stilbenes and Osteoporosis

Over the past years, several studies have found that foods rich in polyphenols protect against age-related disease, such as atherosclerosis, cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes (T2D), hypertension and Alzheimer's disease. Resveratrol and pterostilbene, the polyphenol found in grape and blueberries, have beneficial effects as anti-aging compounds through modulating the hallmarks of aging, including oxidative damage, inflammation, telomere attrition and cell senescence. In this review, we discuss the relationship between resveratrol and pterostilbene and possible aging biomarker, including oxidative stress, inflammation, and high-calorie diets. Moreover, we also discuss the positive effect of resveratrol and pterostilbene on lifespan, aged-related disease, and health maintenance. Furthermore, we summarize a variety of important mechanisms modulated by resveratrol and pterostilbene possibly involved in attenuating age-associated disorders. Overall, we describe resveratrol and pterostilbene potential for prevention or treatment of several age-related diseases by modulating age-related mechanisms. © 2017 BioFactors, 44(1):69-82, 2018.

Topics: AMP-Activated Protein Kinases; Animals; Antioxidants; Cardiovascular Diseases; Cataract; Cellular Senescence; Humans; Inflammation; Longevity; Neoplasms; Neurodegenerative Diseases; NF-E2-Related Factor 2; Osteoporosis; Oxidative Stress; Resveratrol; Sirtuin 1; Stilbenes; Telomere Homeostasis

Osteoporosis is a major public health issue that is expected to rise as the global population ages. Resveratrol (RES) is a plant polyphenol with various anti-aging properties. RES treatment of bone cells results in protective effects, but dose translation from in vitro studies to clinically relevant doses is limited since bioavailability is not taken into account. The aims of this review is to evaluate in vivo evidence for a role of RES supplementation in promoting bone health to reduced osteoporosis risk and potential mechanisms of action. Due to multiple actions on both osteoblasts and osteoclasts, RES has potential to attenuate bone loss resulting from different etiologies and pathologies. Several animal models have investigated the bone protective effects of RES supplementation. Ovariectomized rodent models of rapid bone loss due to estrogen-deficiency reported that RES supplementation improved bone mass and trabecular bone without stimulating other estrogen-sensitive tissues. RES supplementation prior to age-related bone loss was beneficial. The hindlimb unloaded rat model used to investigate bone loss due to mechanical unloading showed RES supplementation attenuated bone loss in old rats, but had inconsistent bone effects in mature rats. In growing rodents, RES increased longitudinal bone growth, but had no other effects on bone. In the absence of human clinical trials, evidence for a role of RES on bone heath relies on evidence generated by animal studies. A better understanding of efficacy, safety, and molecular mechanisms of RES on bone will contribute to the determination of dietary recommendations and therapies to reduce osteoporosis. This article is part of a Special Issue entitled: Resveratol: Challenges in translating pre-clinical findings to improved patient outcomes.

Topics: Animals; Dietary Supplements; Drug Evaluation, Preclinical; Estrogens; Humans; Osteogenesis; Osteoporosis; Resveratrol; Stilbenes

Resveratrol (RSV) is a naturally occurring plant polyphenol that has potential to attenuate osteoporosis with distinct pathologies. This review evaluates preclinical evidence regarding the efficacy and safety of RSV as a therapeutic bone agent using different rat models. Limitations of these animal models are discussed, and suggestions for strengthening the experimental design of future studies are provided. The ovariectomized rat model of postmenopausal osteoporosis reported that RSV supplementation attenuated estrogen deficiency-induced bone loss and trabecular structural deterioration. RSV safety was indicated by the absence of stimulation of estrogen-sensitive tissue. Providing RSV to rats aged >6 months attenuated age-related bone mass loss and structural deterioration but produced inconsistent effects on bones in rats aged <6 months. The hindlimb-suspension rat model of disuse osteoporosis reported that RSV attenuated bone loss in old rats, but higher doses and longer duration supplementation before mechanical loading were required for younger rats. Limitations common to studies using rat models of osteoporosis include requirements to include animals that are skeletally mature, longer study durations, and to adjust for potential confounding effects due to altered body weight and endocrine function. Strengthening experimental design can contribute to translation of animal results to clinically relevant recommendations for humans.

Topics: Animals; Bone Density Conservation Agents; Dietary Supplements; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Osteoporosis; Rats; Resveratrol; Stilbenes

There are a number of pharmacological agents for the treatment of bone mineral loss and osteoporosis. Hormone replacement therapy (HRT) with estrogen is an established treatment, but it has several adverse side effects and can increase the risk of cancer, heart disease, and stroke. There is increasing interest in nutritional factors and naturally occurring phytochemical compounds with the potential for preventing age-related and postmenopausal bone loss. Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a polyphenolic phytoestrogen with osteogenic and osteoinductive properties. It can modify the metabolism of bone cells and has the capacity to modulate bone turnover. This paper provides an overview of current research on resveratrol and its effects on bone cells in vitro, highlighting the challenges and opportunities facing this area of research, especially in the context of providing nutritional support for postmenopausal women who may not benefit from HRT and older patients with various forms of arthritis, metabolic bone disease, and osteoporosis.

