Modulation of osteoclastogenesis in porcine bone marrow cultures by quercetin and rutin.
Flavonols, in contrast to soybean isoflavones, are the most abundant phytoestrogens in western diets, being present in onions, beans, fruits, red wine, and tea. They may protect against atherosclerosis, inhibit certain cancer cell types, and reduce bone resorption. The most widely distributed flavonol is quercetin, which occurs mainly as its glycoside, rutin, but data are very scarce regarding the precise mechanism of action of these compounds on bone-resorbing cells at concentrations similar to those detected in human plasma. We have therefore investigated the effects of nanomolar concentrations of quercetin and rutin on the development and activity of osteoclasts in vitro compared with the effects of 17beta-estradiol. Nonadherent porcine bone marrow cells were cultured on dentine slices in the presence of 10 nM 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), with or without 10 nM quercetin, 10 nM rutin or 10 nM 17beta-estradiol for 11 days. Multinuclear TRAP+ cells that resorbed dentine (osteoclasts) developed in the presence of 1,25(OH)2D3, but their number was significantly reduced by quercetin, rutin, and 17beta-estradiol (P < 0.05). Like 17beta-estradiol, both flavonols also significantly reduced resorption (P<0.05) as assessed by the size of pits resorbed on dentine slices. Osteoclasts and osteoclast progenitors contained estrogen receptor alpha (ERalpha), ERbeta, and RANK proteins. Both flavonols increased nuclear ERbeta protein and decreased ERalpha protein of osteoclast progenitors. Moreover, rutin reduced RANK protein, whereas 17beta-oestradiol and quercetin promoted apoptosis by cleavage of caspase-8 and caspase-3. All the effects of flavonols were reversed by 1 microM ICI 182,780, an estrogen antagonist. Thus, the anti-resorbing properties of flavonols are mainly mediated by ER proteins through the inhibition of RANK protein or the activation of caspases.
Rassi CM, Lieberherr M, Chaumaz G, Pointillart A…
Cell Tissue Res. Mar 2005
Synergism between resveratrol and other phytochemicals: implications for obesity and osteoporosis.
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.
Rayalam S, Della-Fera MA, Baile CA
Mol Nutr Food Res Aug 2011
Quercetin prevents experimental glucocorticoid-induced osteoporosis: a comparative study with alendronate.
Glucocorticoid-induced osteoporosis (GIO) is the most common type of secondary osteoporosis. The aim of this study was to compare the efficacy of quercetin, a plant-derived flavonoid, with alendronate in the prevention of GIO. Fifty-six Sprague-Dawley rats were randomly distributed among 7 groups (8 rats per group) and treated for 6 weeks with one of the following: (i) normal saline; (ii) 40 mg methylprednisolone sodium succinate (MP)/kg body mass; (iii) MP + 40 μg alendronate/kg; (iv) MP + 50 mg quercetin/kg; (v) MP + 40 μg alendronate/kg + 50 mg quercetin/kg; (vi) MP + 150 mg quercetin/kg; and (vii) MP + 40 μg alendronate/kg + 150 mg quercetin/kg. MP and alendronate were injected subcutaneously and quercetin was administered by oral gavage 3 days a week. At the end of the study, femur breaking strength was significantly decreased as a consequence of MP injection. This decrease was completely compensated for in groups receiving 50 mg quercetin/kg plus alendronate, and 150 mg quercetin/kg with or without alendronate. Quercetin noticeably elevated osteocalcin as a bone formation marker, while alendronate did not show such an effect. In addition, administration of 150 mg quercetin/kg increased femoral trabecular and cortical thickness by 36% and 22%, respectively, compared with the MP-treated group. These data suggest that 150 mg quercetin/kg, alone or in combination with alendronate, can completely prevent GIO through its bone formation stimulatory effect.
Derakhshanian H, Djalali M, Djazayery A, Nourijelyani K…
Can. J. Physiol. Pharmacol. May 2013
Quercetin improves bone strength in experimental biliary cirrhosis.
Metabolic bone disorders and reduced bone mass are common complications in patients with biliary cirrhosis. As a result of there being no clear etiology, no specific therapy has been established yet. Previous studies have reported that quercetin, a plant-derived flavonoid, might improve bone quality. The present study was designed to investigate the effect of quercetin on bone strength of biliary cirrhotic rats. Methods: Twenty-four male Sprague-Dawley rats aged 6-7 months were randomized into three groups of eight. One group served as control (sham operated), while the other two groups underwent a complete bile duct ligation (BDL). Four weeks after the operation, serum bilirubin, alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase were measured in animal blood samples to confirm the occurrence of cirrhosis in the BDL rats. Then, one of the BDL groups received placebo and the other one was injected once a day with 150 µmol/kg of quercetin for 4 weeks. At the end of the study, femora were removed and tested for bone strength and histomorphometric parameters. The serum levels of osteocalcin, C-terminal cross-linked telopeptide of type I collagen, calcium and phosphorus were determined as bone turnover markers. Results: Femur breaking strength was dramatically lower in the BDL group compared with control. However, receiving quercetin could reverse the deteriorating effect of cirrhosis on bone strength of BDL rats. Quercetin could noticeably elevate osteocalcin as a bone formation marker. Conclusion: These data suggest that quercetin can significantly improve bone strength particularly due to increasing bone formation in biliary cirrhosis.
