ENDOTHELIN RECEPTORS, 2ND MESSENGERS, AND ACTIONS IN BONE

Endothelins are a class of peptides that are produced by and elicit re sponses in many tissues. A growing literature documents the presence a nd effects of endothelins in bone. Both endothelin, and endothelin, re ceptors have been demonstrated in osteoblastic cells by ligand binding . Major signal transduction pathways for endothelin in bone cells appe ar to be stimulation of phospholipid turnover, by activation of A, C a nd D phospholipases, stimulation of calcium flux from intracellular an d extracellular stores and activation of tyrosine kinases. Endothelins also modulate calcium signaling elicited by other agents in osteoblas tic cells. The parathyroid hormone-stimulated calcium transient in UMR -106 cells is enhanced by endothelins, acting through an endothelin, r eceptor, whereas the parathyroid hormone-stimulated increase in cyclic AMP is inhibited by endothelins. Phenotypic responses to endothelin-l include changes in alkaline phosphatase activity, stimulation of oste ocalcin and osteopontin message, stimulation of collagen and noncollag enous protein synthesis, inhibition of osteoclast motility and stimula tion of prostaglandin-dependent resorption. Endothelin-l also enhances the interleukin-l-induced increase in interleukin-6. Endothelins can also potentially affect calcium metabolism through their actions to in hibit the secretion of parathyroid hormone.