Repurposing erectile dysfunction drugs tadalafil and vardenafil to increase bone mass

We report that two widely-used drugs for erectile dysfunction, tadalafil and vardenafil, trigger bone gain in mice through a combination of anabolic and antiresorptive actions on the skeleton. Both drugs were found to enhance osteoblastic bone formation in vivo using a unique gene footprint and to inhibit osteoclast formation. The target enzyme, phosphodiesterase 5A (PDE5A), was found to be expressed in mouse and human bone as well as in specific brain regions, namely the locus coeruleus, raphe pallidus, and paraventricular nucleus of the hypothalamus. Localization of PDE5A in sympathetic neurons was confirmed by coimmunolabeling with dopamine β-hydroxylase, as well as by retrograde bone-brain tracing using a sympathetic nerve-specific pseudorabies virus, PRV152. Both drugs elicited an antianabolic sympathetic imprint in osteoblasts, but with net bone gain. Unlike in humans, in whom vardenafil is more potent than tadalafil, the relative potencies were reversed with respect to their osteoprotective actions in mice. Structural modeling revealed a higher binding energy of tadalafil to mouse PDE5A compared with vardenafil, due to steric clashes of vardenafil with a single methionine residue at position 806 in mouse PDE5A. Collectively, our findings suggest that a balance between peripheral and central actions of PDE5A inhibitors on bone formation together with their antiresorptive actions specify the osteoprotective action of PDE5A blockade.

Download Full-text

Nuclear medicine imaging technique in the erectile dysfunction evaluation: a mini-review

Brazilian Archives of Biology and Technology ◽

10.1590/s1516-89132007000600010 ◽

2007 ◽

Vol 50 (spe) ◽

pp. 91-96 ◽

Cited By ~ 1

Author(s):

Camila Godinho Ribeiro ◽

Regina Moura ◽

Rosane de Figueiredo Neves ◽

Jean Pierre Spinosa ◽

Mario Bernardo-Filho

Keyword(s):

Nuclear Medicine ◽

Erectile Dysfunction ◽

Sexual Arousal ◽

Single Photon ◽

Photon Emission ◽

Brain Regions ◽

Emission Computed Tomography ◽

Nuclear Medicine Imaging ◽

Positron Emission

Functional imaging with positron emission tomography and single photon emission computed tomography is capable of visualizing subtle changes in physiological function in vivo. Erectile dysfunction(ED) diminishes quality of life for affected men and their partners. Identification of neural substrates may provide information regarding the pathophysiology of types of sexual dysfunction originating in the brain. The aim of this work is to verify the approaches of the nuclear medicine techniques in the evaluation of the erectile function/disfunction. A search using the words ED and nuclear medicine, ED and scintigraphy, ED and spect and ED and pet was done in the PubMed. The number of citations in each subject was determined. Neuroimaging techniques offer insight into brain regions involved in sexual arousal and inhibition. To tackle problems such as hyposexual disorders or ED caused by brain disorders, it is crucial to understand how the human brain controls sexual arousal and penile erection.

Download Full-text

Blocking the ZZ domain of sequestosome1/p62 suppresses myeloma growth and osteoclast formation in vitro and induces dramatic bone formation in myeloma-bearing bones in vivo

Leukemia ◽

10.1038/leu.2015.229 ◽

2015 ◽

Vol 30 (2) ◽

pp. 390-398 ◽

Cited By ~ 27

Author(s):

J Teramachi ◽

R Silbermann ◽

P Yang ◽

W Zhao ◽

K S Mohammad ◽

...

Keyword(s):

Bone Formation ◽

Osteoclast Formation

Download Full-text

Identification of Novel Biphenyl Carboxylic Acid Derivatives as Novel Antiresorptive Agents that Do Not Impair Parathyroid Hormone-Induced Bone Formation

Endocrinology ◽

10.1210/en.2008-0998 ◽

2008 ◽

Vol 150 (1) ◽

pp. 5-13 ◽

Cited By ~ 11

Author(s):

Aymen I. Idris ◽

Iain R. Greig ◽

Euphemie Bassonga-Landao ◽

Stuart H. Ralston ◽

Rob J. van 't Hof

Keyword(s):

