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Erschienen in: Journal of Bone and Mineral Metabolism 1/2014

01.01.2014 | Original Article

Resveratrol supplementation preserves long bone mass, microstructure, and strength in hindlimb-suspended old male rats

verfasst von: Stephanie M. Durbin, Janna R. Jackson, Michael J. Ryan, Joseph C. Gigliotti, Stephan E. Alway, Janet C. Tou

Erschienen in: Journal of Bone and Mineral Metabolism | Ausgabe 1/2014

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Abstract

Resveratrol has gained popularity as an “anti-aging” compound due to its antioxidant and anti-inflammatory properties. Few studies have investigated the role of resveratrol supplementation in the prevention of age-related bone loss and skeletal disuse despite increased inactivity and age-related bone loss in the elderly. The objective of the study was to investigate the effect of resveratrol supplementation on disuse and age-related bone loss. Old (age 33 months) Fischer 344 × Brown Norway male rats were provided either trans-resveratrol (12.5 mg/kg bw/day) or deionized distilled water by oral gavage for 21 days. Rats were hindlimb-suspended (HLS) or kept ambulatory (AMB) for 14 days. Both femora and tibiae were collected. Bone mass was measured by dual-energy X-ray absorptiometry and bone microstructure was determined by micro-computed tomography. HLS of old male rats accelerated loss of bone mineral content, decreased trabecular bone volume per unit of total volume, and increased trabecular separation. Resveratrol supplementation ameliorated bone demineralization and loss of bone microarchitecture in HLS old male rats. The peak force measured by the three-point bending test was reduced (P = 0.007) in HLS/control compared to AMB/control rats. Resveratrol supplementation ameliorated HLS-induced loss of femur strength. Plasma osteocalcin and alkaline phosphatase was higher (P < 0.04) and C-reactive protein was lower (P = 0.04) in old male rats given resveratrol. The bone protective effects of resveratrol appeared to be mediated through increased osteoblast bone formation, possibly due to reduced inflammation. Based on the results, resveratrol supplementation appeared to provide a feasible dietary therapy for preserving the skeletal system during disuse and age-related bone loss.
Literatur
1.
Zurück zum Zitat Duque G, Troen BR (2008) Understanding the mechanisms of senile osteoporosis: new facts for a major geriatric syndrome. J Am Geriatr Soc 56:935–941PubMedCrossRef Duque G, Troen BR (2008) Understanding the mechanisms of senile osteoporosis: new facts for a major geriatric syndrome. J Am Geriatr Soc 56:935–941PubMedCrossRef
2.
Zurück zum Zitat Kanis JA, Johnell O, Oden A (2001) Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds. Osteoporos Int 12:989–995PubMedCrossRef Kanis JA, Johnell O, Oden A (2001) Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds. Osteoporos Int 12:989–995PubMedCrossRef
3.
Zurück zum Zitat Inderjeeth CA, Foo AC, Lai MM, Glendenning P (2009) Efficacy and safety of pharmacological agents in managing osteoporosis in the old: review of the evidence. Bone 44:744–751PubMedCrossRef Inderjeeth CA, Foo AC, Lai MM, Glendenning P (2009) Efficacy and safety of pharmacological agents in managing osteoporosis in the old: review of the evidence. Bone 44:744–751PubMedCrossRef
4.
