Effects of leukemia inhibitory factor on bone resorption and DNA synthesis in neonatal mouse calvaria

Leukemia inhibitory factor (LIF) is a recently characterized cytokine which has been shown to regulate cell growth and differentiation in a variety of tissues. We have shown that LIF stimulates bone resorption and DNA synthesis in bone organ culture and, in vivo, LIF has been shown to have marked effects on bone remodeling. The present study examines further the dose-response, time course and mechanisms of action of LIF in neonatal mouse calvaria. 45Ca release was significantly increased by LIF at concentrations of 10-5,000 U/ml, and its stimulation of bone resorption increased with time from 24 to 96 hours. These concentrations of LIF also increased DNA synthesis at 24 hours. At 72 hours, low concentrations of LIF produced less marked stimulation of [3H]-thymidine incorporation, and 5,000 u/ml actually inhibited DNA synthesis at both this time point and at 96 hours. The effect of LIF on 45Ca release was partially inhibited when DNA synthesis was blocked by hydroxyurea (50 microM). The resorptive effect of supramaximal concentrations of LIF was not additive to that of parathyroid hormone, 1,25-dihydroxyvitamin D3, prostaglandin E2, or transforming growth factor-beta. Although LIF-stimulated resorption is at least partially dependent on DNA synthesis, these results suggest that there are different mechanisms involved in mediating LIF's effects on bone resorption and DNA synthesis. The demonstration of effects of LIF at low concentrations indicates that this cytokine may be involved in the physiological regulation of bone metabolism in vivo.