Carboxylic Acid ◽

Bone Formation ◽

Nuclear Factor Κb ◽

Osteoclast Formation ◽

Nuclear Factor ◽

Inhibitory Effects ◽

Osteoblast Function ◽

Ovariectomized Mice

Bisphosphonates are widely used in the treatment of osteoporosis, but they inhibit bone formation and blunt the anabolic effect of PTH. Here we describe a novel series of compounds that have potent antiresorptive effects in vitro and in vivo that do not adversely affect osteoblast function. The effects of the compounds on osteoclast formation and survival were studied on mouse osteoclasts generated from bone marrow macrophages and on osteoblast function using primary mouse calvarial osteoblast cultures and bone nodule cultures. Studies were performed in vivo using sham-operated or ovariectomized mice. The most potent compound tested was ABD350, a halogen-substituted derivative of the parent compound ABD56 in which the labile ester bond was replaced by a reduced ketone link, with IC50 osteoclast formation at a concentration of 1.3 μm. All compounds inhibited receptor activator of nuclear factor-κB ligand-induced inhibitor of nuclear factor κB phosphorylation and caused osteoclast apoptosis but no inhibitory effects on osteoblast function were observed at concentrations of up to 20μm. ABD350 prevented ovariectomy-induced bone loss when given ip (5 mg/kg · d), whereas ABD56 was only partially effective at this dose. In contrast to the bisphosphonate alendronate, ABD350 had no inhibitory effect on PTH-induced bone formation in ovariectomized mice. In conclusion, the biphenyl carboxylic acid derivatives like ABD350 represent a new class of antiresorptive drugs that inhibit osteoclast activity but have no significant inhibitory effects on osteoblast activity in vitro or PTH-induced bone formation in vivo. The biphenyl-carboxylate ABD350 inhibits osteoclast formation in vitro and in vivo and, unlike the bisphosphonate Alendronate, does not inhibit the bone anabolic effects of PTH.

Download Full-text

Cannabinoid receptor 2 selective agonists stimulate osteoclast formation in vitro but act as anabolic agents in vivo by stimulating bone formation

Bone ◽

10.1016/j.bone.2007.12.044 ◽

2008 ◽

Vol 42 ◽

pp. S31

Author(s):

Antonia Sophocleous ◽

Euphemie Landao ◽

Rob vant Hof ◽

Aymen I. Idris ◽

Stuart H. Ralston

Keyword(s):

Bone Formation ◽

Cannabinoid Receptor ◽

Osteoclast Formation ◽

Anabolic Agents ◽

Cannabinoid Receptor 2 ◽

Selective Agonists

Download Full-text

Osteoblast-osteoclast co-culture amplifies inhibitory effects of FG-4592 on osteoclast formation and reduces bone resorption activity

10.1101/863498 ◽

2019 ◽

Author(s):

Philippa A Hulley ◽

Ioanna Papadimitriou-Olivgeri ◽

Helen J Knowles

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Formation ◽

Enzyme Inhibitors ◽

Enzyme Inhibitor ◽

Osteoclast Formation ◽

Potential Contribution ◽

Non Union

AbstractThe link between bone and blood vessels is regulated by hypoxia and the hypoxia-inducible transcription factor, HIF, which drives both osteogenesis and angiogenesis. The recent clinical approval of PHD enzyme inhibitors, which stabilise HIF protein, introduces the potential for a new clinical strategy to treat osteolytic conditions such as osteoporosis, osteonecrosis and skeletal fracture and non-union. However, bone-resorbing osteoclasts also play a central role in bone remodelling and pathological osteolysis and HIF promotes osteoclast activation and bone loss in vitro. It is therefore likely that the final outcome of PHD enzyme inhibition in vivo would be mediated by a balance between increased bone formation and increased bone resorption. It is essential that we improve our understanding of the effects of HIF on osteoclast formation and function, and consider the potential contribution of inhibitory interactions with other musculoskeletal cells.The PHD enzyme inhibitor FG-4592 stabilised HIF protein and stimulated osteoclast-mediated bone resorption, but inhibited differentiation of human CD14+ monocytes into osteoclasts. Formation of osteoclasts in a more physiologically relevant 3D collagen gel did not affect the sensitivity of osteoclastogenesis to FG-4592, but increased sensitivity to reduced concentrations of RANKL. Co-culture with osteoblasts amplified inhibition of osteoclastogenesis by FG-4592, whether the osteoblasts were proliferating, differentiating or in the presence of exogenous M-CSF and RANKL. Osteoblast co-culture dampened the ability of high concentrations of FG-4592 to increase bone resorption.This data provides support for the therapeutic use of PHD enzyme inhibitors to improve bone formation and/or reduce bone loss for treatment of osteolytic pathologies, and indicates that FG-4592 might also act to inhibit the formation and activity of the osteoclasts that drive osteolysis.

