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1.  Different skeletal effects of the peroxisome proliferator activated receptor (PPAR)α agonist fenofibrate and the PPARγ agonist pioglitazone 
Background
All the peroxisome proliferator activated receptors (PPARs) are found to be expressed in bone cells. The PPARγ agonist rosiglitazone has been shown to decrease bone mass in mice and thiazolidinediones (TZDs) have recently been found to increase bone loss and fracture risk in humans treated for type 2 diabetes mellitus. The aim of the study was to examine the effect of the PPARα agonist fenofibrate (FENO) and the PPARγ agonist pioglitazone (PIO) on bone in intact female rats.
Methods
Rats were given methylcellulose (vehicle), fenofibrate or pioglitazone (35 mg/kg body weight/day) by gavage for 4 months. BMC, BMD, and body composition were measured by DXA. Histomorphometry and biomechanical testing of excised femurs were performed. Effects of the compounds on bone cells were studied.
Results
The FENO group had higher femoral BMD and smaller medullary area at the distal femur; while trabecular bone volume was similar to controls. Whole body BMD, BMC, and trabecular bone volume were lower, while medullary area was increased in PIO rats compared to controls. Ultimate bending moment and energy absorption of the femoral shafts were reduced in the PIO group, while similar to controls in the FENO group. Plasma osteocalcin was higher in the FENO group than in the other groups. FENO stimulated proliferation and differentiation of, and OPG release from, the preosteoblast cell line MC3T3-E1.
Conclusion
We show opposite skeletal effects of PPARα and γ agonists in intact female rats. FENO resulted in significantly higher femoral BMD and lower medullary area, while PIO induced bone loss and impairment of the mechanical strength. This represents a novel effect of PPARα activation.
doi:10.1186/1472-6823-9-10
PMCID: PMC2678137  PMID: 19331671
2.  Skeletal Effects of the Saturated 3-Thia Fatty Acid Tetradecylthioacetic Acid in Rats 
PPAR Research  2011;2011:436358.
This study explores the skeletal effects of the peroxisome proliferator activated receptor (PPAR)pan agonist tetradecylthioacetic acid (TTA). Rats, without (Study I) and with ovariectomy (OVX) or sham operation (Study II), were given TTA or vehicle daily for 4 months. Bone markers in plasma, whole body and femoral bone mineral density and content (BMD and BMC), and body composition were examined. Histomorphometric and biomechanical analyses (Study I) and biomechanical and μCT analyses (Study II) of the femur were performed. Normal rats fed TTA had higher femoral BMD and increased total and cortical area in femur compared to controls. The ovariectomized groups had decreased BMD and impaired microarchitecture parameters compared to SHAM. However, the TTA OVX group maintained femoral BMC, trabecular thickness in the femoral head, and cortical volume in the femoral metaphysis as SHAM. TTA might increase BMD and exert a light preventive effect on estrogen-related bone loss in rats.
doi:10.1155/2011/436358
PMCID: PMC3236357  PMID: 22190907
3.  Effect of whole body vibration therapy on circulating serotonin levels in an ovariectomized rat model of osteoporosis 
Objective(s): Studies have reported that whole body vibration (WBV) played a vital role in bone remodeling. Circulating serotonin is also involved in negative regulating bone mass in rodents and humans. However, both WBV and inhibition of serotonin biosynthesis may suppress receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclastogenesis in vitro. The purpose of the current study was to investigate the effect of WBV therapy on the levels of serum serotonin in ovariectomized rats.
Materials and Methods: Thirty-six-month-old female Sprague Dawley rats weighing 276.15±37.75 g were ovariectomized to induce osteoporosis, and another ten rats underwent sham operation to establish sham control (SHAM) group. After 3 months, ovariectomized rats were divided into three subgroups and then separately treated with WBV, Alendronate (ALN) and normal saline (OVX), SHAM group was given normal saline. After 6 weeks of treatment, rats were sacrificed. Serum serotonin, RANKL, bone turnover markers, and bone mineral density (BMD), bone strength were evaluated.
Results: The serum serotonin level was significantly lower in WBV group than OVX and ALN groups (P<0.05 and P<0.001). RANKL levels significantly decreased in WBV and ALN groups compared to OVX group (P<0.001 for both). BMD and biomechanical parameters of femur significantly increased (P<0.05 for both) and bone turnover levels decreased (P<0.001 for both) in WBV group compared to OVX group.
Conclusion: These data indicated that WBV enhanced the bone strength and BMD in ovariectomized rats most likely by reducing the levels of circulating serotonin.
PMCID: PMC3938888  PMID: 24592309
Osteoporosis; Ovariectomy; Serotonin; Whole body vibration
4.  Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor gamma. 
Journal of Clinical Investigation  1996;98(4):1004-1009.
The ob gene product, leptin, is a signaling factor regulating body weight and energy balance. ob gene expression in rodents is increased in obesity and is regulated by feeding patterns and hormones, such as insulin and glucocorticoids. In humans with gross obesity, ob mRNA levels are higher, but other modulators of human ob expression are unknown. In view of the importance of peroxisome proliferator-activated receptor gamma (PPARgamma) in adipocyte differentiation, we analyzed whether ob gene expression is subject to regulation by factors activating PPARs. Treatment of rats with the PPARalpha activator fenofibrate did not change adipose tissue and body weight and had no significant effect on ob mRNA levels. However, administration of the thiazolidinedione BRL49653, a PPARgamma ligand, increased food intake and adipose tissue weight while reducing ob mRNA levels in rats in a dose-dependent manner. The inhibitory action of the thiazolidinedione BRL49653 on ob mRNA levels was also observed in vitro. Thiazolidinediones reduced the expression of the human ob promoter in primary adipocytes, however, in undifferentiated 3T3-L1 preadipocytes lacking endogenous PPARgamma, cotransfection of PPARgamma was required to observe the decrease. In conclusion, these data suggest that PPARgamma activators reduce ob mRNA levels through an effect of PPARgamma on the ob promoter.