Topics: Animals; Bone Density; Estrogen Replacement Therapy; Humans; Osteocytes; Osteoporosis; Resveratrol; Stilbenes; Treatment Outcome

Although reactive oxygen species (ROS) such as superoxide, hydrogen peroxide and hydroxyl radical are generated as the natural byproduct of normal oxygen metabolism, they can create oxidative damage via interaction with bio-molecules. The role of oxidative stress as a remarkable upstream part is frequently reported in the signaling cascade of inflammation as well as chemo attractant production. Even though hydrogen peroxide can control cell signaling and stimulate cell proliferation at low levels, in higher concentrations it can initiate apoptosis and in very high levels may create necrosis. So far, the role of ROS in cellular damage and death is well documented with implicating in a broad range of degenerative alterations e.g. carcinogenesis, aging and other oxidative stress related diseases (OSRDs). Reversely, it is cleared that antioxidants are potentially able to suppress (at least in part) the immune system and to enhance the normal cellular protective responses to tissue damage. In this review, we aimed to provide insights on diverse OSRDs, which are correlated with the concept of oxidative stress as well as its cellular effects that can be inhibited by antioxidants. Resveratrol, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, statins, nebivolol and carvedilol, pentaerythritol tetranitrate, mitochondria-targeted antioxidants, and plant-derived drugs (alone or combined) are the potential medicines that can be used to control OSRD.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Benzopyrans; Carbazoles; Carvedilol; Diabetes Mellitus; Disease Models, Animal; Ethanolamines; Humans; Hydrogen Peroxide; Inflammatory Bowel Diseases; Nebivolol; Neoplasms; Neurodegenerative Diseases; Osteoporosis; Oxidative Stress; Propanolamines; Reactive Oxygen Species; Resveratrol; Stilbenes; Vascular Diseases

From a nutritional point of view, several factors are involved in ensuring optimal bone health. The most documented of these are calcium and vitamin D. However, it is now well acknowledged that some phytochemicals, also known as phytonutrients, which are plant-based compounds that are present in our daily diet, can positively regulate a number of physiological functions in mammalian systems involved in chronic diseases such as osteoporosis. Indeed, emerging data in animal models of postmenopausal osteoporosis has shown that exposure to some of these naturally plant-derived compounds (e.g. flavonoids) positively influences bone metabolism through preserved bone mineral density. In vitro experiments with bone cells have reported cellular and molecular mechanisms of phytonutrients involved in bone metabolism. Indeed, phytonutrients and especially polyphenols can act on both osteoblasts and osteoclasts to modulate bone metabolism, a balance between both cell type activities being required for bone health maintenance. To date, most studies investigating the effects of polyphenols on osteoblast cells have reported involvement of complex networks of anabolic signalling pathways such as BMPs or estrogen receptor mediated pathways. This review will report on the interaction between phytochemicals and bone metabolism in cell or animal models with a particular focus on the molecular mechanisms involved in the bone anabolic response.

Topics: Bone and Bones; Bone Density; Carotenoids; Catechin; Flavonoids; Humans; Lignans; Osteoporosis; Plants; Polyphenols; Signal Transduction; Stilbenes

Resveratrol, a phytoalexin, has gained much attention recently due to its effects on sirtuins. While the anti-cancer properties of resveratrol have been extensively investigated, the anti-adipogenic and osteogenic effects of resveratrol are also gaining considerable interest. The finding that resveratrol supplementation mimics caloric restriction prompted researchers to study the effects of resveratrol on lipid metabolism. Mesenchymal stem cells are the precursors for both adipocytes and osteoblasts. In the aging population, differentiation to adipocytes dominates over the differentiation to osteoblasts in bone marrow, contributing to the increased tendency for fractures to occur in the elderly. Thus, an inverse relationship exists between adipocytes and osteoblasts in the bone marrow. Resveratrol acts on several molecular targets in adipocytes and osteoblasts leading to a decrease in adipocyte number and size and an increase in osteogenesis. Furthermore, resveratrol in combination with genistein and quercetin synergistically decreased adipogenesis in murine and human adipocytes. A recent in vivo study showed that phytochemicals including resveratrol in combination with vitamin D prevented weight gain and bone loss in a postmenopausal rat model. Therefore, combinations of resveratrol with other phytochemicals may lead to potential novel potent therapies for both obesity and osteoporosis.

Topics: Adipocytes; Animals; Caloric Restriction; Drug Synergism; Humans; Lipolysis; Obesity; Osteoblasts; Osteoporosis; Resveratrol; Stilbenes

The recognition of selective estrogen receptor modulation in the laboratory has resulted in the development of two selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, for clinical application in healthy women. SERMs are antiestrogenic in the breast but estrogen-like in the bones and reduce circulating cholesterol levels. SERMs also have different degrees of estrogenicity in the uterus. Tamoxifen is used specifically to reduce the incidence of breast cancer in premenopausal and postmenopausal women at risk for the disease. In contrast, raloxifene is used specifically to reduce the risk of osteoporosis in postmenopausal women at high risk for osteoporosis. The study of tamoxifen and raloxifene (STAR) trial is currently comparing the ability of these SERMs to reduce breast cancer incidence in high-risk postmenopausal women. There is intense interest in understanding the molecular mechanism(s) of action of SERMs at target sites in a woman's body. An understanding of the targeted actions of this novel drug group will potentially result in the introduction of new multifunctional medicines with applications as preventive agents or treatments of breast cancer and endometrial cancer, coronary heart disease, and osteoporosis.

Topics: Adult; Aged; Bone and Bones; Breast; Breast Neoplasms; Cardiovascular System; Cinnamates; Clinical Trials as Topic; Coronary Disease; Endometrial Neoplasms; Estrogen Replacement Therapy; Female; Heart; Hot Flashes; Humans; Middle Aged; Models, Biological; Organ Specificity; Osteoporosis; Postmenopause; Premenopause; Prospective Studies; Protein Structure, Tertiary; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic; Receptors, Estrogen; Risk; Risk Assessment; Selective Estrogen Receptor Modulators; Stilbenes; Tamoxifen; Thrombophilia; Transcription, Genetic

