cyclic-gmp and Osteoporosis

Nitric oxide (NO) is a ubiquitous molecule involved in most cellular functions. While osteocytes communicate between bone cells, diffusible small molecules-H(+) and NO-are involved in short-term regulation of bone metabolism. Studies conducted over the past two decades have demonstrated the regulatory role of NO in bone metabolism. Circulating NO products are significantly lower in postmenopausal women, and estrogen supplementation restores this. Skeletal beneficial effects of estrogen are abolished with NO-synthase enzyme inhibitors, suggesting some estrogenic skeletal effects are mediated through NO/cGMP pathway. Since estrogen/hormone replacement therapy (HRT) has potential adverse effects, supplementing NO directly is sensible. NO is also involved with other cellular functions, such as isoprenylation of the Rho GTPase that stimulates Rho-PK (the functioning Rho-PK in turn inactivates something that would otherwise turn on the BMP-2/Cbfa1-Runx-2 cycle), and likely to be the final common pathway of other agents including statins. The first human study using nitroglycerine in the prevention of oophorectomy-induced bone loss demonstrated an equivalent efficacy to estrogen in the prevention of bone loss. A randomized NIH-funded NOVEL clinical study is currently assessing the effectiveness of topically administered nitroglycerine in the prevention of postmenopausal bone loss. If efficacy of nitroglycerine is confirmed, it may become a highly cost-effective and safe alternative therapy to treat osteoporosis. Nitroglycerine has beneficial effects in multiple systems, especially the cardiovascular system. If results of this study confirm our hypothesis, it is plausible that nitroglycerine therapy may supplant estrogen replacement and SERMs in preventing and treating postmenopausal osteoporosis.

Topics: Animals; Bone and Bones; Bone Density; Clinical Trials as Topic; Cyclic GMP; Estrogens; Female; Humans; Models, Biological; Nitric Oxide; Nitric Oxide Synthase; Nitroglycerin; Osteoporosis; Osteoprotegerin; RANK Ligand; Treatment Outcome

Mechanical stimulation induces bone growth and remodeling by the secondary messenger, cyclic guanosine 3', 5'-monophosphate (cGMP), in osteoblasts. However, the role of cGMP in the regulation of estrogen biosynthesis, whose deficiency is a major cause of osteoporosis, remains unclear. Here, we found that the prenylated flavonoids, 3-

Topics: 3T3 Cells; Animals; Aromatase; Cell Differentiation; Cell Line; Cell Survival; Cyclic AMP; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 5; Estrogens; Flavonoids; HEK293 Cells; Humans; Mice; Molecular Docking Simulation; Osteoblasts; Osteoporosis; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Stress, Mechanical

KMUP-1 is a xanthine derivative with inhibitory activities on the phosphodiesterase (PDE) 3,4 and 5 isoenzymes to suppress the degradation of cyclic AMP and cyclic GMP. However, the effects of KMUP-1 on osteoclast differentiation are still unclear. In this study, we investigated whether KMUP-1 inhibits osteoclastogenesis induced by RANKL in RAW 264.7 cells and bone loss induced by ovariectomy in mice, and the underlying mechanisms.. In vitro, KMUP-1 inhibited RANKL-induced TRAP activity, the formation of multinucleated osteoclasts and resorption-pit formation. It also inhibited key mediators of osteoclastogenesis including IL-1β, IL-6, TNF-α and HMGB1. In addition, KMUP-1 inhibited RANKL-induced activation of signaling molecules (Akt, MAPKs, calcium and NF-κB), mRNA expression of osteoclastogensis-associated genes (TRAP, MMP-9, Fra-1, and cathepsin K) and transcription factors (c-Fos and NFATc1). Furthermore, most inhibitory effects of KMUP-1 on RANKL-mediated signal activations were reversed by a protein kinase A inhibitor (H89) and a protein kinase G inhibitor (KT5823). In vivo, KMUP-1 prevented loss of bone mineral content, preserved serum alkaline phosphate and reduced serum osteocalcin in ovariectomized mice.. KMUP-1 inhibits RANKL-induced osteoclastogenesis in vitro and protects against ovariectomy-induced bone loss in vivo. These effects are mediated, at least in part, by cAMP and cGMP pathways. Therefore, KMUP-1 may have a role in pharmacologic therapy of osteoporosis.

Topics: Animals; Bone Density; Bone Density Conservation Agents; Calcineurin; Calcium; Cyclic AMP; Cyclic GMP; Female; Gene Expression Regulation; Humans; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; NF-kappa B; NFATC Transcription Factors; Osteoclasts; Osteoporosis; Ovariectomy; Piperidines; Proto-Oncogene Proteins c-akt; RANK Ligand; Signal Transduction; Xanthines

Topics: Animals; Arrestins; beta-Arrestins; Cyclic GMP; Endosomes; Humans; Osteoporosis; Parathyroid Hormone; Receptors, G-Protein-Coupled; Signal Transduction