PMCID: PMC507516  PMID: 8770873
5.  Addition of Fructooligosaccharides and Dried Plum to Soy-Based Diets Reverses Bone Loss in the Ovariectomized Rat 
Dietary bioactive components that play a role in improving skeletal health have received considerable attention in complementary and alternative medicine practices as a result of their increased efficacy to combat chronic diseases. The objectives of this study were to evaluate the additive or synergistic effects of dried plum and fructooligosaccharides (FOS) and to determine whether dried plum and FOS or their combination in a soy protein-based diet can restore bone mass in ovarian hormone deficient rats. For this purpose, 72 3-month-old female Sprague-Dawley rats were divided into six groups (n = 12) and either ovariectomized (Ovx, five groups) or sham-operated (sham, one group). The rats were maintained on a semipurified standard diet for 45 days after surgery to establish bone loss. Thereafter, the rats were placed on one of the following dietary treatments for 60 days: casein-based diet (Sham and Ovx), soy-based diet (Ovx + soy) or soy-based diet with dried plum (Ovx + soy + plum), FOS (Ovx + soy + FOS) and combination of dried plum and FOS (Ovx + soy + plum + FOS). Soy protein in combination with the test compounds significantly improved whole-body bone mineral density (BMD). All test compounds in combination with soy protein significantly increased femoral BMD but the combination of soy protein, dried plum and FOS had the most pronounced effect in increasing lumbar BMD. Similarly, all of the test compounds increased ultimate load, indicating improved biomechanical properties. The positive effects of these test compounds on bone may be due to their ability to modulate bone resorption and formation, as shown by suppressed urinary deoxypyridinoline excretion and enhanced alkaline phosphatase activity.
doi:10.1093/ecam/nen050
PMCID: PMC3137675  PMID: 18955356
6.  Additive Renoprotection by Pioglitazone and Fenofibrate against Inflammatory, Oxidative and Apoptotic Manifestations of Cisplatin Nephrotoxicity: Modulation by PPARs 
PLoS ONE  2015;10(11):e0142303.
Nephrotoxicity is a major side effect for the antineoplastic drug cisplatin. Here, we employed pharmacological, biochemical, and molecular studies to investigate the role of peroxisome proliferator-activated receptors (PPARs) in cisplatin nephrotoxicity. Rats were treated with a single i.p. dose of cisplatin (5 mg/kg) alone or combined with pioglitazone (PPARγ agonist), fenofibrate (PPARα agonist), pioglitazone plus fenofibrate, or thalidomide (Tumor necrosis factor-α inhibitor; TNF-α). Cisplatin nephrotoxicity was evidenced by rises in renal indices of functional (blood urea nitrogen, BUN, and creatinine), inflammatory (TNF-α, interleukin 6, IL-6), oxidative (increased malondialdehyde, MDA, and decreased superoxide dismutase, SOD and nitric oxide metabolites, NOx), apoptotic (caspase 3), and histological (glomerular atrophy, acute tubular necrosis and vacuolation) profiles. Cisplatin effects were partly abolished upon concurrent exposure to pioglitazone, fenofibrate, or thalidomide; more renoprotection was observed in rats treated with pioglitazaone plus fenofibrate. Immunostaining showed that renal expressions of PPARα and PPARγ were reduced by cisplatin and restored to vehicle-treated values after simultaneous treatment with pioglitazone or fenofibrate. Fenofibrate or pioglitazone renoprotection remained unaltered after concurrent blockade of PPARα (GW6471) and PPARγ (GW9662), respectively. To complement the rat studies, we also report that in human embryonic kidney cells (HEK293 cells), increases caused by cisplatin in inflammatory, apoptotic, and oxidative biomarkers were (i) partly improved after exposure to pioglitazone, fenofibrate, or thalidomide, and (ii) completely disappeared in cells treated with a combination of all three drugs. These data establish that the combined use of pioglitazone and fenofibrate additively improved manifestations of cisplatin nephrotoxicity through perhaps GW6471/GW9662-insensitive mechanisms.
doi:10.1371/journal.pone.0142303
PMCID: PMC4633146  PMID: 26536032
7.  Effect of dietary legumes on bone-specific gene expression in ovariectomized rats 
Nutrition Research and Practice  2013;7(3):185-191.
In previous studies, we found that the consumption of legumes decreased bone turnover in ovariectomized rats. The purpose of the present study is to determine whether the protective effects on bone mineral density (BMD) and the microarchitecture of a diet containing legumes are comparable. In addition, we aim to determine their protective actions in bones by studying bone specific gene expression. Forty-two Sprague-Dawley rats are being divided into six groups during the 12 week study: 1) rats that underwent sham operations (Sham), 2) ovariectomized rats fed an AIN-93M diet (OVX), 3) ovariectomized rats fed an AIN-93M diet with soybeans (OVX-S), 4) ovariectomized rats fed an AIN-93M diet with mung beans (OVX-M), 5) ovariectomized rats fed an AIN-93M diet with cowpeas (OVX-C), and 6) ovariectomized rats fed an AIN-93M diet with azuki beans (OVX-A). Consumption of legumes significantly increased BMD of the spine and femur and bone volume of the femur compared to the OVX. Serum calcium and phosphate ratio, osteocalcin, expression of osteoprotegerin (OPG), and the receptor activator of nuclear factor κB ligand (RANKL) ratio increased significantly, while urinary excretion of calcium and deoxypyridinoline and expression of TNF-α and IL-6 were significantly reduced in OVX rats fed legumes, compared to OVX rats that were not fed legumes. This study demonstrates that consumption of legumes has a beneficial effect on bone through modulation of OPG and RANKL expression in ovariectomized rats and that legume consumption can help compensate for an estrogen-deficiency by preventing bone loss induced by ovarian hormone deficiency.
