The NO-cGMP-PKG pathway in skeletal remodeling.

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  • Additional Information
    • Source:
      Publisher: New York Academy of Sciences Country of Publication: United States NLM ID: 7506858 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1749-6632 (Electronic) Linking ISSN: 00778923 NLM ISO Abbreviation: Ann N Y Acad Sci Subsets: MEDLINE
    • Publication Information:
      Publication: 2006- : New York, NY : Malden, MA : New York Academy of Sciences ; Blackwell
      Original Publication: New York, The Academy.
    • Subject Terms:
      Bone Remodeling/*physiology ; Cyclic GMP/*metabolism ; Cyclic GMP-Dependent Protein Kinases/*metabolism ; Nitric Oxide/*metabolism; Animals ; Bone and Bones/physiology ; Cyclic Nucleotide Phosphodiesterases, Type 5/physiology ; Humans ; Mice ; Signal Transduction/physiology
    • Abstract:
      The nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway plays a critical role in skeletal homeostasis. Preclinical data using NO and its donors and genetically modified mice demonstrated that NO was required in bone remodeling and partly mediated the anabolic effects of mechanical stimuli and estrogen. However, the off-target effects and tachyphylaxis of NO limit its long-term use, and previous clinical trials using organic nitrates for osteoporosis have been disappointing. Among the other components in the downstream pathway, targeting cGMP-specific phosphodiesterase to promote the NO-cGMP-PKG signal is a viable option. There are growing in vitro and in vivo data that, among many other PDE families, PDE5A is highly expressed in skeletal tissue, and inhibiting PDE5A using currently available PDE5A inhibitors might increase the osteoanabolic signal and protect the skeleton. These preclinical data open the possibility of repurposing PDE5A inhibitors for treating osteoporosis. Further research is needed to address the primary target bone cell of PDE5A inhibition, the contribution of direct and indirect effects of PDE5A inhibition, and the pathophysiological changes in skeletal PDE5A expression in aging and hypogonadal animal models.
      (© 2020 New York Academy of Sciences.)
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    • Grant Information:
      R01 AG071870 United States AG NIA NIH HHS; R01 DK113627 United States DK NIDDK NIH HHS; U19 AG060917 United States AG NIA NIH HHS
    • Contributed Indexing:
      Keywords: PDE5A; PKG; bone; cGMP; nitric oxide; soluble guanylate cyclase
    • Accession Number:
      31C4KY9ESH (Nitric Oxide)
      EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinases)
      EC 3.1.4.35 (Cyclic Nucleotide Phosphodiesterases, Type 5)
      EC 3.1.4.35 (PDE5A protein, human)
      H2D2X058MU (Cyclic GMP)
    • Publication Date:
      Date Created: 20200830 Date Completed: 20210323 Latest Revision: 20240807
    • Publication Date:
      20240807
    • Accession Number:
      PMC7914295
    • Accession Number:
      10.1111/nyas.14486
    • Accession Number:
      32860248