Abstract
Diabetes mellitus disrupts bone homeostasis, inducing bone fragility, through mechanisms involving chronic inflammation and altered cellular signaling. Osteocytes, the primary mechanosensory cells in bone, play a pivotal role in regulating bone remodeling via the secretion of factors that influence both osteoclast and osteoblast activity. We investigated the impact of high glucose on osteocytic parathyroid hormone receptor type 1 (PTH1R) expression and its downstream effects on interleukin-6 (IL-6) secretion, macrophage polarization, and osteoclastogenesis. Using both in vitro and ex vivo bone models, we demonstrate that elevated glucose levels in static conditions without mechanical stimulation induce the overexpression of PTH1R in osteocytes. PTH1R upregulation in turn enhances osteocytic IL-6 secretion associated with the promotion of a pro-inflammatory macrophage M1 phenotype (increased tumor necrosis factor (TNF)-α/CD206 and inducible nitric oxide synthase (iNOS)/CD206 ratios) and the upregulation of the pro-osteoclastogenic markers tartrate-resistant acid phosphatase (TRAP) and receptor activator of nuclear factor kappa-Β (RANK). Neutralization of IL-6 in the osteocytic secretome attenuated macrophage inflammatory gene overexpression, underscoring IL-6's critical role in this regulatory axis. Our findings reveal that a high-glucose environment triggers osteocytic dysregulation of PTH1R-mediated signaling pathways, amplifying inflammatory and osteoclastogenic activity in bone via IL-6. This osteocyte-macrophage crosstalk may contribute to the increased bone resorption and impaired regeneration observed in diabetic bone disease. Targeting PTH1R upregulation and the IL-6 signaling pathway in osteocytes could represent a novel therapeutic approach to mitigating bone complications associated with diabetes.