doi:10.4162/nrp.2013.7.3.185
PMCID: PMC3679327  PMID: 23766879
Bone mass density; bone-specific gene expression; cytokines; legumes; ovariectomized rats
8.  Prolonged Treatments With Antiresorptive Agents and PTH Have Different Effects on Bone Strength and the Degree of Mineralization in Old Estrogen-Deficient Osteoporotic Rats 
Current approved medical treatments for osteoporosis reduce fracture risk to a greater degree than predicted from change in BMD in women with postmenopausal osteoporosis. We hypothesize that bone active agents improve bone strength in osteoporotic bone by altering different material properties of the bone. Eighteen-month-old female Fischer rats were ovariectomized (OVX) or sham-operated and left untreated for 60 days to induce osteopenia before they were treated with single doses of either risedronate (500 μg/kg, IV), zoledronic acid (100 μg/kg, IV), raloxifene (2 mg/kg, PO, three times per week), hPTH(1-34) (25 μg/kg, SC, three times per week), or vehicle (NS; 1 ml/kg, three times per week). Groups of animals were killed after days 60 and 180 of treatment, and either the proximal tibial metaphysis or lumbar vertebral body were studied. Bone volume and architecture were assessed by μCT and histomorphometry. Measurements of bone quality included the degree of bone mineralization (DBM), localized elastic modulus, bone turnover by histomorphometry, compression testing of the LVB, and three-point bending testing of the femur. The trabecular bone volume, DBM, elastic modulus, and compressive bone strength were all significantly lower at day 60 post-OVX (pretreatment, day 0 study) than at baseline. After 60 days of all of the bone active treatments, bone mass and material measurements agent were restored. However, after 180 days of treatment, the OVX + PTH group further increased BV/TV (+30% from day 60, p < 0.05 within group and between groups). In addition, after 180 days of treatment, there was more highly mineralized cortical and trabecular bone and increased cortical bone size and whole bone strength in OVX + PTH compared with other OVX + antiresorptives. Treatment of estrogen-deficient aged rats with either antiresorptive agents or PTH rapidly improved many aspects of bone quality including microarchitecture, bone mineralization, turnover, and bone strength. However, prolonged treatment for 180 days with PTH resulted in additional gains in bone quality and bone strength, suggesting that the maximal gains in bone strength in cortical and trabecular bone sites may require a longer treatment period with PTH.
doi:10.1359/jbmr.81005
PMCID: PMC3276355  PMID: 18847326
PTH(1-34); intravenous bisphosphonates; bone mineralization; compression and bending strengths; bone mineral homogeneity
9.  Fenofibrate Does Not Affect Burn-Induced Hepatic Endoplasmic Reticulum Stress 
The Journal of surgical research  2013;185(2):10.1016/j.jss.2013.06.029.
Background
Burn injury causes major metabolic derangements such as hypermetabolism, hyperlipidemia, and insulin resistance and is associated with liver damage, hepatomegaly, and hepatic endoplasmic reticulum (ER) stress. Although the physiological consequences of such derangements have been delineated, the underlying molecular mechanisms remain unknown. Previously, it was shown that fenofibrate improves patient outcome by attenuating post-burn stress responses.
Methods
Fenofibrate, a peroxisome proliferator-activated receptor (PPAR)-α agonist, regulates liver lipid metabolism and has been used to treat hypertriglyceridemia and hypercholesterolemia for many years. The aim of the present study is to determine the effects of fenofibrate on burn-induced hepatic morphologic and metabolic changes. We randomized rats to sham, burn injury, and burn injury plus fenofibrate. Animals were sacrificed and livers were assessed at 24 or 48 hours post-burn.
Results
Burn injury decreased albumin and increased alanine transaminase (p = 0.1 vs. sham), indicating liver injury. Fenofibrate administration did not restore albumin or decrease alanine transaminase. In addition, ER stress was significantly increased after burn injury both with and without fenofibrate (p < 0.05 vs. sham). Burn injury increased fatty acid metabolism gene expression (p < 0.05 vs. sham), downstream of PPARα. Fenofibrate treatment increased fatty acid metabolism further, which reduced post-burn hepatic steatosis (burn vs. sham p < 0.05, burn+fenofibrate vs. sham not significant).
Conclusions
Fenofibrate did not alleviate thermal injury induced hepatic ER stress and dysfunction but reduced hepatic steatosis by modulating hepatic genes related to fat metabolism.
doi:10.1016/j.jss.2013.06.029
PMCID: PMC3823693  PMID: 23866789
burn; liver metabolism; fenofibrate; steatosis; endoplasmic reticulum stress; apoptosis
10.  Establishing a rapid animal model of osteoporosis with ovariectomy plus low calcium diet in rats 
The objective of this study was to rapidly develop osteoporotic model animals by combining ovariectomy with a low calcium diet in rats. Thirty, eight-week-old, female, Sprague-Dawley rats were either sham-operated (Sham) or ovariectomized (Ovx) and divided into three groups: Sham, Ovx, and Ovx + low calcium diet. Rats in the Sham and Ovx groups were fed a standard diet containing 1.1% w/w calcium while rats in the Ovx + low calcium diet group were fed a diet containing 0.1% w/w calcium. Serum osteocalcin and bone mineral density (BMD) of the lumbar vertebrae were measured 4 and 8 weeks after surgery. The rats were euthanized 12 weeks after surgery, and the BMD of the right femur and histomorphometry of the femoral neck were assessed at that time. The Ovx + low-calcium diet group had a significantly lower mean BMD of the lumbar vertebra and higher mean serum osteocalcin concentration than the Sham and Ovx groups. Twelve weeks after surgery, rats in the Ovx + low calcium diet group had a significantly lower BMD, smaller Tb.Th and Tb.N, and larger Tb.Sp of the right femoral neck than did rats in the Sham and Ovx groups. These data indicate that a low calcium diet can significantly accelerate bone loss in ovariectomized rats. Combining ovariectomy and a low calcium diet can save considerable time in the creation of osteoporotic model animals.
PMCID: PMC4152076  PMID: 25197386
Animal model; osteoporosis; ovariectomy; low calcium diet
11.  Peroxisome proliferator-activated receptors α and γ are linked with alcohol consumption in mice and withdrawal and dependence in humans 
Background
Peroxisome proliferator-activated receptor (PPAR) agonists reduce voluntary ethanol consumption in rat models and are promising therapeutics in the treatment of drug addictions. We studied the effects of different classes of PPAR agonists on chronic ethanol intake and preference in mice with a genetic predisposition for high alcohol consumption and then examined human genome wide association data for polymorphisms in PPAR genes in alcohol-dependent subjects.