Zurück zum Zitat Ebeling PR (1998) Osteoporosis in men. New insights into aetiology, pathogenesis, prevention, and management. Drugs Aging 13:421–434PubMedCrossRef Ebeling PR (1998) Osteoporosis in men. New insights into aetiology, pathogenesis, prevention, and management. Drugs Aging 13:421–434PubMedCrossRef
5.
Zurück zum Zitat Vidavalur R, Otani H, Singal PK, Maulik N (2006) Significance of wine and resveratrol in cardiovascular disease: French paradox revisited. Exp Clin Cardiol 11:217–225PubMedCentralPubMed Vidavalur R, Otani H, Singal PK, Maulik N (2006) Significance of wine and resveratrol in cardiovascular disease: French paradox revisited. Exp Clin Cardiol 11:217–225PubMedCentralPubMed
6.
Zurück zum Zitat Cottart C, Nivet-Antoine V, Laguillier-Morizot, Beaudeux J (2010) Resveratrol bioavailability and toxicity in humans. Mol Nutr Food Res 54:7–16PubMedCrossRef Cottart C, Nivet-Antoine V, Laguillier-Morizot, Beaudeux J (2010) Resveratrol bioavailability and toxicity in humans. Mol Nutr Food Res 54:7–16PubMedCrossRef
7.
Zurück zum Zitat Williams LD, Burdock GA, Edwards JA, Beck M, Bausch J (2009) Safety studies conducted on high-purity trans-resveratrol in experimental animals. Food Chem Toxicol 47:2170–2182PubMedCrossRef Williams LD, Burdock GA, Edwards JA, Beck M, Bausch J (2009) Safety studies conducted on high-purity trans-resveratrol in experimental animals. Food Chem Toxicol 47:2170–2182PubMedCrossRef
8.
Zurück zum Zitat Chachay VS, Kirkpatrick CM, Hickman IJ, Ferguson M, Prins JB, Martin JH (2011) Resveratrol – pills to replace a healthy diet? Br J Clin Pharmacol 72:27–38PubMedCrossRef Chachay VS, Kirkpatrick CM, Hickman IJ, Ferguson M, Prins JB, Martin JH (2011) Resveratrol – pills to replace a healthy diet? Br J Clin Pharmacol 72:27–38PubMedCrossRef
9.
Zurück zum Zitat Dehority W, Halloran BP, Bikle DD, Curren T, Kostenuik PJ, Wronski TJ, Shen Y, Rabkin B, Bouraoui A, Morey-Holton E (1999) Bone and hormonal changes induced by skeletal unloading in the mature male rat. Am J Physiol 276:E62–E69PubMed Dehority W, Halloran BP, Bikle DD, Curren T, Kostenuik PJ, Wronski TJ, Shen Y, Rabkin B, Bouraoui A, Morey-Holton E (1999) Bone and hormonal changes induced by skeletal unloading in the mature male rat. Am J Physiol 276:E62–E69PubMed
10.
Zurück zum Zitat Habold C, Momken I, Ouadi A, Bekaert V, Brasse D (2011) Effect of prior treatment with RES on density and structure of rat long bones under tail-suspension. J Bone Miner Metab 29:15–22PubMedCrossRef Habold C, Momken I, Ouadi A, Bekaert V, Brasse D (2011) Effect of prior treatment with RES on density and structure of rat long bones under tail-suspension. J Bone Miner Metab 29:15–22PubMedCrossRef
11.
Zurück zum Zitat Momken I, Stevens L, Bergouignan A, Desplanches D, Rudwill F, Chery I, Zahariev A, Zahn S, Stein TP, Sebedio JL, Pujos-Guillot E, Falempin M, Simon C, Coxam V, Andrianjafiniony T, Gauquelin-Koch G, Picquet F, Blanc S (2011) Resveratrol prevents the wasting disorders of mechanical unloading by acting as a physical exercise mimetic in the rat. FASEB J 25:3646–3660PubMedCrossRef Momken I, Stevens L, Bergouignan A, Desplanches D, Rudwill F, Chery I, Zahariev A, Zahn S, Stein TP, Sebedio JL, Pujos-Guillot E, Falempin M, Simon C, Coxam V, Andrianjafiniony T, Gauquelin-Koch G, Picquet F, Blanc S (2011) Resveratrol prevents the wasting disorders of mechanical unloading by acting as a physical exercise mimetic in the rat. FASEB J 25:3646–3660PubMedCrossRef
12.
