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The inter-dependent signaling of cGMP and calcium on activation of Akt in murine osteoblasts

  • Author(s): Tran, Trish Phuong
  • et al.
Abstract

Osteoporosis is a common bone disease that is characterized by reduced bone strength. Weight bearing and exercise promotes fluid flow through the bone canalicular canal system resulting in fluid shear stress (FSS) which is believed to stimulate osteoblast proliferation and growth. Unfortunately, individuals with osteoporosis may find exercise unsafe due to the risk of suffering bone fracture. This advocates for a treatment that can mimic the effects of mechanical loading and induce osteoblast proliferation. Exposure of osteoblasts to laminar fluid shear stress results in elevation of intracellular calcium leading to increased NO and cGMP synthesis, and activation of cGMP-dependent protein kinases (PKGs). Calcium can exert its anabolic effects in an NO independent signaling pathway. It has been reported that the Akt/mTOR/p70S6K signaling pathway plays a crucial role in regulating the proliferation of osteoblast-like cells in response to oscillatory fluid shear stress. We used pharmacological inhibitors and siRNA-mediated knockdown to analyze the molecular mechanism by which calcium regulates NO/cGMP/ PKGII dependent and independent pathways to activate Akt in murine osteoblasts. We found that FSS-induced Akt activation is dependent on both calcium and NO/cGMP/PKGII signaling pathways. Treatment with 8-pCPT-cGMP or a calcium ionophore mimicked the effects of FSS, and worked additively to increase Akt phosphorylation. FSS-induced Akt phosphorylation via the NO/cGMP/PKGII pathways required Src, whereas calcium signaling required both FAK and Src. Our results establish the role of calcium and NO/ cGMP/PKGII pathways in regulating osteoblast proliferation and support using PKG-activating drugs as mechano-mimetics for the treatment of osteoporosis

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