Methods
Two different behavioral tests were used to measure intake of 15% ethanol in C57BL/6J male mice: 24-hour two-bottle choice and limited access (3-hour) two-bottle choice, drinking in the dark. We measured the effects of pioglitazone (10 and 30 mg/kg), fenofibrate (50 and 150 mg/kg), GW0742 (10 mg/kg), tesaglitazar (1.5 mg/kg) and bezafibrate (25 and 75 mg/kg) on ethanol intake and preference. Fenofibric acid, the active metabolite of fenofibrate, was quantified in mouse plasma, liver, and brain by LC-MS/MS. Data from a human genome wide association study (GWAS) completed in the Collaborative Study on the Genetics of Alcoholism (COGA) was then used to analyze the association of single nucleotide polymorphisms (SNPs) in different PPAR genes (PPARA, PPARD, PPARG, and PPARGC1A) with two phenotypes: DSM-IV alcohol dependence (AD) and the DSM-IV criterion of withdrawal.
Results
Activation of two isoforms of PPARs, α and γ, reduced ethanol intake and preference in the two different consumption tests in mice. However, a selective PPARδ agonist or a pan agonist for all three PPAR isoforms did not decrease ethanol consumption. Fenofibric acid, the active metabolite of the PPARα agonist fenofibrate, was detected in liver, plasma, and brain after 1 or 8 days of oral treatment. The GWAS from COGA supported an association of SNPs in PPARA and PPARG with alcohol withdrawal and PPARGC1A with AD but found no association for PPARD with either phenotype.
Conclusions
We provide convergent evidence using both mouse and human data for specific PPARs in alcohol action. Reduced ethanol intake in mice and the genetic association between AD or withdrawal in humans highlight the potential for repurposing FDA-approved PPARα or PPARγ agonists for the treatment of AD.
doi:10.1111/acer.12610
PMCID: PMC4308472  PMID: 25516156
two-bottle choice; C57BL/6J; pioglitazone; fenofibrate; fenofibric acid; tesaglitazar; GWAS
12.  Effects of low-magnitude, high-frequency mechanical stimulation in the rat osteopenia model 
Osteoporosis International  2009;20(12):1999-2008.
Summary
In this study, short-term, whole-body vertical vibration at 90 Hz improved trabecular bone quality. There was an improvement of bone quality and density in both osteoporotic and control rats. This treatment may therefore be an attractive option for the treatment of osteoporosis.
Introduction
Aside from pharmacological treatment options, physical exercise is known to augment bone mass. In this study, the effects of whole-body vertical vibration (WBVV) on bone quality and density were evaluated using an osteoporotic rat model.
Methods
Sixty female Sprague Dawley rats were ovariectomized (C) or sham (SHAM) operated at the age of 3 months. After 3 months, both groups were divided into two subgroups that received either WBVV at 90 Hz for 35 days or no treatment. After sacrificing the rats, we evaluated vertebral bone strength, histomorphometric parameters, and bone mineral density (BMD).
Results
Treatment with WBVV resulted in improved biomechanical properties. The yield load after WBVV was significantly enhanced. According to yield load and Young’s modulus, the treated OVX rats reached the level of the untreated SHAM animals. In all measured histomorphometric parameters, WBVV significantly improved bone density. Treatment with WBVV demonstrated greater effects on the trabecular bone compared to the cortical bone. The ash-BMD index showed significant differences between treated and untreated rats.
Conclusion
Using WBVV as a non-pharmacological supportive treatment option for osteoporosis demonstrated an enhancement of bone strength and bone mass. This procedure may be an attractive option for the treatment of osteoporosis.
doi:10.1007/s00198-009-0892-3
PMCID: PMC2777215  PMID: 19283328
Mechanical stimuli; Osteoporosis; Trabecular bone; Whole-body vibration
13.  Time Related Changes of Mineral and Collagen and Their Roles in Cortical Bone Mechanics of Ovariectomized Rabbits 
PLoS ONE  2015;10(6):e0127973.
As cortical bone has a hierarchical structure, the macroscopic bone strength may be affected by the alterations of mineral crystal and collagen, which are main components of cortical bone. Limited studies focused on the time related alterations of these two components in osteoporosis, and their contributions to bone mechanics at tissue level and whole-bone level. Therefore, the purpose of this study was to elucidate the time related changes of mineral and collagen in cortical bone of ovariectomized (OVX) rabbits, and to relate these changes to cortical bone nanomechanics and macromechanics. 40 Rabbits (7-month-old) were randomly allocated into two groups (OVX and sham). OVX group received bilateral ovariectomy operation. Sham group received sham-OVX operation. Cortical bone quality of five rabbits in each group were assessed by DXA, μCT, nanoindentation, Fourier transform infrared (FTIR) spectroscopy and biomechanical tests (3-point bending of femoral midshaft) at pre-OVX, 4, 6, and 8 weeks after OVX. As time increased from pre-OVX to 8 weeks, the mineral to matrix ratio decreased with time, while both collagen crosslink ratio and crystallinity increased with time in OVX group. Elastic modulus and hardness measured by nanoindentation, whole-bone strength measured by biomechanical tests all decreased in OVX group with time. Bone material properties measured by FTIR correlated well with nano or whole-bone level mechanics. However, bone mineral density (BMD), structure, tissue-level and whole-bone mechanical properties did not change with age in sham group. Our study demonstrated that OVX could affect the tissue-level mechanics and bone strength of cortical bone. And this influence was attributed to the time related alterations of mineral and collagen properties, which may help us to design earlier interventions and more effective treatment strategies on osteoporosis.
doi:10.1371/journal.pone.0127973
PMCID: PMC4457815  PMID: 26046792
14.  Effects of Sigma Anti-bonding Molecule Calcium Carbonate on bone turnover and calcium balance in ovariectomized rats 
Laboratory Animal Research  2011;27(4):301-307.
