Abstract
Background: The receptor activator of NF-κβ (RANK)/RANK ligand/ osteoprotegerin system is essential for osteoclast maturation and activation to induce bone loss, which plays a role in postmenopausal osteoporosis. Estrogen deficiency in postmenopausal women is associated with T-cell mediated inflammation with increased proinflammatory cytokines, such as IL-17A, IL-1, IL-6 and tumor necrosis factor alpha. Bone repair and remodeling processes highlight the role of nerve growth factor β (NGFβ), whose non-neural production is associated with T-cell mediated inflammation.
Aims: To investigate the involvement of IL-17A and NGFβ cytokines in the elevation of serum soluble RANK ligand levels in postmenopausal and control women.
Methods: Fifty-two postmenopausal and 37 control women were studied for age, body mass index, homeostasis model assessment (HOMA) index, serum levels of IL-17A, NGFβ, soluble RANK ligand (measured by indirect enzyme-linked immunosorbent assay) and estrogen (measured by chemiluminescence assay). Two- and three-way ANOVA (expressed as median with Q1 to Q3) and linear regression analysis were used to evaluate the strength of relationship between soluble RANK ligand levels as dependent and age, serum IL-17A and NGFβ levels as independent variables.
Results: A significant difference in age, serum NGFβ and estrogen levels could be demonstrated between postmenopausal and control women (with borderline significance in HOMA indices). The differences in serum IL-17A and NGFβ levels were relevant between categories for body mass index in postmenopausal and control women, but in soluble RANK ligand levels only in postmenopausal women. The increase in soluble RANK ligand levels was greater in elevated IL-17A [101(291.75 to 39.92) vs. 45.24(95.56 to 25.34) ng/ml, p<0.015] and elevated NGFβ [222.2(142.75 to 1086.87) vs. 52.44(25.87 to 76.88) ng/ml, p<0.0001] categories compared to low categories in postmenopause, but not in controls. Both elevated IL-17A and NGFβ levels resulted in the greatest increase in serum levels of soluble RANK ligand [252.27(159.9 to 1099.64) vs. 41.4(35.91 to 59.94) ng/ml, p<0.0001] compared to elevated IL-17A levels alone.
Conclusion: Both IL-17A and NGFβ cytokines were involved in the increased serum levels of soluble RANK ligand in postmenopausal women. Their joint involvement in postmenopausal osteoporosis highlighted that neurogenic inflammation may play a critical role in bone loss via greater elevated soluble RANK ligand levels induced by concomitant elevated IL-17A and NGFβ levels.