OBJECTIVE: Osteoporosis is a severe degenerative chronic metabolic bone disease associated with high fracture risk. Polydatin (PD), a major bioactive component of Polygonum cuspidatum, has antioxidant and anti-inflammatory effects. This study investigated the anti-osteoporotic activity of PD in ovariectomized (OVX) mice and elucidated its underlying molecular mechanisms. SUBJECTS AND METHODS: An osteoporosis mouse model was established using OVX mice. OVX mice were then administered 10 or 40 mg/kg of PD for 60 days. Micro-CT and three-point bending tests were used to determine the therapeutic activities of PD in OVX mice. H&E staining was used to determine whether PD induced hepatorenal toxicity. In addition, the cellular and molecular mechanisms underlying the functionality of PD were elucidated. RESULTS: Micro-CT results showed that compared to control mice, the bone mass of OVX mice was significantly reduced due to estrogen deficiency; however, PD administration significantly elevated bone mass. Furthermore, PD substantially improved the trabecular microstructure parameters of the femur and enhanced bone strength compared with OVX mice. Hepatorenal toxicity was not observed in liver and kidney samples stained with H&E. PD significantly increased the proliferation of pre-osteoblast MC3T3-E1 cells and upregulated the expression of osteogenic differentiation markers compared to those in controls, as determined by qRT-PCR and western blotting. CONCLUSIONS: PD exerted a significant anti-osteoporotic effect in OVX mice by promoting osteogenesis. PD has great potential as a therapeutic option for osteoporosis.

Topics: Animals; Female; Glucosides; Humans; Mice; Osteoblasts; Osteogenesis; Osteoporosis; Ovariectomy; Stilbenes

Prolonged glucocorticoid treatment often leads to glucocorticoid-induced osteoporosis (GIOP), a common iatrogenic complication. This study has explored the anti-osteoporotic potential of semi-synthetic compound, pterostilbene isothiocyanate (PTER-ITC) in GIOP rat model and bone formation potential in vitro. Dysregulated bone-remodelling leads to osteoporosis. PTER-ITC has shown anti-osteoclastogenic activity in vitro. However, its molecular target remains unidentified, which has been explored in this study through in silico and experimental approaches. Alizarin Red S and von-Kossa staining, and alkaline phosphatase (ALP) activity showed the osteogenic differentiation potential of PTER-ITC in pre-osteoblastic mouse MC3T3-E1 and human hFOB 1.19 cells, further, confirmed through the expressions of osteogenic markers at transcriptional (RT-qPCR) and translational (immunoblotting) levels. The anti-osteoclastogenic property of PTER-ITC was confirmed through inhibition of actin ring formation in mouse RAW 264.7 and human THP-1 macrophagic cells. Molecular docking and molecular dynamic simulation showed that PTER-ITC inhibited the crucial osteoclastogenic RANK/TRAF6 interaction, which was further confirmed biochemically through co-immunoprecipitation assay. Osteoporotic bone architecture [validated through scanning electron microscopy (SEM), X-ray radiography, and micro-computed tomography (µ-CT)], physiology (confirmed through compression testing, Young's modulus and stress versus strain output) and histology (verified through hematoxylin-eosin, Alizarin Red S, von-Kossa and Masson-trichrome staining) of PTER-ITC-treated GIOP female Wistar rats were assuaged. Osteoporotic amelioration through PTER-ITC treatment was further substantiated through serum biomarkers, like, parathyroid hormone (PTH), ALP, calcium (Ca

Topics: Animals; Cell Differentiation; Female; Glucocorticoids; Humans; Isothiocyanates; Mice; Molecular Docking Simulation; Osteoblasts; Osteogenesis; Osteoporosis; Rats; Rats, Wistar; Receptor Activator of Nuclear Factor-kappa B; Stilbenes; TNF Receptor-Associated Factor 6; X-Ray Microtomography

Rhaponticin is a constituent isolated from numerous medicinal herbs. It has been reported earlier that rhaponticin possesses numerous biological effects like antiallergic, antidiabetic, hepatoprotective, and antithrombosis. The goal of this exploration was to scrutinize the therapeutic potential of rhaponticin on ovariectomy (OVX)-triggered osteoporosis in rats. Female Sprague Dawley rats were arbitrarily allocated to a sham-operated control group I, group II, which underwent OVX, and groups III and IV that underwent OVX were administered with rhaponticin (10 and 20 mg/kg). Rhaponticin was supplemented orally after 4 weeks of OVX and continued for about 16 weeks. Our findings exhibit that rhaponticin prevented the BMD diminution of femurs, induced by OVX, and protected the worsening of trabecular microarchitecture that are assisted through a noteworthy decline in skeletal remodeling as noticed through the diminished status of bone markers in a dose-dependent manner (10 and 20 mg/kg). OVX rats treated with rhaponticin efficiently enhanced body weight, lipid profiles, uterine index, bone turnover markers, inflammatory markers, and augmented the incidence of calcium in the OVX rats. Rhaponticin was established to restrain the functions of acid phosphatase, estradiol, and bone gla protein in OVX rats. Also, rhaponticin displayed some beneficial effects on histomorphometric and histopathological examination. It was observed that tabular area and thickness were reinstated in sham control and rhaponticin-treated OVX rats. We recognized that rhaponticin did not induce a damaging outcome on the skeletal organization of OVX rats. Moreover, we denote that rhaponticin can be an exceptional agent for the treatment and deal with associated bone diseases.

