Exercise, interleukins and bone homeostasis

The proper balance between the production of osteoclastogenic and anti-osteoclastogenic interleukins by immune and bone cells is critical for the preservation of bone homeostasis and the maintenance of optimal bone mass. This article summarizes the mechanisms whereby interleukins with osteoclastogenic properties (interleukin1β, interleukin 17A, interferon-γ, and tumor necrosis factor-α) and anti-osteoclastogenic properties (interleukin-1 receptor antagonist, interleukin 4, interleukin-6, interleukin-10, interleukin 13, and transforming factor-β) effect the activities of osteoblasts, osteoclasts and osteocytes. It points out that long term moderate intensity aerobic exercise training can provide a cost-effective means for achieving a proper balance between immune cells producing osteoclastogenic and anti-osteoclastogenic interleukins. Introduction Interest in cytokines as regulators of bone metabolism began with the experiments of Horton and associates who, in 1972, found that conditioned medium from phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells contained bone resorbing (osteoclastogenic) activity [1]. This activity was eventually found to be due to interleukin (IL)-1 and tumour necrosis factor (TNF)-α [2,3], prompting a series of studies examining the role of these and other proinflammatory cytokines as mediators of bone resorption in periodontal disease, rheumatoid arthritis, osteolytic malignancies, and osteoporosis [4-9]. In addition to IL-1 and TNF-α, the spectrum of cytokines with osteoclastogenic effects has expanded to include IL-17A [10]. In blood, these cytokines are variably produced by T helper type 1 (Th1) cells, natural killer (NK) cells, Th1-derived CD8+ T cells, Th17 cells, and M1polarized macrophages [11,12]. Subsequent studies have identified several interleukins whose activities inhibit bone resorption and/or promote bone formation (antiosteoclastogenic cytokines). These include IL-1 receptor antagonist (IL-1Ra), IL4, IL-10, IL-13 and transforming growth factor (TGF)-β [10,13]. In blood, these cytokines are variably produced by Th2 cells, T and B regulatory cells, T follicular helper (TFH) cells, M2-polarized macrophages, and T2-derived CD8+ T cells [10-13]. There are several pleiotropic cytokines, interferon (IFN)-λ and IL6, whose effects on bone varies depending on experimental conditions; however, in most circumstances IL-6 is anti-osteoclastogenic whereas IFNλ is osteoclastogenic [14]. In blood, IFN-λ is produced by Th1 cells and M1-polarized macrophages, whereas IL-6 is produced primarily by macrophages [10-13]. Immune cells occupying the microenvironment of bone are ideally situated to influence the ontogeny and functioning of cells responsible for bone formation (osteoblasts), bone resorption (osteoclasts) and the transduction of bone loading signals (osteocytes) [14]. Osteoblasts and osteoclasts are derived from bone marrow stromal mononuclear cells, and retain the capacity to produce several cytokines, particularly IL-6 and TGF-β. Osteocytes are derived from osteoblasts as they age and become imbedded in the lacuno-canalicular network of bone [15]. Mechanism of action Osteoclastogenic interleukins IL-1α and TNF-α promote osteoclastogenesis by inducing osteoblasts to express receptor activator of nuclear factor kappa B (NFKB) ligand (RANKL) and bind to RANKL receptors (RANK) on stromal osteoclast precursors, or produce soluble RANKL to perform the same function [5,8]. TNF-α potently activates osteoclasts through a direct action independent of and strongly synergistic with RANKL [16]; it also inhibits bone formation in vitro [17]. IL-1α and TNF-α exert potent anti-apoptotic effects on osteoclasts [10], and interact synergistically with one another [18] and with PTH [19] to enhance their bone resorptive capacities. IL-17A induces RANKL expression in osteoblasts, promoting the differentiation of osteoclasts from their stromal mononuclear cell precursors. This cytokine has the capacity to activate macrophages to secrete IL-1β and TNF-α, thereby indirectly upregulating osteoclastogenesis. In rodents, neutralization of IL-17A with polyclonal anti-17A antibody has been shown to downregulate bone erosion, RANKL expression, and the number of RANKL positive cells in inflamed joints [10]. IFN-λ effects on bone metabolism varies depending on experimental conditions [20]. It inhibits RANKLinduced osteoclastogenesis by degrading the RANK adapter protein TRAF6 (tumor necrosis factor receptor-associated factor 6), a mechanism felt to protect against excessive. T cell-mediated bone resorption [21]. Recombinant IFN-λ has also been shown to preferentially inhibit IL-1 and TNF-stimulated bone resorption in vitro [22], and to be osteoprotective when administered to ovariectomized mice [23]. In Correspondence to: John Kelly Smith, Department of Academic Affairs, East Tennessee State University, Tennessee, USA, Tel: + 423-439-8005; E-mail: SMITHJ@mail.etsu. edu