Nitric Oxide Donors for the Treatment of Osteoporosis

Jamal, Sophie A.; Hamilton, Celeste J.

doi:10.1007/s11914-011-0087-7

Cited by 22 publications

(12 citation statements)

References 50 publications

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“…Epidemiological studies indicate a protective effect of nitrates on bone, with a reduction in fracture risk (15)(16)(17), and several prospective, randomized trials have examined the effects of nitrates on BMD in women after natural or OVX-induced menopause (18 -20). Three of these trials showed positive effects of NO on BMD and bone formation markers similar to those observed with PTH, but the studies were not powered to assess fracture risk (20).…”

Section: Discussionmentioning

confidence: 99%

“…Some estrogen effects in bone are mediated by NO, because: 1) NOS3-deficient mice have exaggerated bone loss after ovariectomy (OVX) and a blunted response to estrogens; 2) NO-generating nitrates prevent bone loss after OVX in rats; and 3) bone-protective estrogen effects are blocked by NOS inhibitors (11)(12)(13)(14). In addition, epidemiological studies and clinical trials in postmenopausal women suggest a positive effect of nitrates on bone mineral density (BMD), although results are conflicting (15)(16)(17)(18)(19)(20). The beneficial effect of nitrates may be limited by development of tolerance and induction of oxidative stress (21).…”

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confidence: 99%

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Soluble Guanylate Cyclase as a Novel Treatment Target for Osteoporosis

et al. 2014

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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.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Soluble Guanylate Cyclase as a Novel Treatment Target for Osteoporosis

et al. 2014

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“…The putative estrogen‐like effect of nitric oxide without estrogenic side effects makes it a suitable therapeutic agent to be used as an alternative treatment for osteoporosis. Organic nitrates are widely available, inexpensive, and have potential to increase BMD with limited side effects . Data from randomized trials and observational studies suggests that nitrates increase BMD and decrease the risk of fractures .…”

Section: Novel Targetsmentioning

confidence: 99%

The underlying pathophysiology and therapeutic approaches for osteoporosis

Awasthi

Mani

Singh

et al. 2018

Medicinal Research Reviews

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With an increase in the ageing population worldwide, the prevalence of osteoporosis increases at an alarming rate in both male and female irrespective of their ethnicity. At present, the currently available therapeutic options are mostly limited to either bone resorptive or bone forming efficacies and both approaches are associated with serious side effects. Despite these options, there is still need for newer therapeutics to treat osteoporosis, which can offer beneficial effects for maintaining balanced dynamics between bone formation and bone resorption, devoid of any side effect. The proper understanding of pathophysiology of the disease is essential for designing or investigating an effective and safe anti-osteoporotic agent. This review represents a discussion around the molecular targets with their implications in disease progression, available therapeutic options, the emerging targets, and the importance of designing an effective anti-osteoporotic agent.

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“…Previous studies have shown that NO donors improve fracture healing in animals. In our studies it was effective in U2OS osteosarcoma cells [37]. NO donors improve wound healing in both animals and humans, and intake of the NO synthase substrate L-arginine can improve collagen deposition and wound strength [38].…”

Section: Discussionmentioning

confidence: 58%

Nitrosyl-cobinamide (NO-Cbi), a new nitric oxide donor, improves wound healing through cGMP/cGMP-dependent protein kinase

Spitler

Schwappacher

et al. 2013

Cellular Signalling

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a b s t r a c t a r t i c l e i n f oNitric oxide (NO) donors have been shown to improve wound healing, but the mechanism is not well defined. Here we show that the novel NO donor nitrosyl-cobinamide (NO-Cbi) improved in vitro wound healing in several cell types, including an established line of lung epithelial cells and primary human lung fibroblasts. On a molar basis, NO-Cbi was more effective than two other NO donors, with the effective NO-Cbi concentration ranging from 3 to 10 μM, depending on the cell type. Improved wound healing was secondary to increased cell migration and not cell proliferation. The wound healing effect of NO-Cbi was mediated by cGMP, mainly through cGMPdependent protein kinase type I (PKGI), as determined using pharmacological inhibitors and activators, and siRNAs targeting PKG type I and II. Moreover, we found that Src and ERK were two downstream mediators of NO-Cbi's effect. We conclude that NO-Cbi is a potent inducer of cell migration and wound closure, acting via cGMP, PKG, Src, and extracellular signal regulated kinase (ERK).

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Nitric Oxide Donors for the Treatment of Osteoporosis

Cited by 22 publications

References 50 publications

Soluble Guanylate Cyclase as a Novel Treatment Target for Osteoporosis

Soluble Guanylate Cyclase as a Novel Treatment Target for Osteoporosis

The underlying pathophysiology and therapeutic approaches for osteoporosis

Nitrosyl-cobinamide (NO-Cbi), a new nitric oxide donor, improves wound healing through cGMP/cGMP-dependent protein kinase

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