on human OC apoptosis. Human OCs were differentiated in vitro from peripheral blood mononuclear cells in the presence of receptor activator for nuclear factor κB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF), and treated with PGD2, its specific agonists and antagonists. Treatment with PGD2 for 24 hours in the presence of naproxen (10 μM) to inhibit endogenous prostaglandin production increased the percentage of apoptotic OCs in a dose-dependent manner, as did the specific CRTH2 agonist compound DK-PGD2 but not the DP agonist compound BW 245C. In the absence of naproxen, the CRTH2 antagonist compound CAY 10471 reduced OC apoptosis rate but the DP antagonist BW A868C had no effect. The induction of PGD2-CRTH2 dependent apoptosis was associated with the activation of caspase-9, but not caspase-8, leading to caspase-3 cleavage. These data show that PGD2 induces human OC apoptosis through activation of CRTH2 and the apoptosis intrinsic pathway.

► Prostaglandin D2 increases apoptosis rate in humans osteoclasts in culture. ► This apoptotic effect is mediated by the CRTH2 but not by the DP receptor. ► Activation of the CRTH2 receptors leads to osteoclast apoptosis through the intrinsic pathway.