Topics: Animals; Bone Density; Cancellous Bone; Female; Osteoporosis; Ovariectomy; Rats; Rats, Sprague-Dawley; Stilbenes

Phytochemical investigation of the stems of

Topics: Anti-HIV Agents; Dipterocarpaceae; Magnetic Resonance Spectroscopy; Osteoporosis; Plant Stems; Stilbenes

Tetrahydroxy stilbene glucoside (TSG), an active component from medicinal herb Polygonum multiflorum Thunb, could block the activity of the tissue renin-angiotensin system (RAS), which plays a critical role in development of diabetic osteoporosis. This study aimed to determine if TSG therapy could alleviate bone deteriorations in diabetic mouse model induced by streptozotocin. The diabetic mice showed the loss of trabecular bone mass and the changes of trabecular bone microarchitectural parameters as well as the increase in amount of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts at the distal metaphysis of femur when compared with those of nondiabetic mice. Treatment with TSG significantly elevated calcium content in serum and bone and improved biological parameters of trabecular bone, accompanied by increasing messenger RNA (mRNA) expression of RUNX-2, COL-I, and OCN and protein expression of β-catenin as well as down-regulating protein expression of RAS components including renin and AT1R. In addition, TSG repressed diabetes-induced decrease in ratio of OPG/RANKL expression and increase in sclerostin expression in bone. The similar effects of TSG on osteoblasts-specific genes were found in MC3T3-E1 cells. Taken together, the present study demonstrated the osteopreserve effects of TSG in diabetic mice, and the underlying mechanism might be attributed to its regulation on osteogenesis and osteoclastogenesis.

Topics: Animals; Bone and Bones; Diabetes Mellitus, Experimental; Femur; Glucosides; Hyperglycemia; Male; Mice; Mice, Inbred C57BL; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Renin-Angiotensin System; Stilbenes; Streptozocin; Tartrate-Resistant Acid Phosphatase

Osteoporosis is a form of osteolytic disease caused by an imbalance in bone homeostasis, with reductions in osteoblast bone formation, and augmented osteoclast formation and resorption resulting in reduced bone mass. Cajaninstilbene acid (CSA) is a natural compound derived from pigeon pea leaves. CSA possesses beneficial properties as an anti-inflammatory, antibacterial, antihepatitis, and anticancer agent; however, its potential to modulate bone homeostasis and osteoporosis has not been studied. We observed that CSA has the ability to suppress RANKL-mediated osteoclastogenesis, osteoclast marker gene expression, and bone resorption in a dose-dependent manner. Mechanistically, it was revealed that CSA attenuates RANKL-activated NF-κB and nuclear factor of activated T-cell pathways and inhibited phosphorylation of key signaling mediators c-Fos, V-ATPase-d2, and ERK. Moreover, in osteoclasts, CSA blocked RANKL-induced ROS activity as well as calcium oscillations. We further evaluated the therapeutic effect of CSA in a preclinical mouse model and showed that in vivo treatment of ovariectomized C57BL/6 mice with CSA protects the mice from osteoporotic bone loss. Thus, this study demonstrates that osteolytic bone diseases can potentially be treated by CSA.

Topics: Animals; Bone Resorption; Calcium; Gene Expression Regulation; Mice, Inbred C57BL; NF-kappa B; NFATC Transcription Factors; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Ovariectomy; RANK Ligand; Reactive Oxygen Species; Salicylates; Signal Transduction; Stilbenes

Resveratrol (3,5,4-trihydroxystilbene, RES), a natural antioxidant, prevents bone loss by attenuating damage caused by oxidative stress. Our previous research revealed that the forkhead box O1 (FoxO1)/β-catenin signaling pathway affected the proliferation and differentiation of osteoblasts through its regulation of redox balance, and RES regulated the expression of FoxO1 to control white adipose tissue and then ameliorate an overweight condition. Based on previous research, we hypothesized that RES regulates FoxO1 transcriptional activity through the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway to achieve an antioxidative effect on osteoporosis and then we confirmed this hypothesis in the present study. An ovariectomized (OVX) rat model of osteoporosis and a H2O2‑induced oxidative cell injury model in RAW 264.7 cells were established to explore the underlying molecular mechanisms of how RES confers an antioxidant effect and prevents bone loss. The obtained results demonstrated that RES strongly prevented bone loss induced by oxidative stress in vivo. More specifically, RES effectively decreased the receptor activator of nuclear factor-κB ligand (RANKL) together with the tartrate-resistant acid phosphatase‑5b (TRAP‑5b) level, but elevated the osteoproprotegrin (OPG) level and attenuated bone microarchitecture damage. Notably, RES, due to its antioxidant effect, suppressed RANKL production and then inhibited osteoclastogenesis in the OVX rats. In vitro, RES improved the oxidative stress status of cells and thus inhibited the mRNA expression of osteoclast-specific enzymes. These data indicate that RES has a significant bone protective effect by antagonizing oxidative stress to suppress osteoclast activity, function and formation both in vivo and in vitro. Moreover, at the molecular level, we confirmed, for the first time, that RES upregulated FoxO1 transcriptional activity by inhibiting the PI3K/AKT signaling pathway, and hence promoted resistance to oxidative damage and restrained osteoclastogenesis. Inhibition of the PI3K/AKT signaling pathway may be induced by RANKL. FoxO1 is a major action target of RES to confer anti-osteoporosis function, and whose effect stems from its power to improve redox balance.

Topics: Animals; Cell Differentiation; Disease Models, Animal; Female; Forkhead Box Protein O1; Gene Expression Regulation; Humans; Hydrogen Peroxide; Mice; Osteoclasts; Osteoporosis; Osteoprotegerin; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; RANK Ligand; RAW 264.7 Cells; Resveratrol; Signal Transduction; Stilbenes

Topics: Adipocytes; Adipogenesis; Animals; Body Weight; Bone Marrow; Caffeic Acids; CCAAT-Enhancer-Binding Protein-alpha; Down-Regulation; Fatty Acid-Binding Proteins; Female; Forkhead Box Protein O3; Kruppel-Like Transcription Factors; Osteogenesis; Osteoporosis; PPAR gamma; Prednisone; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Up-Regulation; Wnt Signaling Pathway

Topics: Animals; Biomarkers; Body Weight; Bone and Bones; Disease Models, Animal; Glucosides; Humans; Mice; Organ Size; Osteoporosis; Ovariectomy; Plant Extracts; Protective Agents; Stilbenes; X-Ray Microtomography

