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The NO–cGMP–PKG pathway in skeletal remodeling
Author(s) -
Kim SeMin,
Yuen Tony,
Iqbal Jameel,
Rubin Mishaela R.,
Zaidi Mone
Publication year - 2021
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/nyas.14486
Subject(s) - cgmp dependent protein kinase , cyclic guanosine monophosphate , phosphodiesterase , protein kinase a , signal transduction , cyclic adenosine monophosphate , cgmp specific phosphodiesterase type 5 , phosphodiesterase 3 , anabolism , medicine , endocrinology , osteoporosis , nitric oxide , sildenafil , biology , kinase , microbiology and biotechnology , receptor , biochemistry , mitogen activated protein kinase kinase , enzyme
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.