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Protein Kinase G Activation Reverses Oxidative Stress and Restores Osteoblast Function and Bone Formation in Male
Hema Kalyanaraman1, Gerburg Schwaerzer1, Ghania Ramdani1
1Department of Medicine, University of California, San Diego, La Jolla, CA.
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.
Insights
Type 1 diabetes impairs bone health by reducing osteoblast function. Cinaciguat, a novel drug, restored bone formation and survival in diabetic models by targeting the nitric oxide/cyclic guanosine monophosphate/protein kinase G pathway.
Area of Science:
- Endocrinology
- Bone Biology
- Pharmacology
Background:
- Type 1 diabetes is linked to bone loss and fractures, primarily due to impaired osteoblast function.
- Mechanisms include insulin deficiency, poor glycemic control, and oxidative stress, but are not fully understood.
- Insulin signaling via nitric oxide/cyclic guanosine monophosphate/protein kinase G (NO/cGMP/PKG) promotes osteoblast proliferation and survival.
Purpose of the Study:
- To investigate the mechanisms of osteoblast dysfunction in type 1 diabetes.
- To evaluate the therapeutic potential of cinaciguat, an activator of guanylate cyclase, in diabetic bone disease.
Main Methods:
- Examined NO/cGMP/PKG signaling in osteoblasts under high glucose conditions.
- Assessed the effects of cinaciguat on osteoblast function and bone parameters in type 1 diabetic mice.
- Investigated cinaciguat's impact on oxidative stress markers and antioxidant gene expression.
Main Results:
- High glucose reduced NO/cGMP/PKG signaling in osteoblasts through O-linked N-acetylglucosamine modification of NO synthase-3, guanylate cyclase inhibition, and PKG suppression.
- Cinaciguat restored osteoblast proliferation, differentiation, and survival under diabetic conditions.
- Cinaciguat increased trabecular and cortical bone mass in diabetic mice by enhancing bone formation and osteocyte survival, while reducing oxidative stress.
Conclusions:
- Dysfunctional NO/cGMP/PKG signaling contributes to bone loss in type 1 diabetes.
- Cinaciguat effectively reverses diabetes-associated bone loss by activating cGMP synthesis and reducing oxidative stress.
- cGMP-elevating agents represent a promising therapeutic strategy for managing osteoporosis in type 1 diabetes.
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