Leukemia Inhibitory Factor Suppresses Proliferation, Alkaline Phosphatase Activity, and Type I Collagen Messenger Ribonucleic Acid Level and Enhances Osteopontin mRNA Level in Murine Osteoblast-Like (MC3T3E1) Cells

Abstract

The effect of leukemia inhibitory factor (LIF) on proliferation and phenotypic expression in murine osteoblast-like (MC3T3E1) cells was examined. LIF inhibited the proliferation of these cells by up to 20% and DNA synthesis was inhibited in a dose-dependent manner with an ED50 of about 0.2 ng/ml. The effect of LIF relative to matched controls increased with decreasing serum concentration, reaching 30% inhibition at 0.2% serum. LIF also reduced the stimulatory effects of platelet-derived growth factor and insulin-like growth factor I on DNA synthesis. The inhibition of the DNA synthesis by saturating concentration of transforming growth factor beta was further enhanced by the addition of LIF, suggesting independent pathways for the action of the two growth inhibitors. In addition, LIF reduced alkaline phosphatase activity and the abundance of type I collagen messenger RNA, but increased the level of osteopontin messenger RNA. These findings suggest that LIF may play a role in regulating the function of osteoblasts.

Leukemia inhibitory factor is expressed in cartilage and synovium and can contribute to the pathogenesis of arthritis.

“…Under physiological conditions such as during normal development and in wound healing qualitatively distinct phases of (a) inflammation and protease-mediated connective tissue resorption, (b) inhibition of the expression and function of proteases, and (c) connective tissue cell proliferation and the formation of organ-specific connective tissue can be distinguished. (32)(33)(34)(35)(36)(37). IL-6 is considered to be a major hepatocyte stimulating factor (7) that induces the production of several acute phase proteins that are increased in the serum of patients with arthritis and are used as markers ofdisease activity.…”

“…LIF appears to stimulate osteoblasts directly and it induces the expression of alkaline phosphatase. LIF activation of osteoclasts probably results from the indirect activation of osteoclasts by osteoblasts, since only the latter express LIF receptors (35)(36)(37).…”

cAMP Stimulates Osteoblast-like Differentiation of Calcifying Vascular Cells

“…[ 3 H]Thymidine was added at 1 mCi/ml for an additional 24 h, and [ 3 H]thymidine incorporation was determined as described previously (26). The data were shown as the means Ϯ S.D.…”

Passive immunization of mice against D factor blocks lethality and cytokine release during endotoxemia.

“…First described because of its ability to induce differentiation of murine M1 leukemia cells (3,4), D factor has been independently identified under several synonyms: leukemia inhibitory factor (LIF), differentiation-inhibiting factor (D factor), osteoclast-activating factor (OAF), human interleukin for DA-1 cells (HILDA), cholinergic neuronal differentiation factor (CNDF), hepatocyte-stimulating factor (HSF-II and III), and melanocyte-derived lipoprotein lipase inhibitor (MLPLI), and is now recognized to have pleiotropic actions in regulating metabolism, growth, and differentiation. Although diverse effects of D factor have been identified in vitro (5)(6)(7)(8)(9)(10)(11) and in vivo (12)(13)(14)(15)(16), little is known about its role during acute and chronic inflammation. It can be produced by a variety of cells, including fibroblasts (3,17), monocytes, macrophages (18), and T lymphocytes (19), and its synthesis can be induced by TNF, IL-1, and endotoxin (LPS) (17,20,21).…”