Osteoblasts display receptors for and responses to leukemia‐inhibitory factor

Abstract

Specific binding of leukemia-inhibitory factor (LIF) to osteoblasts, but not multinucleated osteoclasts, was demonstrated by receptor autoradiography by using cells isolated from newborn rat long bones. The clonal rat osteogenic sarcoma cells, UMR 106-06, which have several phenotypic properties of osteoblasts, expressed 300 LIF receptors per cell, with an apparent KD of 60 pM. Treatment of calvarial osteoblasts or UMR 106-01 cells with LIF resulted in a dose-dependent inhibition of plasminogen activator (PA) activity. Both calvarial osteoblasts and osteogenic sarcoma cells were shown by Western blotting and reverse fibrin autography to produce plasminogen activator inhibitor-1 (PAI-1), the production of which was increased by LIF treatment. Northern blot analysis revealed that LIF treatment resulted in a rapid (peak 1 hour), dose-dependent increase in mRNA for PAI-1. LIF treatment of the preosteoblast cell line, UMR 201, enhanced the alkaline phosphatase response of these cells to retinoic acid. Each of the osteoblast-like cell types (calvarial osteoblasts, UMR 106-06, and UMR 201) was shown to produce LIF by bioassay and, by using the polymerase chain reaction (PCR), was shown to express low levels of mRNA for LIF. These data establish that cells of the osteoblast lineage are targets for LIF action. The reported anabolic effects of this cytokine on bone formation in vivo could be related to inhibition of protease activity. LIF may be an important paracrine modulator in bone, or perhaps an autocrine one, based on the evidence for its production by osteoblasts and osteoblast-like cells.

Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice

“…Adult mouse bone stained positively for OSMR and LIFR in osteoblasts, bone-lining cells, and osteocytes, but not in osteoclasts or negative control sections (Figure 1, C-E). LIFR was also detected in marrow cells, including megakaryocytes and endothelial cells, consistent with previous reports (27)(28)(29).…”

Stimulation by Parathyroid Hormone of Interleukin-6 and Leukemia Inhibitory Factor Expression in Osteoblasts Is an Immediate-early Gene Response Induced by cAMP Signal Transduction

“…18). IL-1, IL-6, tumor necrosis factor, transforming growth factor ␤, and lipopolysaccharide have also been shown to stimulate LIF expression by osteoblasts (3,4,10,16,17,36,77). Thus, production of IL-6, and perhaps LIF, may be critically involved in stimulation of resorption by a wide variety of agents in addition to those examined in this study that activate cAMP signal transduction.…”

“…Murine IL-6 primers were previously described (3) and the rat IL-6 primers were modified versions of the mouse primers based on the published rat sequence (34). LIF primers were previously described (3) and were used for both mouse and rat, as they are based on the murine sequence (35) and have been used by other workers with UMR cells (36). Actin mRNA levels were employed in all experiments as a constitutive control using the PCR primers described in Ref.…”

“…Thus, production of IL-6, and perhaps LIF, may be critically involved in stimulation of resorption by a wide variety of agents in addition to those examined in this study that activate cAMP signal transduction. Alternatively, LIF may be involved in stimulation of bone formation by PTH (78) since LIF increases osteoblastic differentiation (36,79) while IL-6 has been reported to inhibit this process (80).…”

Detection of receptors for interleukin-6, interleukin-11, leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor in bone marrow stromal/osteoblastic cells.

“…Besides IL-6 and IL-11, another member of the cytokine subfamily that uses gp130, namely LIF, has been shown to play a role in bone biology. Indeed, LIF receptors have been detected in stromal/ osteoblastic cells and LIF potentiates the expression of alkaline phosphatase and type I collagen synthesis in these cells (16)(17)(18)(19). Further, overexpression of LIF causes ectopic bone formation and resorption (20), and targeted disruption of the LIFR ␤ gene results in decreased bone volume (threefold) and increased osteoclast numbers (sixfold) (21).…”