This study was designed to investigate the anti‑osteoporotic activity of polydatin and its possible underlying mechanism. Osteoporosis was induced in mice by ovariectomy (OVX) and the mice were divided into 5 groups: An OVX only group, polydatin groups (10, 20 and 40 mg/kg) and a sham group (n=10/group). After 12 weeks of treatment, body weight, uterine index and the dry weight of thigh‑bones were recorded. In addition, the serum calcium, serum phosphorus, alkaline phosphatase (ALP) and osteoprotegerin (OPG) levels were also determined. Western blot analysis was then conducted to investigate the possible mechanism underlying the effect of polydatin via determining the expression of OPG, receptor activators of nuclear factor‑κB ligand (RANKL) and β‑catenin in the ST2 cell line. The results indicated that intraperitoneal injection of polydatin (10, 20 and 40 mg/kg/day) decreased body weight, and increased uterine index and dry weights of thigh‑bones of ovariectomized mice (P<0.05), and polydatin also significantly increased the serum calcium, phosphorus, ALP and OPG of ovariectomized mice (P<0.05). Results of western blot analysis showed that polydatin upregulated the ratio of OPG/RANKL (P<0.05) and β‑catenin protein in ST2 cells. In conclusion, the results demonstrated that polydatin exhibits anti‑osteoporotic activity via regulating osteoprotegerin, RANKL and β‑catenin.

Topics: Alkaline Phosphatase; Animals; beta Catenin; Biomarkers; Body Weight; Bone and Bones; Calcium; Cell Line; Disease Models, Animal; Female; Gene Expression Regulation; Glucosides; Mice; Osteoporosis; Osteoprotegerin; Ovariectomy; RANK Ligand; Stilbenes

Osteoporosis is a disease characterized by loss of bone mass and degeneration of the microstructure of bone. Resveratrol (3,5,4-tri-hydroxystilbene; RESV) may delay the onset of a variety of age-related diseases. In the present study, an ovariectomized female rat model was used to detect the changes in microRNAs (miRNAs/miRs) following RESV treatment. Subsequently, the target genes of miRNA were predicted using TargetScan software and determined using a dual-luciferase reporter assay. Finally, the role of miR-338-3p in the proliferation and differentiation of human osteoblast (HOB) cells was confirmed. The predominant finding of the present study was the identification of an intact mechanism of the effect of RESV in osteoporosis treatment. The results suggested that RESV suppresses miR-338-3p, followed by an increase in the expression of runt-related transcription factor 2 in HOB cells.

Topics: Animals; Antioxidants; Base Sequence; Body Weight; Bone and Bones; Cell Differentiation; Cell Line; Cell Proliferation; Core Binding Factor Alpha 1 Subunit; Down-Regulation; Female; Gene Expression Regulation; Humans; MicroRNAs; Molecular Sequence Data; Osteoblasts; Osteoporosis; Ovariectomy; Phylogeny; Rats; Rats, Wistar; Resveratrol; Sequence Alignment; Stilbenes

Estrogen deficiency has been considered to be a major cause of osteoporosis, but recent epidemiological evidence and mechanistic studies have indicated that aging and the associated increase in reactive oxygen species (ROS) are the proximal pathogenic factors. Through ROS-mediated reactions, iron can induce disequilibrium of oxidation and antioxidation and can cause bone loss in mice. Therefore, we investigated the effects of resveratrol (RES) on bone mineral density, bone microstructure and the osteoblast functions under iron-overload conditions. Excess iron disrupted the antioxidant/prooxidant equilibrium of the mice and induced the defect and the lesion of the bone trabecula as well as disequilibrium between bone formation and bone resorption in iron-overload mice. Oral administration of RES significantly prevented bone loss in the osteoporotic mice. RES reversed the reduction of Runx2, OCN and type I collagen from excess iron; up-regulated the level of FOXO1; and maintained the antioxidant/prooxidant equilibrium in the mice. RES also reduced the ratio of OPG/RANKL in MC3T3-E1 cells and in mice and significantly inhibited subsequent osteoclastogenesis. These results provide new insights into the antiosteoporosis mechanisms of RES through antioxidative effects, suggesting that RES can be considered a potential natural resource for developing medicines or dietary supplements to prevent and treat osteoporosis.

Topics: Animals; Antioxidants; Bone Density; Cell Line; Dietary Supplements; Femur; Interleukin-6; Iron Overload; Male; Mice, Inbred C57BL; Osteoporosis; Osteoprotegerin; RANK Ligand; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha

Three series of resveratrol oligomer derivatives were synthesized, including the indenone-type, indene-type and octahydropentalene-type derivatives, among which ten derivatives were novel compounds. Compounds 2, 14f, and 4d were confirmed as ERβ agonists by yeast two-hybrid assay, and compound 2 (isopaucifloral F) was further chosen to evaluate its anti-osteoporosis activity in vivo. Compared with the sham-operated and the positive control groups, isopaucifloral F (10 μg/kg) showed a notable anti-osteoporosis effect in the ovariectomized (OVX) female rats based on a micro-CT analysis and the following measurements: bone mineral density, bone volume/tissue volume, trabecular thickness, trabecular separation/spacing, and the serum biochemical parameters. LD50 of isopaucifloral F was found to be greater than 5 mg/kg and its effective dose (ED) was found to be about 10 μg/kg. Therefore, isopaucifloral F may be a promising lead compound for the treatment of postmenopausal osteoporosis.

