P2X7R-Panx1 Complex Impairs Bone Mechanosignaling under High Glucose Levels Associated with Type-1 Diabetes
Year: 2016
Type: article
Abstract: Type 1 diabetes (T1D) causes a range of skeletal problems, including reduced bone density and increased risk for bone fractures. However, mechanisms underlying skeletal complications in diabetes are still not well understood. We hypothesize that high glucose levels in T1D alters expression and function of purinergic receptors (P2Rs) and pannexin 1 (Panx1) channels, and thereby impairs ATP signaling that is essential for proper bone response to mechanical loading and maintenance of skeletal integrity. We first established a key role for P2X7 receptor-Panx1 in osteocyte mechanosignaling by showing that these proteins are co-expressed to provide a major pathway for flow-induced ATP release. To simulate in vitro the glucose levels to which bone cells are exposed in healthy vs. diabetic bones, we cultured osteoblast and osteocyte cell lines for 10 days in medium containing 5.5 or 25 mM glucose. High glucose effects on expression and function of P2Rs and Panx1 channels were determined by Western Blot analysis, quantification of Ca2+ responses to P2R agonists and oscillatory fluid shear stress (± 10 dyne/cm(2)), and measurement of flow-induced ATP release. Diabetic C57BL/6J-Ins2Akita mice were used to evaluate in vivo effects of high glucose on P2R and Panx1. Western blotting indicated altered P2X7R, P2Y2R and P2Y4R expression in high glucose exposed bone cells, and in diabetic bone tissue. Moreover, high glucose blunted normal P2R- and flow-induced Ca2+ signaling and ATP release from osteocytes. These findings indicate that T1D impairs load-induced ATP signaling in osteocytes and affects osteoblast function, which are essential for maintaining bone health.
Source: PLoS ONE
Authors: Zeynep Seref-Ferlengez, Stephanie Maung, Mitchell B. Schaffler, David C. Spray, Sylvia O. Suadicani, Mia M. Thi
Language: English
Subfield: Physiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,382
Awards: Urothelial ATP Signaling and Diabetic Bladder Dysfunction, Liver Pathobiology and Gene Therapy Research Core Center, Ostecocyte Intergrity and Bone Remodeling, Structural, Molecular, and Functional Specialization in Osteocyte Mechanosensing, G3524644092, G363488643, G3670665632, Luminescence Imaging: Molecules, Cells and Tissues, G589777270, G6257264241, Effects of High Glucose on Bone Cell Mechanosensing, Transduction, and Signaling, NYR-Diabetes Research Center (NYR-DRC)
OpenAlex ID: W2346358086