P2X7R-Panx1 complex impairs bone mechanosignaling under high glucose levels associated with type-1 diabetes

Zeynep Seref-Ferlengez, Stephanie Maung, Mitchell B. Schaffler, David C. Spray, Sylvia O. Suadicani, Mia M. Thi

Research output: Contribution to journalArticle

22 Citations (Scopus)

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/cm2), 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.

Original languageEnglish (US)
Article numbere0155107
JournalPLoS One
Volume11
Issue number5
DOIs
StatePublished - May 1 2016

Fingerprint

insulin-dependent diabetes mellitus
Medical problems
Type 1 Diabetes Mellitus
Bone
Osteocytes
bones
Bone and Bones
Glucose
glucose
Adenosine Triphosphate
osteoblasts
Osteoblasts
Western blotting
Western Blotting
Purinergic P2X7 Receptors
calcium
Purinergic Receptors
bone fractures
Bone Fractures
bone density

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

P2X7R-Panx1 complex impairs bone mechanosignaling under high glucose levels associated with type-1 diabetes. / Seref-Ferlengez, Zeynep; Maung, Stephanie; Schaffler, Mitchell B.; Spray, David C.; Suadicani, Sylvia O.; Thi, Mia M.

In: PLoS One, Vol. 11, No. 5, e0155107, 01.05.2016.

Research output: Contribution to journalArticle

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