Topics: Animals; Disease Models, Animal; Estrogen Receptor beta; Estrogens; Female; Osteoporosis; Ovariectomy; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

Sublesional osteoporosis predisposes individuals with spinal cord injury (SCI) to an increased risk of low-trauma fracture. The aim of the present work was to investigate the effect of treatment with resveratrol (RES) on sublesional bone loss in spinal cord-injured rats.. Complete SCI was generated by surgical transaction of the cord at the T10-12 level. Treatment with RES (400 mg·kg(-1) body mass per day(-1) , intragastrically) was initiated 12 h after the surgery for 10 days. Then, blood was collected and femurs and tibiae were removed for evaluation of the effects of RES on bone tissue after SCI.. Treatment of SCI rats with RES prevented the reduction of bone mass including bone mineral content and bone mineral density in tibiae, preserved bone structure including trabecular bone volume fraction, trabecular number, and trabecular thickness in tibiae, and preserved mechanical strength including ultimate load, stiffness, and energy in femurs. Treatment of SCI rats with RES enhanced femoral total sulfhydryl content, reduced femoral malondialdehyde and IL-6 mRNA levels. Treatment of SCI rats with RES suppressed the up-regulation of mRNA levels of PPARγ, adipose-specific fatty-acid-binding protein and lipoprotein lipase, and restored mRNA levels of Wnt1, low-density lipoprotein-related protein 5, Axin2, ctnnb1, insulin-like growth factor 1 (IGF-1) and receptor for IGF-1 in femurs and tibiae.. Treatment with RES attenuated sublesional bone loss in spinal-cord-injured rats, associated with abating oxidative stress, attenuating inflammation, depressing PPARγ signalling, and restoring Wnt/β-catenin and IGF-1 signalling.

Topics: Animals; Bone Density; Bone Density Conservation Agents; Disease Models, Animal; Femur; Gene Expression Regulation; Inflammation Mediators; Male; Malondialdehyde; Osteoporosis; Oxidative Stress; Radiography; Rats; Rats, Sprague-Dawley; Resveratrol; RNA, Messenger; Signal Transduction; Spinal Cord Injuries; Stilbenes; Sulfhydryl Compounds; Tibia

The osteoprotective effect of resveratrol and a combination of resveratrol with enalapril has been investigated in white Wistar female rats with experimental osteoporosis. It is established that, in rats after ovariectomy, the endothelial dysfunction of microcirculation vessels of the osteal tissue is developed, resulting in the occurrence of osteoporosis. Resveratrol and the combination of resveratrol with enalapril prevented depression of the microcirculation level in the osteal tissue, thus preventing the thinning of osteal trabecules and preventing their microfractures.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bone and Bones; Drug Therapy, Combination; Enalapril; Endothelium; Female; Microcirculation; Osteoporosis; Ovariectomy; Rats; Rats, Wistar; Resveratrol; Stilbenes; Vasodilator Agents

The deleterious bone effects of mechanical unloading have been suggested to be due to oxidative stress and (or) inflammation. Resveratrol has both antioxidant and anti-inflammatory properties; therefore, the study's objective was to determine whether providing resveratrol in the low supplementation range for a short duration prevents bone loss during mechanical unloading. Mature (6 months old) Fischer 344 × Brown Norway male rats were hindlimb-suspended (HLS) or kept ambulatory for 14 days. Rats were provided either trans-resveratrol (RES; 12.5 mg/kg body mass per day) or deionized distilled water by oral gavage for 21 days (7 days prior to and during the 14 days of HLS). Bone mass was measured by dual energy X-ray absorptiometry. Bone microstructure was determined by microcomputed tomography. HLS of rats resulted in femur trabecular bone deterioration. Resveratrol supplementation did not attenuate trabecular bone deterioration in HLS rats. Unexpectedly, HLS-RES rats had the lowest tibial bone mineral content (P < 0.05), calcium content and lower cortical thickness (P < 0.05), and increased porosity compared with HLS/control rats. Plasma osteocalcin was also lower (P < 0.04) in HLS/resveratrol rats. There were no significant effects on plasma C-reactive protein, a marker of systemic inflammation, or total antioxidant capacity. However, HLS-RES rats showed a negative relationship (r(2) = 0.69, P = 0.02) between plasma osteocalcin and thiobarbituric acid reactive substances, a marker of lipid peroxidation. Based on the results, resveratrol supplementation of 6-month-old HLS male rats had no bone protective effects and possibly even detrimental bone effects.

Topics: Absorptiometry, Photon; Animals; Biomechanical Phenomena; Bone and Bones; Bone Density; Bone Diseases, Metabolic; Calcium; Dietary Supplements; Hindlimb; Hindlimb Suspension; Male; Osteocalcin; Osteoporosis; Rats; Rats, Inbred BN; Rats, Inbred F344; Resveratrol; Stilbenes; Tibia

Resveratrol is a polyphenolic phytoestrogen that has been shown to exhibit potent anti-oxidant, anti-inflammatory, and anti-catabolic properties. Increased osteoclastic and decreased osteoblastic activities result in bone resorption and loss of bone mass. These changes have been implicated in pathological processes in rheumatoid arthritis and osteoporosis. Receptor activator of NF-κB ligand (RANKL), a member of the TNF superfamily, is a major mediator of bone loss. In this study, we investigated the effects of resveratrol on RANKL during bone morphogenesis in high density bone cultures in vitro. Untreated bone-derived cell cultures produced well organized bone-like structures with a bone-specific matrix. Treatment with RANKL induced formation of tartrate-resistant acid phosphatase-positive multinucleated cells that exhibited morphological features of osteoclasts. RANKL induced NF-κB activation, whereas pretreatment with resveratrol completely inhibited this activation and suppressed the activation of IκBα kinase and IκBα phosphorylation and degradation. RANKL up-regulated p300 (a histone acetyltransferase) expression, which, in turn, promoted acetylation of NF-κB. Resveratrol inhibited RANKL-induced acetylation and nuclear translocation of NF-κB in a time- and concentration-dependent manner. In addition, activation of Sirt-1 (a histone deacetylase) by resveratrol induced Sirt-1-p300 association in bone-derived and preosteoblastic cells, leading to deacetylation of RANKL-induced NF-κB, inhibition of NF-κB transcriptional activation, and osteoclastogenesis. Co-treatment with resveratrol activated the bone transcription factors Cbfa-1 and Sirt-1 and induced the formation of Sirt-1-Cbfa-1 complexes. Overall, these results demonstrate that resveratrol-activated Sirt-1 plays pivotal roles in regulating the balance between the osteoclastic versus osteoblastic activity result in bone formation in vitro thereby highlighting its therapeutic potential for treating osteoporosis and rheumatoid arthritis-related bone loss.