This study was conducted to evaluate the effect of Sigma Anti-bonding Molecule Calcium Carbonate (SAC) as therapy for ovariectomy-induced osteoporosis in rats. Three weeks after surgery, fifteen ovariectomized Sprague-Dawley rats were divided randomly into 3 groups: sham-operated group (sham), ovariectomized group (OVX) and SAC-treatment group (OVX+SAC). The OVX+SAC group was given drinking water containing 0.0012% SAC for 12 weeks. Bone breaking force and mineralization as well as blood parameters related to the bone metabolism were analyzed. In OVX animals, blood concentration of 17β-estradiol decreased significantly, while osteocalcin and type I collagen C-terminal telopeptides (CTx) increased. Breaking force, bone mineral density (BMD), calcium and phosphorus in femurs, as well as uterine and vaginal weights, decreased significantly following OVX. However, SAC treatment (0.0012% in drinking water) not only remarkably restored the decreased 17β-estradiol and increased osteocalcin and CTx concentrations, but also recovered decreased femoral breaking force, BMD, calcium and phosphorus, although it did not reversed reproductive organ weights. It is suggested that SAC effectively improve bone density by preventing bone turnover mediated osteocalcin, CTx and minerals, and that it could be a potential candidate for therapy or prevention of postmenopausal osteoporosis.
doi:10.5625/lar.2011.27.4.301
PMCID: PMC3251760  PMID: 22232638
Osteoporosis; bone mineral density; Sigma Anti-bonding Molecule Calcium Carbonate; 17β-estradiol; osteocalcin; type I collagen C-terminal telopeptides
15.  Effect of Cistanches Herba Aqueous Extract on Bone Loss in Ovariectomized Rat 
To assess the ability of traditional Chinese medicine Cistanches Herba extract (CHE) to prevent bone loss in the ovariectomized (OVX) rat, Cistanches Herba extract (CHE) was administered intragastrically to the rats. Female rats were anesthetized with pentobarbital sodium (40 mg kg−1, i.p.), and their ovaries were removed bilaterally. The rats in the sham-operated group were anesthetized, laparotomized, and sutured without removing their ovaries. After 1 week of recovery from surgery, the OVX rats were randomly divided into three groups and orally treated with H2O (OVX group) or CHE (100 or 200 mg kg−1 daily) for 3 months. The sham-operated group (n = 8) was orally treated with H2O. After 3 months, the total body bone mineral density (BMD), bone mineral content (BMC), Bone biomechanical index, blood mineral levels and blood antioxidant enzymes activities were examined in sham-operated, ovariectomized and Cistanches Herba extract treated rats. Results showed that Cistanches Herba extract treatment significantly dose-dependently enhanced bone mineral density (BMD), bone mineral content (BMC), maximum load, displacement at maximum load, stress at maximum load, load at auto break, displacement at auto break, and stress at auto break, and blood antioxidant enzymes activities, decreased blood Ca, Zn and Cu levels compared to the OVX group. This experiment demonstrates that the administration of Cistanches Herba extract to ovariectomized rats reverses bone loss and prevents osteoporosis.
doi:10.3390/ijms12085060
PMCID: PMC3179152  PMID: 21954345
ovariectomy; rat; bone; antioxidant; Cistanches Herba
16.  PPARα: A Master Regulator of Bilirubin Homeostasis 
PPAR Research  2014;2014:747014.
Hypolipidemic fibrates activate the peroxisome proliferator-activated receptor (PPAR) α to modulate lipid oxidation and metabolism. The present study aimed at evaluating how 3 PPARα agonists, namely, fenofibrate, gemfibrozil, and Wy14,643, affect bilirubin synthesis and metabolism. Human umbilical vein epithelial cells (HUVEC) and coronary artery smooth muscle cells (CASMC) were cultured in the absence or presence of the 3 activators, and mRNA, protein, and/or activity levels of the bilirubin synthesizing heme oxygenase- (HO-) 1 and biliverdin reductase (BVR) enzymes were determined. Human hepatocytes (HH) and HepG2 cells sustained similar treatments, except that the expression of the bilirubin conjugating UDP-glucuronosyltransferase (UGT) 1A1 enzyme and multidrug resistance-associated protein (MRP) 2 transporter was analyzed. In HUVECs, gemfibrozil, fenofibrate, and Wy14,643 upregulated HO-1 mRNA expression without affecting BVR. Wy14,643 and fenofibrate also caused HO-1 protein accumulation, while gemfibrozil and fenofibrate favored the secretion of bilirubin in cell media. Similar positive regulations were also observed with the 3 PPARα ligands in CASMCs where HO-1 mRNA and protein levels were increased. In HH and HepG2 cells, both UGT1A1 and MRP2 transcripts were also accumulating. These observations indicate that PPARα ligands activate bilirubin synthesis in vascular cells and metabolism in liver cells. The clinical implications of these regulatory events are discussed.
doi:10.1155/2014/747014
PMCID: PMC4134828  PMID: 25147562
17.  Long-term effects of ovariectomy on the properties of bone in goats 
Large animal models of osteoporosis are essential for osteoporosis research. However, the time required to establish an accurate osteoporosis model is unknown. Therefore, the aim of the present study was to establish a large animal model of osteoporosis in goats. In total, 14 Chinese goats were divided into an ovariectomized (OVX, n=7) or sham-operated (SHAM, n=7) group. Vertebral bodies were used to measure the bone mineral density (BMD) prior to the ovariectomy and at 24 months after the ovariectomy. In addition, the BMD of the femoral neck, femoral diaphysis and tibial diaphysis were measured 24 months postoperatively. Bone samples from the vertebral body, femoral head and femoral neck were scanned by micro-computed tomography (CT) to visualize the trabecular and cortical microstructure. Furthermore, the vertebral body, femoral head, femoral neck and tibial diaphysis were analyzed for mechanical strength. The BMD of vertebral body of the OVX group decreased significantly (P<0.01) at 24 months after the ovariectomy when compared with the baseline measurements. Micro-CT scans of the vertebral body revealed that the bone volume fraction, trabecular number, trabecular thickness and the degree of anisotropy decreased by 37.1, 36.7, 10.5 and 16.5%, respectively (P<0.01) in the OVX group when compared with the SHAM group. Additionally, the specific bone surface and trabecular spacing significantly increased by 37.7 and 62%, respectively in the OVX group (P<0.001). Cortical bone porosity in the vertebral body and femoral neck was greater in the OVX group when compared with the SHAM group (P<0.05). In addition, mechanical testing revealed a statistically significant difference between the vertebral bodies of the OVX group and the SHAM group. In conclusion, the present study demonstrated that an ovariectomy was able to induce significant osteoporosis and deterioration of mechanical properties in the bones of goats.
