1. Academic Validation
  2. Protein Kinase G Activation Reverses Oxidative Stress and Restores Osteoblast Function and Bone Formation in Male Mice With Type 1 Diabetes

Protein Kinase G Activation Reverses Oxidative Stress and Restores Osteoblast Function and Bone Formation in Male Mice With Type 1 Diabetes

  • Diabetes. 2018 Apr;67(4):607-623. doi: 10.2337/db17-0965.
Hema Kalyanaraman 1 Gerburg Schwaerzer 1 Ghania Ramdani 1 Francine Castillo 1 Brian T Scott 1 Wolfgang Dillmann 1 Robert L Sah 2 Darren E Casteel 1 Renate B Pilz 3
Affiliations

Affiliations

  • 1 Department of Medicine, University of California, San Diego, La Jolla, CA.
  • 2 Department of Bioengineering, University of California, San Diego, La Jolla, CA.
  • 3 Department of Medicine, University of California, San Diego, La Jolla, CA rpilz@ucsd.edu.
Abstract

Bone loss and fractures are underrecognized complications of type 1 diabetes and are primarily due to impaired bone formation by osteoblasts. The mechanisms leading to osteoblast dysfunction in diabetes are incompletely understood, but Insulin deficiency, poor glycemic control, and hyperglycemia-induced oxidative stress likely contribute. Here we show that Insulin promotes osteoblast proliferation and survival via the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) signal transduction pathway and that PKG stimulation of Akt provides a positive feedback loop. In osteoblasts exposed to high glucose, NO/cGMP/PKG signaling was reduced due in part to the addition of O-linked N-acetylglucosamine to NO synthase-3, oxidative inhibition of Guanylate Cyclase activity, and suppression of PKG transcription. Cinaciguat-an NO-independent activator of oxidized guanylate cyclase-increased cGMP synthesis under diabetic conditions and restored proliferation, differentiation, and survival of osteoblasts. Cinaciguat increased trabecular and cortical bone in mice with type 1 diabetes by improving bone formation and osteocyte survival. In bones from diabetic mice and in osteoblasts exposed to high glucose, cinaciguat reduced oxidative stress via PKG-dependent induction of antioxidant genes and downregulation of excess NADPH oxidase-4-dependent H2O2 production. These results suggest that cGMP-elevating agents could be used as an adjunct treatment for diabetes-associated osteoporosis.

Figures
Products