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Leukotriene B⁴ Increases Intracellular Calcium Concentration and Phosphoinositide Metabolism in Mouse Osteoblasts via Cyclic Adenosine 3', 5'-Monophosphate-Independent Pathways^*

Strangeways Research Laboratory Wort's Causeway, Cambridge CB1 4RN
Cambridge University Biochemistry Department Cambridge CB2 1QW, United Kingdom

Address correspondence and reprint requests to: Dr. R. W. Farndale, Cambridge University Biochemistry Department, Tennis Court Road, Cambridge CB2 1QW, United Kingdom.

Abstract

Leukotriene B₄ is one of a number of agents which stimulate bone resorption by acting on osteoblasts. Some agonists, such as PTH or prostaglandins, are known to activate adenylate cyclase in osteoblasts, whereas others, such as vitamin D₃, have no effect on adenylate cyclase. Recent evidence suggests that both classes of agonist may raise the intracellular calcium concentration, although the relative importance for bone resorption of calcium mobilization and adenylate cyclase activity in the osteoblast is not clear. Here it is shown 1) that leukotriene B₄ does not activate but may be inhibitory toward adenylate cyclase in intact osteoblasts or membrane preparations, 2) that leukotriene B₄ causes an elevation of intracellular calcium levels in osteoblast monolayers, 3) leukotriene B₄ rapidly activates phosphatidylinositol bisphosphate breakdown in osteoblast membranes and intact osteoblasts, and 4) that leukotriene B₄ stimulates phosphatidylinositol kinase activity concurrently with phosphoinositidase C in intact osteoblasts over a similar timescale. These results suggest that leukotriene B₄ may increase the concentration of intracellular calcium in osteoblasts by stimulating phosphoinositide turnover, and support the proposal that calcium signaling rather than activation of adenylate cyclase in osteoblasts may be of overriding importance in the regulation of bone resorption.

Footnotes

^* This work was supported by Medical Research Council grants (to J.R.S., R.W.F., and M.C.M.). Dr. Meikle is also supported by the Arthritis and Rheumatism Council and Dr. Farndale by CORDA, the heart charity.

Received December 3, 1990.

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