doi:10.3892/etm.2015.2303
PMCID: PMC4471718  PMID: 26136924
osteoporosis model; Chinese mountain goats; bone mineral density; biomechanical test; estrogen deficiency
18.  Effects of Chronic Estrogen Treatment on Modulating Age-Related Bone Loss in Female Mice 
While female mice do not have the equivalent of a menopause, they do undergo reproductive senescence. Thus, to dissociate effects of aging versus estrogen deficiency on age-related bone loss, we sham operated, ovariectomized, or ovariectomized and estrogen replaced female C57/BL6 mice at 6 months of age and followed them to age 18-22 months. Lumbar spines and femurs were excised for analysis, and bone marrow hematopoietic lineage negative (lin-) cells (enriched for osteoprogenitor cells) were isolated for gene expression studies. Six month old intact control mice were sacrificed to define baseline parameters. Compared to young mice, aged/sham mice had a 42% reduction in lumbar spine bone volume/total volume (BV/TV), and maintaining constant estrogen levels over life in ovariectomized/estrogen-treated mice did not prevent age-related trabecular bone loss at this site. By contrast, life-long estrogen treatment of ovariectomized mice completely prevented the age-related reduction in cortical volumetric BMD and thickness at the tibial diaphysis present in the aged/sham mice. As compared to cells from young mice, lin- cells from aged/sham mice expressed significantly higher mRNA levels for osteoblast differentiation and proliferation marker genes. These data thus demonstrate that, in mice, age-related loss of cortical bone in the appendicular skeleton, but not loss of trabecular bone in the spine, can be prevented by maintaining constant estrogen levels over life. The observed increase in osteoblastic differentiation and proliferation marker gene expression in progenitor bone marrow cells from aged as compared to young mice may represent a compensatory mechanism in response to ongoing bone loss.
doi:10.1002/jbmr.129
PMCID: PMC3119867  PMID: 20499336
Aging; estrogen; bone; mice; ovariectomy
19.  Effect of an isoflavones-containing red clover preparation and alkaline supplementation on bone metabolism in ovariectomized rats 
The aim of this study was to test the combined effect of a quality-controlled red clover extract (RCE) standardized to contain 40% isoflavones by weight (genistein, daidzein, biochanin A, and formononetin present as hydrolyzed aglycones) together with a modified alkaline supplementation on bone metabolic and biomechanical parameters in an experimental model of surgically-induced menopause. Sprague–Dawley female rats were maintained under controlled standard conditions of light and fed with conventional food of standard calcium content and no alfalfa or soybean components. Rats were randomized into four groups: Group A represented normal rats (sham operated) while three other groups were ovariectomized (OVX) and fed for three months as follows: standard food (group B), 6 mg/kg/day food mixed with RCE (Group C), or given 6 mg/kg/day of RCE plus a modified alkaline supplementation (BP) through a nasogastric tube at a dose of 16 mg (group D). The animals were killed 90 days after surgery. As compared to group B, RCE or RCE + BP treatments brought about significantly higher level of estradiol and mitigated the weight loss of the uterus and improved maximum load of the femoral neck. Osteocalcin level showed an over 65% increase in group B but both RCE and RCE + BP treatments prevented such abnormality with a significantly better result in RCE + BP group which virtually normalized such parameter as well as urinary excretion of DPD. Group C and D reduced the over 20% loss of bone mineral density and bone mineral content/body weight ratio observed in untreated post-ovariectomy group. Untreated ovariectomy caused about 48% decrease of cancellous bone mass in the femoral neck while this abnormality was prevented at similar extent by both RCE and RCE + BP treatments. Ovariectomy determined an over 80% increase of bone alkaline phosphatase (BALP) level but both RCE and RCE + BP treatments significantly mitigated such variable. The BALP decrease yielded by the combined RCE + BP treatment was statistically lower than RCE alone. Taken together these data show that red clover preparation in dosages amenable to clinical practice do improve OVX-induced osteoporosis while a mild metabolic alkalosis might further synergize some therapeutic aspects.
PMCID: PMC2685230  PMID: 19503771
red clover; alkaline supplementation; osteoporosis; ovariectomy
20.  Anti-inflammatory effect of antidiabetic thiazolidinediones prevents bone resorption rather than cartilage changes in experimental polyarthritis 
Background
Rosiglitazone and pioglitazone are high-affinity peroxisome proliferator-activated receptor (PPAR)-γ agonists with potent anti-diabetic properties and potential anti-inflammatory effects. We compared the ability of a range of oral doses of these thiazolidinediones, including those sufficient to restore insulin sensitization, to inhibit the pathogenesis of adjuvant-induced arthritis (AIA).
Methods
AIA was induced in Lewis rats by a subcutaneous injection of 1 mg of complete Freund's adjuvant. Rats were treated orally for 21 days with pioglitazone 3, 10 or 30 mg/kg/day, rosiglitazone 3 or 10 mg/kg/day, or with vehicle only. The time course of AIA was evaluated by biotelemetry to monitor body temperature and locomotor activity, by clinical score and plethysmographic measurement of hindpaw oedema. At necropsy, RT-PCR analysis was performed on synovium, liver and subcutaneous fat. Changes in cartilage were evaluated by histological examination of ankle joints, radiolabelled sulphate incorporation (proteoglycan synthesis), glycosaminoglycan content (proteoglycan turnover) and aggrecan expression in patellar cartilage. Whole-body bone mineral content was measured by dual-energy X-ray absorptiometry.
