Protein kinase G2 activation restores Wnt signaling and bone mass in glucocorticoid-induced osteoporosis in mice.

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  • Additional Information
    • Source:
      Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: Electronic Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE
    • Publication Information:
      Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]-
    • Subject Terms:
      Osteoporosis*/chemically induced ; Osteoporosis*/metabolism ; Osteoporosis*/pathology ; Glucocorticoids*/adverse effects ; Osteoblasts*/drug effects ; Osteoblasts*/metabolism ; Dexamethasone*/pharmacology ; Dexamethasone*/adverse effects ; Wnt Signaling Pathway*/drug effects ; Mice, Transgenic* ; Cyclic GMP-Dependent Protein Kinases*/metabolism; Animals ; Mice ; Cell Differentiation/drug effects ; Osteocytes/metabolism ; Osteocytes/drug effects ; Osteogenesis/drug effects ; Disease Models, Animal ; Female ; Cell Proliferation/drug effects ; Bone Density/drug effects
    • Abstract:
      Osteoporotic fractures are a major complication of long-term glucocorticoid therapy. Glucocorticoids transiently increase bone resorption, but they predominantly inhibit bone formation and induce osteocyte apoptosis, leading to bone loss. Current treatments of glucocorticoid-induced osteoporosis aim mainly at reducing bone resorption and are, therefore, inadequate. We previously showed that signaling via the NO/cGMP/protein kinase G pathway plays a key role in skeletal homeostasis. Here, we show that pharmacological PKG activation with the guanylyl cyclase-1 activator cinaciguat or expression of a constitutively active, mutant PKG2R242Q restored proliferation, differentiation, and survival of primary mouse osteoblasts exposed to dexamethasone. Cinaciguat treatment of WT mice or osteoblast-specific expression of PKG2R242Q in transgenic mice prevented dexamethasone-induced loss of cortical bone mass and strength. These effects of cinaciguat and PKG2R242Q expression were due to preserved bone formation parameters and osteocyte survival. The basis for PKG2's effects appeared to be through recovery of Wnt/β-catenin signaling, which was suppressed by glucocorticoids but critical for proliferation, differentiation, and survival of osteoblast-lineage cells. Cinaciguat reduced dexamethasone activation of osteoclasts, but this did not occur in the PKG2R242Q transgenic mice, suggesting a minor role in osteoprotection. We propose that existing PKG-targeting drugs could represent a novel therapeutic approach to prevent glucocorticoid-induced osteoporosis.
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    • Grant Information:
      P30 NS047101 United States NS NINDS NIH HHS; R01 AG070778 United States AG NIA NIH HHS; R01 AR068601 United States AR NIAMS NIH HHS
    • Contributed Indexing:
      Keywords: Bone biology; Cyclic nucleotides; Osteoclast/osteoblast biology; Osteoporosis
    • Accession Number:
      0 (Glucocorticoids)
      7S5I7G3JQL (Dexamethasone)
      EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinases)
    • Publication Date:
      Date Created: 20240617 Date Completed: 20240812 Latest Revision: 20240923
    • Publication Date:
      20240923
    • Accession Number:
      PMC11383176
    • Accession Number:
      10.1172/jci.insight.175089
    • Accession Number:
      38885330