Derakhshanian H, Ghadbeigi S, Rezaian M, Bahremand A…
Hepatol. Res. Apr 2013
[Comparative study on effects of rutin and quercetin on metabolism in osteoblast cells].
To investigate the mechanism of rutin and its aglycone (quercetin) in preventing and treating osteoporosis and their effects on stimulating bone formation were studied comparatively in osteoblast cells.
The effects of rutin and quercetin on the proliferation, differentiation and mineralization were studied respectively by using tetrazolium (MTT), alkaline phosphatase (ALP) and mineralized nodules assays in newborn rat calvarial osteoblast (ROB) cells.
Quercetin showed significant stimulatory effects on proliferation and mineralization in ROB cells, so it could promote bone formation. However, rutin could not improve stimulation of bone formation because it increased proliferation and inhibited differentation and had no remarkable influence on ROB cells in vitro.
Rutin showed less activity than quercetin on bone formation in ROB cells in vitro. Therefore the mechanism that some foods and traditional Chinese medicine containing rutin can prevent and treat osteoporosis is that its metaboite in vivo can promote bone formation in ROB cells.
Yang YJ, Yang ZL, Wang DC, Xiao XC…
Zhong Yao Cai May 2006
Oral administration of quercetin inhibits bone loss in rat model of diabetic osteopenia.
Diabetic osteopenia can result in an increased incidence of bone fracture and a delay in fracture healing. Quercetin, one of the most widely distributed flavonoids in plants, possesses antioxidant property and beneficial effect on osteoporosis in ovariectomized mice. All these properties make quercetin a potential candidate for controlling the development of diabetic osteopenia. Therefore, the present study was designed to investigate the putative beneficial effect of quercetin on diabetic osteopenia in rats. Diabetes mellitus was induced by streptozotocin. The diabetic rats received daily oral administration of quercetin (5mg/kg, 30 mg/kg and 50mg/kg) for 8 weeks, which was started at 4 weeks after streptozotocin injection. Quercetin at 5mg/kg showed little effect on diabetic osteopenia, while quercetin at 30 mg/kg and 50mg/kg could increase the decreased serum osteocalcin, serum alkaline phosphatase activity, and urinary deoxypyridinoline in diabetic rats. In addition, quercetin (30 mg/kg and 50mg/kg) could partially reverse the decreased biomechanical quality and the impaired micro-architecture of the femurs in diabetic rats. Histomorphometric analysis showed that both decreased bone formation and resorption were observed in diabetic rats, which was partially restored by quercetin (30 mg/kg and 50mg/kg). Further investigations showed that quercetin significantly lowered the oxidative DNA damage level, up-regulated the total serum antioxidant capability and the activity of serum antioxidants in diabetic rats. All those findings indicate the beneficial effect of quercetin on diabetic osteopenia in rats, and raise the possibility of developing quercetin as potential drugs or an ingredient in diet for controlling diabetic osteopenia.
Liang W, Luo Z, Ge S, Li M…
Eur. J. Pharmacol. Nov 2011
Quercetin, a potent suppressor of NF-κB and Smad activation in osteoblasts.
Osteoclasts, the bone resorbing cells of the body, form when osteoclast precursors are exposed to the key osteoclastogenic cytokine receptor activator of NF-κB ligand (RANKL), a process requiring induction of NF-κB signaling. Quercetin is a ubiquitous plant-derived flavonoid with well documented anti-inflammatory properties, in part, a consequence of its capacity to downmodulate the NF-κB signal transduction pathway. Consistent with this mechanism of action quercetin is reported to suppress osteoclastogenesis in vitro and prevent bone loss in ovariectomized mice in vivo. By contrast, the effect of quercetin on osteoblasts, the cells responsible for bone formation, is contradictory with conflicting reports of inhibition as well as stimulation. Given our previous reports that NF-κB antagonists promote osteoblast differentiation and activity, we compared the effects of quercetin on osteoclast and osteoblast differentiation and on NF-κB signal transduction in vitro. As expected, quercetin potently suppressed osteoclastogenesis and NF-κB activation induced by RANKL in osteoclast precursors. However, the same doses of quercetin had no effect on osteoblast mineralization, and failed to significantly alleviate the inhibitory effect of NF-κB-induced by TNFα, even though quercetin potently suppressed NF-κB activation in these cells. This apparent contradiction was explained by the fact that addition to its anti-NF-κB activity, quercetin also potently antagonized both TGFβ and BMP-2-induced Smad activation in osteoblast precursors. Taken together our data suggest that multiple competing actions of quercetin mediate both stimulatory and inhibitory actions on osteoblasts with the final physiological effect likely a function of the net balance between these stimulatory and inhibitory effects.
Yamaguchi M, Weitzmann MN
Int. J. Mol. Med. Oct 2011
Preventing bone loss and weight gain with combinations of vitamin D and phytochemicals.