Results
The highest doses of rosiglitazone (10 mg/kg/day) or pioglitazone (30 mg/kg/day) were required to reduce fever peaks associated with acute or chronic inflammation, respectively, and to decrease arthritis severity. At these doses, thiazolidinediones reduced synovitis and synovial expression of TNF-α, IL-1β and basic fibroblast growth factor without affecting neovascularization or the expression of vascular endothelial growth factor. Thiazolidinediones failed to prevent cartilage lesions and arthritis-induced inhibition of proteoglycan synthesis, aggrecan mRNA level or glycosaminoglycan content in patellar cartilage, but reduced bone erosions and inflammatory bone loss. A trend towards lower urinary levels of deoxipyridinolin was also noted in arthritic rats treated with thiazolidinediones. Rosiglitazone 10 mg/kg/day or pioglitazone 30 mg/kg/day increased the expression of PPAR-γ and adiponectin in adipose tissue, confirming that they were activating PPAR-γ in inflammatory conditions, although an increase in fat mass percentage was observed for the most anti-arthritic dose.
Conclusion
These data emphasize that higher dosages of thiazolidinediones are required for the treatment of arthritis than for restoring insulin sensitivity but that thiazolidinediones prevent inflammatory bone loss despite exposing animals to increased fatness possibly resulting from excessive activation of PPAR-γ.
doi:10.1186/ar2354
PMCID: PMC2374462  PMID: 18199331
21.  Pycnogenol® treatment inhibits bone mineral density loss and trabecular deterioration in ovariectomized rats 
Context: Pycnogenol® extracted from French maritime pine bark (Pinus pinaster Ait. subsp. atlantica) is functional for its antioxidant activity. Objective: To investigate the effects of Pycnogenol® on bone mineral density (BMD), trabecular microarchitecture and bone metabolism in ovariectomized (OVX) rats. Materials and methods: Thirty Sprague-Dawley rats were randomized into 3 groups: SHAM group (sham-operated rats), OVX group (OVX rats), and treatment group (OVX rats supplemented with 40 mg/kg Pycnogenol® by oral gavage). Serum levels of procollagen type I N-terminal propeptide (PINP), alkaline phosphatase (ALP) and minerals were detected at the end of 9 weeks of gavage. Deoxypyridinoline/creatinine (DPYD/Cr) and N-telopeptide of type I collagen/creatinine (NTX/Cr) rate in urine were also calculated. Left femora were collected for BMD determination, and the right distal femora were made into undecalcified specimens for histomorphometry analysis. Results: At the end of study, PINP level, DPYD/Cr and NTX/Cr rate were significantly increased, and femoral BMD were dramatically decreased in OVX group compared with SHAM group (P < 0.01) while serum minerals and ALP concentrations showed no significant difference. The treatment group had dramatically decreased biomarkers and increased BMD than OVX group (P < 0.01). Histomorphometry analysis showed worse bone microarchitecture parameters in the OVX group compared with the SHAM group which were significantly improved in the treatment group compared with the OVX group (P < 0.01). Discussion and conclusion: Pycnogenol® (40 mg/kg) can inhibit aggravated bone resorption, prevent BMD loss, and restore the impaired trabecular microarchitecture in OVX rats after 9-week-intervention.
PMCID: PMC4565266  PMID: 26379883
Pycnogenol®; ovariectomy; histomorphometry; bone mineral density; bone turnover biomarkers; oxidative stress
22.  Improvement of Femoral Bone Quality After Low-Magnitude, High-Frequency Mechanical Stimulation in the Ovariectomized Rat as an Osteopenia Model 
Calcified Tissue International  2010;88(1):33-40.
The treatment and prevention of osteoporosis involve great challenges. Nonpharmacological and supportive therapy procedures, sport, and physical exercises seem to prevent bone loss and improve bone mass. In the present study, we examined the effect of whole-body vertical vibration (WBVV) on femoral intertrochanteric bone quality in the rat osteoporosis model. Sixty female Sprague–Dawley rats, 3-month old, were ovariectomized (OVX) or sham-operated. After 3 months, each group was divided into two subgroups. In one of the subgroups, rats were treated with WBVV at 90 Hz (3.9 g) for 35 days; the second subgroup remained untreated. After killing the animals, biomechanical strength and trabecular bone architecture of the proximal region of femurs were analyzed. New cortical bone appositions and mineral density of femurs were additionally measured. Treatment with WBVV resulted in improved biomechanical properties. Maximal load and stiffness of the intertrochanteric region of femurs after WBVV were significantly enhanced. Maximal load and stiffness in treated OVX animals reached the levels observed in untreated sham rats. WBVV significantly improved all measured histomorphometric parameters in the trabecular area. Treated rats showed significantly improved mineral content in ashed femurs compared to untreated animals. A comparison of widths of fluorescence bands in cortical bone of subtrochanteric cross sections did not show any significant differences between the groups after WBVV. Low-magnitude, high-frequency mechanical stimulation improves bone strength in the proximal femur and may be a possible nonpharmacologic treatment option for postmenopausal osteoporosis.
