Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation

Abstract

Bone remodeling, comprising resorption of existing bone and de novo bone formation, is required for the maintenance of a constant bone mass. Prostaglandin (PG)E 2 promotes both bone resorption and bone formation. By infusing PGE 2 to mice lacking each of four PGE receptor (EP) subtypes, we have identified EP4 as the receptor that mediates bone formation in response to this agent. Consistently, bone formation was induced in wild-type mice by infusion of an EP4-selective agonist and not agonists specific for other EP subtypes. In culture of bone marrow cells from wild-type mice, PGE2 induced expression of core-binding factor ␣1 (Runx2͞Cbfa1) and enhanced formation of mineralized nodules, both of which were absent in the culture of cells from EP4-deficient mice. Furthermore, administration of the EP4 agonist restored bone mass and strength normally lost in rats subjected to ovariectomy or immobilization. Histomorphometric analysis revealed that the EP4 agonist induced significant increases in the volume of cancellous bone, osteoid formation, and the number of osteoblasts in the affected bone of immobilized rats, indicating that activation of EP4 induces de novo bone formation. In addition, osteoclasts were found on the increased bone surface at a density comparable to that found in the bone of control animals. These results suggest that activation of EP4 induces bone remodeling in vivo and that EP4-selective drugs may be beneficial in humans with osteoporosis.B ones undergo continuous remodeling through repeated cycles of destruction and rebuilding (1). This remodeling is mediated by the well balanced actions of osteoclasts, which resorb old bones, and osteoblasts, which form new bones. However, in the elderly, especially in postmenopausal women, the extent of bone resorption far exceeds that of bone rebuilding, resulting in osteoporosis and the associated increases in bone fragility and susceptibility to fractures (2). About 100 million people are estimated to suffer from this debilitating disease worldwide. Several drugs have been developed to treat osteoporosis, with most inhibiting bone resorption and only a few promoting bone formation (3). Such modulation of only one of the two processes in bone remodeling renders these drugs of limited efficacy in restoring the normal balance and bone mass.Recently, significant advances have been made in our understanding of molecular mechanisms of osteoclast and osteoblast differentiation (4), but such knowledge has not been exploited fully to develop a drug that corrects the imbalance and restores normal bone remodeling. Prostaglandins (PGs) are a group of lipid mediators that are produced from arachidonic acid in a variety of tissues under various physiological and pathophysiological conditions and serve to maintain local homeostasis (5). Among them, PGs of the E type work bimodally in bone metabolism (6). PGE 2 potently induces bone resorption in bone organ cultures, whereas repeated injection of this compound in vivo induces bone formation in a variety of animals includ...

Prostaglandin E2 receptors in bone formation

“…In the bone marrow cell cultures, mineralised nodule formation was absent and could not be increased by treatment with PGE 2 [25]. When PGE 2 was infused onto the periosteal surfaces of femurs, it caused local bone formation in the wild type but not in EP4 KO mice [26]. The lack of skeletal phenotype in the adult EP4 KO mice suggests that EP4 receptor is not essential for the bone growth and maturation in mice [17].…”

Peptide drugs accelerate BMP‐2‐induced calvarial bone regeneration and stimulate osteoblast differentiation through mTORC1 signaling

“…Signaling through the BMP 21, PGE2 22, or Wnt receptors 23 eventually results in the stimulation of Runx2 expression, an early marker of osteoblast differentiation. It was recently demonstrated that rapamycin, which is an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), a serine/threonine kinase, inhibited osteoblast differentiation through the reduction of Runx2 expression in an osteoblast cell line and bone marrow‐derived stromal cells 24.…”

Nanogel‐based scaffold delivery of prostaglandin E2 receptor–specific agonist in combination with a low dose of growth factor heals critical‐size bone defects in mice

“…Prostaglandin E 2 (PGE 2 ) is an anabolic nonpeptide reagent that has been implicated as having a role in bone formation (5)(6)(7)(8)(9). However, PGE 2 causes severe side effects systemically, and 3 daily injections of PGE 2 for several weeks are required to stimulate bone formation (9).…”

“…However, PGE 2 causes severe side effects systemically, and 3 daily injections of PGE 2 for several weeks are required to stimulate bone formation (9). The anabolic action of PGE 2 in target cells is mediated by G protein-coupled receptor subtypes, including EP1, EP2, EP3, and EP4.…”

“…Among these, EP4 receptor is predominantly expressed in osteoblasts (10,11). Synthetic agonists specific for EP4 receptor have been developed as chemicals, and systemic administration of EP4 receptor agonist (EP4A) by daily injection for 20 days suppressed bone loss in ovariectomized and immobilized rats (9). In addition, continuous minipump infusion for 6 weeks accelerated fracture healing in animal models (12), and administration of EP4A by subcutaneous injection twice daily for 4 weeks also promoted healing of cortical bone defects produced in femora (13).…”