Download Full-text

Myeloma bone disease and proteasome inhibition therapies

Blood ◽

10.1182/blood-2007-03-067710 ◽

2007 ◽

Vol 110 (4) ◽

pp. 1098-1104 ◽

Cited By ~ 95

Author(s):

Evangelos Terpos ◽

Orhan Sezer ◽

Peter Croucher ◽

Meletios-Athanassios Dimopoulos

Keyword(s):

Bone Resorption ◽

Bone Formation ◽

Bone Disease ◽

Proteasome Inhibitors ◽

Bone Destruction ◽

Osteoclast Formation ◽

Bone Specific Alkaline Phosphatase ◽

Myeloma Bone Disease

AbstractBone disease is one of the most debilitating manifestations of multiple myeloma. A complex interdependence exists between myeloma bone disease and tumor growth, creating a vicious circle of extensive bone destruction and myeloma progression. Proteasome inhibitors have recently been shown to promote bone formation in vitro and in vivo. Preclinical studies have demonstrated that proteasome inhibitors, including bortezomib, which is the first-in-class such agent, stimulate osteoblast differentiation while inhibiting osteoclast formation and bone resorption. Clinical studies are confirming these observations. Bortezomib counteracts the abnormal balance of osteoclast regulators (receptor activator of nuclear factor-κB ligand and osteoprotegerin), leading to osteoclast inhibition and decreased bone destruction, as measured by a reduction in markers of bone resorption. In addition, bortezomib stimulates osteoblast function, possibly through the reduction of dickkopf-1, leading to increased bone formation, as indicated by the elevation in bone-specific alkaline phosphatase and osteocalcin. The effect of bortezomib on bone disease is thought to be direct and not only a consequence of the agent's antimyeloma properties, making it an attractive agent for further investigation, as it may combine potent antimyeloma activity with beneficial effects on bone. However, the clinical implication of these effects requires prospective studies with specific clinical end points.

Download Full-text

5-Lipoxygenase Metabolites Inhibit Bone Formation in Vitro

Endocrinology ◽

10.1210/endo.139.7.6115 ◽

1998 ◽

Vol 139 (7) ◽

pp. 3178-3184 ◽

Cited By ~ 46

Author(s):

Kathy Traianedes ◽

Mark R. Dallas ◽

I. Ross Garrett ◽

Gregory R. Mundy ◽

Lynda F. Bonewald

Keyword(s):

Arachidonic Acid ◽

Bone Resorption ◽

Bone Formation ◽

Osteoclast Formation ◽

Bone Morphogenetic Protein 2 ◽

Inflammatory Conditions ◽

Fetal Rat ◽

Human Bone Morphogenetic Protein

Abstract The leukotrienes and peptido-leukotrienes are 5-lipoxygenase (5-LO) metabolites of arachidonic acid that appear to have unique effects on bone, distinct from those of the prostaglandins. Application of exogenous leukotrienes in vitro and in vivo results in increased osteoclast formation and bone resorption. While 5-LO metabolites of arachidonic acid clearly stimulate osteoclastic bone resorption, little is known concerning their effects on osteoblastic bone formation. We examined the effects of the 5-LO metabolites 5-HETE, the leukotriene LTB4 and, as representative of the peptido-leukotrienes, LTD4 on the formation of mineralized nodules of fetal rat calvarial cells in the presence of dexamethasone and recombinant human bone morphogenetic protein-2 (rhBMP-2). We also examined the effects of these 5-LO metabolites on alkaline phosphatase activity and cell proliferation in these cultures and the effects of 5-HETE and LTB4 on cultured explants of neonatal murine calvariae. We found that the bone-forming capacity of osteoblasts was impaired when cells were cultured in the presence of 5-LO metabolites. These data indicate that metabolites of the 5-LO pathway are negative regulators of bone formation. The continued presence of these metabolites in the bone environment might account, in part, for the bone loss associated with chronic inflammatory conditions.

Download Full-text