cGMP-dependent protein kinase-2 regulates bone mass and prevents diabetic bone loss

NO/cGMP signaling is important for bone remodeling in response to mechanical and hormonal stimuli, but the downstream mediator(s) regulating skeletal homeostasis are incompletely defined. We generated transgenic mice expressing a partly-activated, mutant cGMP-dependent protein kinase type 2 (PKG2R242Q) under control of the osteoblast-specific Col1a1 promoter to characterize the role of PKG2 in post-natal bone formation. Primary osteoblasts from these mice showed a 2- to 3-fold increase in basal and total PKG2 activity; they proliferated faster and were resistant to apoptosis compared to cells from wild type mice. Male Col1a1-Prkg2R242Q transgenic mice had increased osteoblast numbers, bone formation rates, and Wnt/β-catenin-related gene expression in bone, and a higher trabecular bone mass compared to their wild type litter mates. Streptozotocin-induced type 1 diabetes suppressed bone formation and caused rapid bone loss in wild type mice, but male transgenic mice were protected from these effects. Surprisingly, we found no significant difference in bone micro-architecture or Wnt/β-catenin-related gene expression between female wild type and transgenic mice; female mice of both genotypes showed higher systemic and osteoblastic NO/cGMP generation compared to their male counterparts, and a higher level of endogenous PKG2 activity may be responsible for masking effects of the PKG2R242Q transgene in females. Our data support sexual dimorphism in Wnt/β-catenin signaling and PKG2 regulation of this crucial pathway in bone homeostasis. This work establishes PKG2 as a key regulator of osteoblast proliferation and post-natal bone formation.