Topics: Animals; Bone Marrow Cells; Cell Line; Core Binding Factor Alpha 1 Subunit; Dogs; Enzyme Inhibitors; Humans; Mice; Multiprotein Complexes; NF-kappa B; Osteoclasts; Osteoporosis; p300-CBP Transcription Factors; RANK Ligand; Resveratrol; Rheumatic Fever; Signal Transduction; Sirtuin 1; Stilbenes; Up-Regulation

Using mouse gene knock-out models, we identify aldehyde reductase (EC 1.1.1.2, Akr1a4 (GR)) and aldose reductase (EC 1.1.1.21, Akr1b3 (AR)) as the enzymes responsible for conversion of D-glucuronate to L-gulonate, a key step in the ascorbate (ASC) synthesis pathway in mice. The gene knock-out (KO) mice show that the two enzymes, GR and AR, provide approximately 85 and approximately 15% of L-gulonate, respectively. GRKO/ARKO double knock-out mice are unable to synthesize ASC (>95% ASC deficit) and develop scurvy. The GRKO mice ( approximately 85% ASC deficit) develop and grow normally when fed regular mouse chow (ASC content = 0) but suffer severe osteopenia and spontaneous fractures with stresses that increase ASC requirements, such as pregnancy or castration. Castration greatly increases osteoclast numbers and activity in GRKO mice and promotes increased bone loss as compared with wild-type controls and additionally induces proliferation of immature dysplastic osteoblasts likely because of an ASC-sensitive block(s) in early differentiation. ASC and the antioxidants pycnogenol and resveratrol block osteoclast proliferation and bone loss, but only ASC feeding restores osteoblast differentiation and prevents their dysplastic proliferation. This is the first in vivo demonstration of two independent roles for ASC as an antioxidant suppressing osteoclast activity and number as well as a cofactor promoting osteoblast differentiation. Although humans have lost the ability to synthesize ASC, our mouse models suggest the mechanisms by which suboptimal ASC availability facilitates the development of osteoporosis, which has important implications for human osteoporosis.

Topics: Animals; Antioxidants; Ascorbic Acid; Bone and Bones; Cell Proliferation; Flavonoids; Homeostasis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Models, Biological; Osteoblasts; Osteoporosis; Plant Extracts; Resveratrol; Stilbenes

The plant phytoalexin resveratrol was previously demonstrated to inhibit the differentiation and bone resorbing activity of osteoclasts, to promote the formation of osteoblasts from mesenchymal precursors in cultures, and inhibit myeloma cell proliferation, when used at high concentrations. In the current study, we screened five structurally modified resveratrol analogues for their ability to modify the differentiation of osteoclasts and osteoblasts and proliferation of myeloma cells. Compared to resveratrol, analogues showed an up to 5,000-fold increased potency to inhibit osteoclast differentiation. To a lesser extent, resveratrol analogues also promoted osteoblast maturation. However, they did not antagonize the proliferation of myeloma cells. The potency of the best-performing candidate in vitro was tested in vivo in an ovariectomy-induced model of osteoporosis, but an effect on bone loss could not be detected. Based on their powerful antiresorptive activity in vitro, resveratrol analogues might be attractive modulators of bone remodeling. However, further studies are required to establish their efficacy in vivo.

Topics: Animals; Anticarcinogenic Agents; Bone Density Conservation Agents; Cell Line, Tumor; Female; Growth Inhibitors; Humans; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Rats; Resveratrol; Stilbenes; Treatment Outcome

As the average age of society increases, identifying and preventing osteoporosis becomes more important. According to the results of the Women's Health Initiative study, substitution of estradiol is not recommended in hormone replacement therapy (HRT), although phytoestrogens might be a safe alternative. In this study, the osteoprotective effects of genistein (Gen), resveratrol (Res) and 8-prenylnaringenin (8PN) were evaluated by analysing bone biomechanical strength and bone mineral density. After ovariectomy, 88 female rats received soy-free food (C), and according to their grouping, were fed estradiol (E), GEN, RES or 8PN for 12 weeks. The phytohormones were given in two dosages. To analyse the osteoprotective effects of the tested substances, bone biomechanical properties and bone mineral density (BMD) were evaluated on the upper tibial metaphysis. Bone biomechanical properties were significantly improved after treatment with E (F (max): 90.6 N) and 8PN (85.0 N) compared to GEN (76.0 N), RES (72.6 N) and C (76.6 N). Bone biomechanical properties with 8PN (yL: 55.7 N) supplementation reached a level similar to that seen after E (49.3 N) supplementation. Treatment with GEN (38.5 N) was not as effective as E and 8PN, but demonstrated improved biomechanical properties compared to C (40.1 N) and RES (36.3 N). E (Cn.Dn. 217 mg/cm (3)) and 8PN (165 mg/cm3) showed superior results in the analysis of bone mineral density compared to C (112 mg/cm (3)). GEN (164 mg/cm (3)) also demonstrated superior results, though not as good as E and 8PN. RES (124 mg/cm (3)) revealed no effect on bone density. Treatment with 8PN resulted in very good biomechanical properties and showed an increased BMD. GEN had a smaller effect on bone biomechanical strength, while RES did not have an effect on bone biomechanical strength or BMD. Therefore, 8PN might be a safe alternative for HRT, but further studies are needed.

