title: Soluble guanylate cyclase as a novel treatment target for osteoporosis.
abstract: Osteoporosis is a major health problem leading to fractures that cause substantial morbidity and mortality. Current osteoporosis therapies have significant drawbacks, creating a need for novel bone-anabolic agents. We previously showed that the nitric oxide/cyclic GMP (cGMP)/protein kinase G pathway mediates some of the anabolic effects of estrogens and mechanical stimulation in osteoblasts and osteocytes, leading us to hypothesize that cGMP-elevating agents may have bone-protective effects. We tested cinaciguat, a prototype of a novel class of soluble guanylate cyclase activators, in a mouse model of estrogen deficiency-induced osteoporosis. Compared with sham-operated mice, ovariectomized mice had lower serum cGMP concentrations, which were largely restored to normal by treatment with cinaciguat or low-dose 17β-estradiol. Microcomputed tomography of tibiae showed that cinaciguat significantly improved trabecular bone microarchitecture in ovariectomized animals, with effect sizes similar to those obtained with estrogen replacement therapy. Cinaciguat reversed ovariectomy-induced osteocyte apoptosis as efficiently as estradiol and enhanced bone formation parameters in vivo, consistent with in vitro effects on osteoblast proliferation, differentiation, and survival. Compared with 17β-estradiol, which completely reversed the ovariectomy-induced increase in osteoclast number, cinaciguat had little effect on osteoclasts. Direct guanylate cyclase stimulators have been extremely well tolerated in clinical trials of cardiovascular diseases, and our findings provide proof-of-concept for this new class of drugs as a novel, anabolic treatment strategy for postmenopausal osteoporosis, confirming an important role of nitric oxide/cGMP/protein kinase G signaling in bone.
authors.affiliation: Departments of Medicine (J.J., G.K.S., H.K., G.R.B., R.B.P.), Bioengineering (E.C., R.S.S.), Mathematics (M.L.), and Family and Preventive Medicine (F.V.), University of California, San Diego, La Jolla, California 92093-0652.
authors.forename: Jisha
authors.initials: J
authors.lastname: Joshua
authors.forename: Gerburg K
authors.initials: GK
authors.lastname: Schwaerzer
authors.forename: Hema
authors.initials: H
authors.lastname: Kalyanaraman
authors.forename: Esther
authors.initials: E
authors.lastname: Cory
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sah
authors.forename: Mofei
authors.initials: M
authors.lastname: Li
authors.forename: Florin
authors.initials: F
authors.lastname: Vaida
authors.forename: Gerry R
authors.initials: GR
authors.lastname: Boss
authors.forename: Renate B
authors.initials: RB
authors.lastname: Pilz
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D016723:Bone Remodeling / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000097:blood; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D020536:Enzyme Activators / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects*; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy* / Q000201:enzymology; D010052:Ovariectomy; D011897:Random Allocation
chemical_list: D001565:Benzoates; D020536:Enzyme Activators; C480588:BAY 58-2667; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D006152:Cyclic GMP