Biphasic effects of interleukin‐1β on osteoblast differentiation in vitro

Abstract

A rat calvarial cell model of osteoblast differentiation using the formation of bone nodules in vitro as an endpoint was used to assess the effects of IL-1b on osteoblast differentiation. Short-term treatment (2 days) with IL-1b early in culture resulted in increased nodule number and size as well as calcium content in contrast to long-term treatment (6 days) in cultures assessed at 10-12 days. This increase in bone formation was blocked by IL-1 receptor antagonists. Short-term treatment increased COX-2, prostaglandin (PGE 2 ), and iNOS production. Exogenous PGE 2 with IL-1b enhanced this effect. COX-2 inhibitors, indomethacin and N-39, blocked 50% of nodule formation. NO donor did not modify effects of IL-1b, but iNOS inhibitor (1400W) partially blocked the effects. However, PGE 2 and NO donors could not rescue the decreased nodule number resulting from long-term IL-1b treatment. The results of this study suggest a biphasic effect of IL-1b on bone nodule formation activated by IL-1b binding with IL-1 receptors, and the anabolic effect of early short-term treatment with IL-1b is likely mediated by PGE without ruling out nitric oxide. Keywords: IL-1b; bone nodule; prostaglandin; osteoblast; differentiation Local factors regulating bone formation can be grouped into factors isolated from the matrix, factors synthesized by skeletal cells, and factors synthesized by cells from adjoining tissues.1 Inflammatory cytokines, which can be produced by osteoblasts or surrounding stromal or inflammatory cells may play a role in the local control of bone formation. Interleukin-1b (IL-1b), a potent cytokine with diverse biological activities, is produced by osteoblasts 2 and has receptors on osteoblasts. 3 IL-1 has been reported in association with both clinical bone loss and bone formation. Increased local levels of IL-1 in areas of clinical bone loss associated with chronic inflammatory reactions 4-6 have been described. In vitro models have confirmed the catabolic effects of continuous exposure to IL-1 to bone cells. [7][8][9] The anabolic effects of acute inflammatory reactants on bone formation have been largely neglected, although they were reported as early as 1941, when Kü ntscher described his ''callus without fracture '' experiments. 10 An acute inflammatory phase is an early and important phase of fracture healing. IL-1 protein or mRNA has been noted transiently at sites of impending bone formation. In the present study the time and dose effects of IL-1b on bone formation were investigated using cultures of rat calvarial cells that have the capability to form discrete nodules of woven bone.32 Each nodule is the clonal product of differentiation of a single osteoprogenitor cell, 33 allowing assessment of differentiation using bone formation as an endpoint. The role of NO and PGE as mediators of IL-1b effects were also investigated.A better understanding of the role of IL-lb in the local control of osteoblast differentiation may shed light on a variety of clinical problems in which bone formation, or la...

Melatonin mediates protective effects on inflammatory response induced by interleukin‐1 beta in human mesenchymal stem cells

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