ENDOTHELIN-1 ACTIONS ON RESORPTION, COLLAGEN AND NONCOLLAGEN PROTEIN-SYNTHESIS, AND PHOSPHATIDYLINOSITOL TURNOVER IN BONE ORGAN-CULTURES

The effects of endothelin-1 (ET) on several tissues are mediated by prostaglandins. In this study, we investigated the actions of ET on bone and determined whether they are mediated through prostagland-independent pathways. Bone resorption, collagen, and non-collagen protein synthesis and inositol phosphate (IP) production were studied in neonatal mouse calvaria and fetal rat limb bone cultures. The effects of ET in the calvaria model were examined in the presence or absence of the cyclooxygenase inhibitor indomethacin (INDO). Bone resorption was stimulated by ET in the neonatal mouse calvaria, and this effect was inhibited by INDO. Ca-45 release in the fetal rat limb bones was not affected by ET. ET stimulated collagen and noncollagen protein synthesis significantly in the calvaria model in the presence but not in the absence of INDO, suggesting that the anabolic effects of ET were masked by endogenous prostaglandin production. ET increased phosphatidylinositol turnover in both bone organ cultures. Although the addition of INDO reduced IP production slightly in the mouse calvaria, it was still significantly stimulated by ET. Our results demonstrate that ET has marked effects on bone tissue in vitro. Effects on resorption appear to be prostaglandin dependent, whereas the anabolic effects were not prostaglandin mediated. The stimulatory effects of ET on protein synthesis could be mediated through the IP signaling pathway. Since ET stimulates both bone resorption and anabolism, this peptide may have a role in the coupling of bone remodeling.