PMID: 8613966Apr 1, 1996Paper

Effects of wortmannin analogs on bone in vitro and in vivo

The Journal of Pharmacology and Experimental Therapeutics
M SatoC J Vlahos

Abstract

The possible importance of phosphatidylinositol (PI) 3-kinase activity in bone resorption activity in vitro and in vivo were evaluated with synthetic wortmannin analogs in two in vitro bone resorption assays, two in vitro assays for PI 3-kinase activity and for the first time, in two in vivo rat models. Wortmannin and LY301497 were shown to be potent, dose-dependent inhibitors of the bone resorption activity of differentiating chicken osteoclast-like cells and isolated rat osteoclasts. A similar structure/activity profile and potency relationship was observed for the inhibition of osteoclastic activity and of bovine PI 3-kinase activity with purified enzyme, as well as direct inhibition of the PI 3-kinase activity of chicken osteoclast lysates. These in vitro data identified LY301497 as an inhibitor of bone resorption that is 10-fold more potent than wortmannin itself, and the most potent inhibitor of PI 3-kinase activity identified thus far. Wortmannin and analogs also lowered the osteoclast-dependent serum calcium levels like salmon calcitonin in a rat model of secondary hyperparathyroidism. More directly, oral administration of wortmannin analogs prevented the estrogen deficiency-induced loss of trabecular bone in the metaph...Continue Reading

Related Concepts

Related Feeds

AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.