Prostaglandins and Bone

Prostaglandins (PGs) are highly bioactive fatty acids. PGs, especially prostaglandin E₂ (PGE₂), are abundantly produced by cells of both the bone-forming (osteoblast) lineage and the bone-resorbing (osteoclast) lineage. The inducible cyclooxygenase, COX-2, is largely responsible for most PGE₂ production in bone, and once released, PGE₂ is rapidly degraded in vivo. COX-2 is induced by multiple agonists - hormones, growth factors, and proinflammatory factors - and the resulting PGE₂ may mediate, amplify, or, as we have recently shown for parathyroid hormone (PTH), inhibit responses to these agonists. In vitro, PGE₂ can directly stimulate osteoblast differentiation and, indirectly via stimulation of RANKL in osteoblastic cells, stimulate the differentiation of osteoclasts. The net balance of these two effects of PGE₂ in vivo on bone formation and bone resorption has been hard to predict and, as expected for such a widespread local factor, hard to study. Some of the complexity of PGE₂ actions on bone can be explained by the fact that there are four receptors for PGE₂ (EP1-4). Some of the major actions of PGE₂ in vitro occur via EP2 and EP4, both of which can stimulate cAMP signaling, but there are other distinct signaling pathways, important in other tissues, which have not yet been fully elucidated in bone cells. Giving PGE₂ or agonists of EP2 and EP4 to accelerate bone repair has been examined with positive results. Further studies to clarify the pathways of PGE₂ action in bone may allow us to identify new and more effective ways to deliver the therapeutic benefits of PGE₂ in skeletal disorders.