Vitamin D and certain natural compounds have been shown to regulate both lipid metabolism and bone formation. Treatments that prevent or reverse age-related increase in bone marrow adiposity could both increase new bone formation and inhibit bone destruction. We tested the hypothesis that dietary supplementation with combinations of vitamin D and phytochemicals inhibits bone loss and decreases adiposity to a greater extent than control or vitamin D-alone diets. Aged ovariectomized female rats (12 months old, n=50, initial body weight=240 g) were given control (AIN-93M diet), vitamin D (2,400 IU/kg), or vitamin D plus resveratrol (16, 80, or 400 mg/kg of diet [low, medium, and high dose, respectively]), quercetin (80, 400, or 2,000 mg/kg of diet), and genistein (64, 256, or 1,040 mg/kg of diet) for 8 weeks. The high-dose treatment (vitamin D+400 mg/kg resveratrol+2,000 mg/kg quercetin+1,040 mg/kg genistein) reduced body weight gain (P<.05) and the fat pad weights (P<.05). This treatment also increased the serum concentration of insulin-like growth factor-1 (P<.05) and the bone mineral content of the femur. Micro-computed tomography and histomorphometric analyses indicated that the high-dose treatment prevented loss of trabecular bone (P<.05) and reduced marrow adipocytes (P<.001) and osteoclasts (P<.05) compared with the control and vitamin D alone (P<.05). We conclude that aged ovariectomized female rats supplemented with vitamin D combined with genistein, quercetin, and resveratrol had improved bone mineral density and reduced body weight gain and a significant decrease in bone marrow adipocytes. The synergistic effects of a combination of phytochemicals with vitamin D may be effective in reducing bone loss and weight gain after menopause.
Lai CY, Yang JY, Rayalam S, Della-Fera MA…
J Med Food Nov 2011
Dietary quercetin inhibits bone loss without effect on the uterus in ovariectomized mice.
Quercetin is a major dietary flavonoid found in onions and other vegetables, and potentially has beneficial effects on disease prevention. In the present study, we demonstrate for the first time the effects of dietary quercetin on bone loss and uterine weight loss by ovariectomy in vivo. Female mice were ovariectomized (OVX) and were randomly allocated to 3 groups: a control diet or a diet with 0.25% (LQ) or 2.5% quercetin (HQ). After 4 weeks, dietary quercetin had no effects on uterine weight in OVX mice, but bone mineral density of the lumbar spine L4 and femur measured by peripheral quantitative computed tomography (pQCT) was higher in both the sham and the HQ groups than in the OVX group. Histomorphometric analysis showed that the HQ group restored bone volume (BV/TV) completely in distal femoral cancellous bone, but did not reduce the osteoclast surface area and osteoclast number when compared with the OVX group. In in-vitro experiments using mouse monocyte/macrophage cell line RAW264.7 cells, however, quercetin and its conjugate, quercetin-3-O-beta-D: -glucuronide dose-dependently inhibited the receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclast differentiation, and the RANKL-stimulated expression of osteoclast related genes was also inhibited by quercetin. The luciferase reporter assay showed that quercetin did not appear to have estrogenic activity through estrogen receptors. These results suggest that dietary quercetin inhibits bone loss without effect on the uterus in OVX mice and does not act as a potent inhibitor of osteoclastogenesis or as a selective estrogen receptor modulator in vivo.
Tsuji M, Yamamoto H, Sato T, Mizuha Y…
J. Bone Miner. Metab. 2009
Interesting, I wonder how it works if it doesn’t inhibit osteoclasts in vivo and isn’t estrogenic?
Effects of Egb 761 on bone mineral density, bone microstructure, and osteoblast function: Possible roles of quercetin and kaempferol.
The effects of standardized and concentrated extract of Ginkgo biloba, Egb 761, were studied on estrogen deficiency-induced bone loss in ovariectomized (OVx) rats rendered osteopenic. Upon osteopenia development, Egb 761 was administered at a dose of 100mgkg(?1)day(?1) by oral gavage to OVx rats whereas control group received vehicle. Following 5 weeks of treatment, the OVx+Egb 761 group (n=12) of rats exhibited significantly higher whole body BMD and lower bone turnover markers (serum alkaline phosphatase and osteocalcin) than OVx rats that were given vehicle (n=12). BMD levels in excised bones were also found to be higher in both trabecular (most robustly in lumbar vertebrae) and cortical bones of OVx+Egb 761 compared with OVx+vehicle group. Egb 761 did not exhibit estrogen agonistic activity at the uterine level. Microcomputed tomography demonstrated that OVx+Egb 761 group had better bone microarchitectural parameters compared with OVx+vehicle group. Moreover, OVx+Egb 761 group had higher femoral mRNA levels of osterix, type I collagen and osteocalcin compared with OVx+vehicle group. Determination of levels of three flavonoids of Egb 761, that are known to have bone conserving property, in serum and bone marrow suggests that kaempferol and quercetin, and not rutin, likely mediate the beneficial actions observed with Egb 761 treatment. These results show for the first time that oral administration of Egb 761 restores bone mass in aged OVx rats.
Trivedi R, Kumar A, Gupta V, Kumar S…
Mol. Cell. Endocrinol. Apr 2009