Abstract
Mechanical strain is an important determinant of bone mass and architecture, and the aim of this investigation was to further understand the role of the cell–cell signaling molecules, IL-1β, TNF-α, and IL-6 in the mechanobiology of bone. Mouse calvarial osteoblasts in monolayer culture were subjected to a cyclic out-of-plane deformation of 0.69% for 6 s, every 90 s for 2–48 h, and the levels of each cytokine plus their downstream targets RANKL and OPG measured in culture supernatants by ELISAs. Mouse osteoblasts constitutively synthesized IL-1β, TNF-α, and IL-6, the production of which was significantly up-regulated in all three by cyclic mechanical strain. RANKL and OPG were also constitutively synthesized; mechanical deformation however, resulted in a down-regulation of RANKL and an up-regulation OPG synthesis. We next tested whether the immunoreactive RANKL and OPG were biologically active in an isolated osteoclast resorption pit assay – this showed that culture supernatants from mechanically deformed cells significantly inhibited osteoclast-mediated resorptive activity across the 48 h time-course. These findings are counterintuitive, because IL-1β, TNF-α, and IL-6 have well-established reputations as bone resorptive agents. Nevertheless, they are pleiotropic molecules with multiple biological activities, underlining the complexity of the biological response of osteoblasts to mechanical deformation, and the need to understand cell–cell signaling in terms of cytokine networks. It is also important to recognize that osteoblasts cultured in vitro are deprived of the mechanical stimuli to which they are exposed in vivo – in other words, the cells are in a physiological default state that in the intact skeleton leads to decreased bone strains below the critical threshold required to maintain normal bone structure.
Highlights
Mechanical stimuli play an important role in the growth, structure, and maintenance of skeletal tissues
Using mouse calvarial osteoblasts as our model, the aim of this study was to determine the effect of cyclic mechanical strain on the synthesis and biological activity of the pleiotropic cytokines IL-1β, tumor necrosis factor (TNF)-α, IL-6, and their downstream targets RANKL and OPG
Kusumi et al [34] have reported a decrease in RANKL mRNA expression and sRANKL release from human osteoblasts following 7% cyclic tensile strain; they found that mechanical strain increased OPG synthesis
Summary
Mechanical stimuli play an important role in the growth, structure, and maintenance of skeletal tissues. It has been estimated that environmental factors such as physical activity and nutrition account for 20–40% of individual variation in bone mass, the remaining 60–80% being determined by genetic factors [1, 2]. Bone resorption and bone formation are said to be coupled, a process of renewing the skeleton while maintaining its structural integrity, embodied in the A-R-F (activation-resorption-formation) sequence of the bone remodeling cycle. Bone remodeling is orchestrated by cells of the osteoblast lineage and involves a complex network of cell–cell signaling mediated by systemic osteotropic hormones, locally produced cytokines, growth factors, and the mechanical environment of the cells [10,11,12,13]. One of the most significant developments in connective tissue biology during the 1980s was the finding that cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and IL-6, originally identified as immunoregulatory molecules, could act as regulators of pathophysiological resorption [14,15,16,17] and were produced by many different cell types including osteoblasts [18]
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