Topics: Animals; Biomechanical Phenomena; Bone Density; Flavanones; Genistein; Osteoporosis; Plant Growth Regulators; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Tibia

A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging, including reduced albuminuria, decreased inflammation, and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started midlife.

Topics: Age Factors; Aging; Animals; Antioxidants; Apoptosis; Caloric Restriction; Cardiovascular System; Energy Intake; Food Deprivation; Food, Formulated; Gene Expression Regulation; Inflammation; Longevity; Male; Mice; Mice, Inbred C57BL; Osteoporosis; Resveratrol; Stilbenes; Transcription, Genetic; Treatment Outcome

trans-Resveratrol (resveratrol) has been shown in several studies to significantly modulate biomarkers of bone metabolism. But, there is no direct evidence supporting its inhibitory effect towards bone loss. In the present study, effects of resveratrol on bone mineral density (BMD) and bone calcium content (BCC) were examined in the ovariectomized (OVX) rat model. Female Wistar rats were divided into four groups: SHAM group (sham-operated), OVX group (OVX control), OVX + ALD group (OVX and treated with 1.0 mg/kg of body weight of alendronate sodium), and OVX + RES group (OVX and treated with 0.7 mg/kg of body weight of resveratrol). Tested materials were given by gavage for 12 weeks after ovariectomy. Results showed that rats in the OVX, OVX + ALD, and OVX + RES groups had significantly higher body weights and feed efficiency than those in the SHAM group (P < .01). The OVX group had significantly lower femoral epiphysis BMD than the SHAM group, and epiphysis BMD in the OVX + ALD and OVX + RES groups was significantly greater than that in the OVX group (P < .05). However, the femoral midpoint BMD was not significantly different among the four groups. Additionally, animals in the OVX group had significantly lower BCC compared with the SHAM group, while the BCC of the OVX + ALD and OVX + RES groups was significantly higher than that of the OVX group (P < .05). These results indicated that resveratrol could increase epiphysis BMD and inhibit the decrease of femur BCC in OVX rats, suggesting that it could play a role in protecting against bone loss induced by estrogen deficiency.

Topics: Absorptiometry, Photon; Alendronate; Analysis of Variance; Animals; Bone and Bones; Bone Density; Calcium; Disease Models, Animal; Fallopia japonica; Female; Femur; Osteoporosis; Ovariectomy; Random Allocation; Rats; Rats, Wistar; Resveratrol; Stilbenes; Weight Gain

We examined the effect of resveratrol (3,4',5-trihydroxy stilbene), a phenolic compound found in the skins of most grapes, on blood pressure and bone loss in ovariectomized (OVX), stroke-prone spontaneously hypertensive rats (SHRSP). Nineteen-week-old female SHRSP were divided into a sham-ovariectomized (sham) group fed a control diet and two OVX groups fed either a control diet (OVX-Cont) or a diet supplemented with resveratrol (5 mg/kg per d; OVX-Resv). Ovariectomy induced significant increases in systolic blood pressure (SBP). Resveratrol lowered the SBP by 15%) by the third week of administration, and this effect was maintained throughout the study. Resveratrol treatment also significantly enhanced endothelium-dependent vascular relaxation in response to acetylcholine (ACh) in OVX rats. Finally, femur breaking energies measured for the resveratrol-treated (OVX-Resv) group were significantly higher than those of the resveratrol-untreated (OVX-Cont) group. While no significant differences in calcium, magnesium and phosphorus content were found between the femurs of OVX-Cont and OVX-Resv rats, the femur hydroxyproline content in the OVX-Resv group was significantly higher than of the OVX-Cont group. We conclude that, in OVX-SHRSP, resveratrol acts by a similar mechanism to mammalian estrogens, lowering blood pressure by increasing dilatory responses to ACh. The present study also demonstrated that resveratrol was able to prevent ovariectomy-induced decreases in femoral bone strength.

Topics: Animals; Antihypertensive Agents; Bone Density; Disease Models, Animal; Female; Femur; Hypertension; Osteoporosis; Ovariectomy; Rats; Rats, Inbred SHR; Resveratrol; Stilbenes

The estrogen receptor (ER) mixed agonists tamoxifen and raloxifene have been shown to protect against bone loss in ovariectomized rats. However, the mechanism by which these compounds manifest their activity in bone is unknown. We have used a series of in vitro screens to select for compounds that are mechanistically distinct from tamoxifen and raloxifene in an effort to define the properties of an ER modulator required for bone protection. Using this approach, we identified a novel high affinity ER antagonist, GW5638, which when assayed in vitro functions as an ER antagonist, inhibiting the agonist activity of estrogen, tamoxifen, and raloxifene and reversing the "inverse agonist" activity of the pure antiestrogen ICI182,780. Thus, GW5638 appears to function as an antagonist in these in vitro systems, although in a manner distinct from other known ER modulators. Predictably, therefore, GW5638 alone displays minimal uterotropic activity in ovariectomized rats, but will inhibit the agonist activity of estradiol in this environment. Unexpectedly, however, this compound functions as a full ER agonist in bone and the cardiovascular system. These data suggest that the mechanism by which ER operates in different cells is not identical, and that classical agonist activity is not required for the bone protective activity of ER modulators.

Topics: Animals; Bone and Bones; Bone Density; Cinnamates; Estradiol; Estrogen Antagonists; Estrogens; Female; Humans; Osteoporosis; Ovariectomy; Piperidines; Raloxifene Hydrochloride; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Stilbenes; Tamoxifen; Tumor Cells, Cultured; Uterus

Topics: Androgens; Arteriosclerosis; Contraceptive Agents; Contraceptives, Oral; Coronary Disease; Diethylstilbestrol; Estradiol; Estrogens, Conjugated (USP); Ethinyl Estradiol; Female; Humans; Menopause; Methyltestosterone; Osteoporosis; Stilbenes; Surgical Procedures, Operative; Toxicology