doi:10.1007/s00223-010-9423-7
PMCID: PMC3021189  PMID: 21052653
Osteoporosis; Whole-body vertical vibration; Rat femur; Mechanical stimulation
23.  L-Carnitine, but not coenzyme Q10, enhances the anti-osteoporotic effect of atorvastatin in ovariectomized rats 
Objective: Statins’ therapy in osteoporosis can aggravate muscle damage. This study was designed to assess which agent, L-carnitine or coenzyme Q10, could enhance the anti-osteoporotic effect of atorvastatin while antagonizing myopathy in ovariectomized rats. Methods: Forty-eight female Sprague Dawley rats were used; forty rats were ovariectomized while eight were sham-operated. Eight weeks post-ovariectomy, rats were divided into ovariectomized-untreated group and four ovariectomized-treated groups (n=8) which received by gavage (mg/(kg∙d), for 8 weeks) 17β-estradiol (0.1), atorvastatin (50), atorvastatin (50)+L-carnitine (100), or atorvastatin (50)+coenzyme Q10 (20). At the end of therapy, bone mineral density (BMD), bone mineral content (BMC), and serum levels of bone metabolic markers (BMMs) and creatine kinase (CK) were measured. Femurs were used for studying the breaking strength and histopathological changes. Results: Treatment with atorvastatin+L-carnitine restored BMD, BMC, and bone strength to near normal levels. Estrogen therapy restored BMD and BMC to near normal levels, but failed to increase bone strength. Although atorvastatin and atorvastatin+coenzyme Q10 improved BMD, BMC, and bone strength, they failed to restore levels to normal. All treatments decreased BMMs and improved histopathological changes maximally with atorvastatin+L-carnitine which restored levels to near normal. Atorvastatin aggravated the ovariectomy-induced increase in CK level while estrogen, atorvastatin+L-carnitine, and atorvastatin+coenzyme Q10 decreased its level mainly with atorvastatin+L-carnitine which restored the level to near normal. Conclusions: Co-administration of L-carnitine, but not coenzyme Q10, enhances the anti-osteoporotic effect of atorvastatin while antagonizing myopathy in ovariectomized rats. This could be valuable in treatment of osteoporotic patients. However, further confirmatory studies are needed.
doi:10.1631/jzus.B1500065
PMCID: PMC4710839  PMID: 26739525
Atorvastatin; Coenzyme Q10;  L-Carnitine; Ovariectomized
24.  Royal Jelly Prevents Osteoporosis in Rats: Beneficial Effects in Ovariectomy Model and in Bone Tissue Culture Model 
Royal jelly (RJ) has been used worldwide for many years as medical products, health foods and cosmetics. Since RJ contains testosterone and has steroid hormone-type activities, we hypothesized that it may have beneficial effects on osteoporosis. We used both an ovariectomized rat model and a tissue culture model. Rats were divided into eight groups as follows: sham-operated (Sham), ovariectomized (OVX), OVX given 0.5% (w/w) raw RJ, OVX given 2.0% (w/w) RJ, OVX given 0.5% (w/w) protease-treated RJ (pRJ), OVX given 2.0% (w/w) pRJ, OVX given 17β-estradiol and OVX given its vehicle, respectively. The Ovariectomy decreased tibial bone mineral density (BMD) by 24%. Administration of 17β-estradiol to OVX rats recovered the tibial BMD decrease by 100%. Administration of 2.0% (w/w) RJ and 0.5–2.0% (w/w) pRJ to OVX rats recovered it by 85% or more. These results indicate that both RJ and pRJ are almost as effective as 17β-estradiol in preventing the development of bone loss induced by ovariectomy in rats. In tissue culture models, both RJ and pRJ increased calcium contents in femoral-diaphyseal and femoral-metaphyseal tissue cultures obtained from normal male rats. However, in a mouse marrow culture model, they neither inhibited the parathyroid hormone (PTH)-induced calcium loss nor affected the formation of osteoclast-like cells induced by PTH in mouse marrow culture system. Therefore, our results suggest that both RJ and pRJ may prevent osteoporosis by enhancing intestinal calcium absorption, but not by directly antagonizing the action of PTH.
doi:10.1093/ecam/nel019
PMCID: PMC1513150  PMID: 16951718
bone mineral density; bone tissue culture; ovariectomized rats; post-menopausal osteoporosis model; protease-treated RJ; royal jelly
25.  Higher Doses of Bisphosphonates Further Improve Bone Mass, Architecture, and Strength but Not the Tissue Material Properties in Aged Rats 
Bone  2009;46(5):1267-1274.
We report the results of a series of experiments designed to determine the effects of ibandronate (Ibn) and risedronate (Ris) on a number of bone quality parameters in aged osteopenic rats to explain how bone material and bone mass may be affected by the dose of bisphosphonates (BP) and contribute to their anti-fracture efficacy.
Eighteen-month old female rats underwent either ovariectomy or sham surgery. The ovariectomized (OVX) groups were left untreated for 2 months to develop osteopenia. Treatments started at 20 months of age as follows: sham and OVX control (treated with saline), OVX+risedronate 30 and 90 (30 or 90 μg/kg/dose), and OVX+ibandronate 30 and 90 (30 or 90 μg/kg/dose). The treatments were given monthly for four months by subcutaneous injection. At sacrifice at 24 months of age the 4th lumbar vertebra was used for μCT scans (bone mass, architecture, and degree of mineralization of bone, DMB) and histomorphometry, and the 6th lumbar vertebra, tibia, and femur were collected for biomechanical testing to determine bone structural and material strength, cortical fracture toughness, and tissue elastic modulus. The compression testing of the vertebral bodies (LVB6) was simulated using finite-element analysis (FEA) to also estimate the bone structural stiffness.
Both Ibn and Ris dose-dependently increased bone mass and improved vertebral bone microarchitecture and mechanical properties compared to OVX control. Estimates of vertebral maximum stress from FEA were correlated with vertebral maximum load (r=0.5, p<0.001) and maximum stress (r=0.4, p<0.005) measured experimentally. Tibial bone bending modulus and cortical strength increased compared to OVX with both BP but no dose-dependent effect was observed. DMB and elastic modulus of trabecular bone were improved with Ibn30 compared to OVX but were not affected in other BP-treated groups. DMB of tibial cortical bone showed no change with BP treatments. The fracture toughness examined in midshaft femurs did not change with BP even with the higher doses. In summary, the anti fracture efficacy of BP is largely due to their preservation of bone mass and while the higher doses further improve the bone structural properties do not improve the localized bone material characteristics such as tissue strength, elastic modulus, and cortical toughness.
doi:10.1016/j.bone.2009.11.019
PMCID: PMC3003226  PMID: 19931661
bisphosphonate; bisphosphonate dose; structural properties; material properties; bone mineralization

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