Zurück zum Zitat Zhang YB, Zhong ZM, Hou G, Jiang H, Chen JT (2011) Involvement of oxidative stress in age-related bone loss. J Surg Res 169:37–42CrossRef Zhang YB, Zhong ZM, Hou G, Jiang H, Chen JT (2011) Involvement of oxidative stress in age-related bone loss. J Surg Res 169:37–42CrossRef
13.
Zurück zum Zitat Yun AJ, Lee PY (2004) Maldaptation of the link between inflammation and bone turnover may be a key determinant of osteoporosis. Med Hypotheses 63:532–537PubMedCrossRef Yun AJ, Lee PY (2004) Maldaptation of the link between inflammation and bone turnover may be a key determinant of osteoporosis. Med Hypotheses 63:532–537PubMedCrossRef
14.
Zurück zum Zitat Bar-Shai M, Carmeli E, Ljubuncic P, Reznick AZ (2008) Exercise and immobilization in aging animals: the involvement of oxidative stress and NF-kappaB activation. Free Radic Biol Med 44:202–214PubMedCrossRef Bar-Shai M, Carmeli E, Ljubuncic P, Reznick AZ (2008) Exercise and immobilization in aging animals: the involvement of oxidative stress and NF-kappaB activation. Free Radic Biol Med 44:202–214PubMedCrossRef
15.
Zurück zum Zitat Smith BJ, Lucas EA, Turner RT, Evans GL, Lerner MR, Brackett DJ, Stoecker BJ, Arjmandi BH (2005) Vitamin E provides production for bone in mature hindlimb unloaded male rats. Calcif Tissue Int 76:272–279PubMedCrossRef Smith BJ, Lucas EA, Turner RT, Evans GL, Lerner MR, Brackett DJ, Stoecker BJ, Arjmandi BH (2005) Vitamin E provides production for bone in mature hindlimb unloaded male rats. Calcif Tissue Int 76:272–279PubMedCrossRef
16.
Zurück zum Zitat Boissy P, Andersen TL, Abdallah BM, Kassem M, Plesner T, Delaissé JM (2005) Resveratrol inhibits myeloma cell growth, prevents osteoclast formation, and promotes osteoblast differentiation. Cancer Res 65:9943–9952PubMedCrossRef Boissy P, Andersen TL, Abdallah BM, Kassem M, Plesner T, Delaissé JM (2005) Resveratrol inhibits myeloma cell growth, prevents osteoclast formation, and promotes osteoblast differentiation. Cancer Res 65:9943–9952PubMedCrossRef
17.
Zurück zum Zitat Pervaiz S, Holme AL (2009) Resveratrol: its biologic targets and functional activity. Antioxid Redox Signal 11:2851–2880PubMedCrossRef Pervaiz S, Holme AL (2009) Resveratrol: its biologic targets and functional activity. Antioxid Redox Signal 11:2851–2880PubMedCrossRef
18.
Zurück zum Zitat Institute of Laboratory Animal Resources Commission on Life Sciences (1995) Guide for the care and use of laboratory animals. National Academy Press, Washington, pp 21–55 Institute of Laboratory Animal Resources Commission on Life Sciences (1995) Guide for the care and use of laboratory animals. National Academy Press, Washington, pp 21–55
19.
Zurück zum Zitat Morey-Holton E, Globus RK (2002) The hindlimb unloading rodent model: technical aspects. J Appl Physiol 92:1367–1377PubMed Morey-Holton E, Globus RK (2002) The hindlimb unloading rodent model: technical aspects. J Appl Physiol 92:1367–1377PubMed
20.
Zurück zum Zitat Yuan YV, Kitts DD (1992) Estimation of dietary calcium utilization in rats using a biomechanical functional test. Food Chem 44:1–47CrossRef Yuan YV, Kitts DD (1992) Estimation of dietary calcium utilization in rats using a biomechanical functional test. Food Chem 44:1–47CrossRef
21.
Zurück zum Zitat Ortoft G, Oxlund H, Jorgensen PH, Andreassen TT (1992) Glucocorticoid treatment of food deprivation counteracts the simulation effect of growth hormone on rat cortical bone strength. Acta Paediatr 81:912–917PubMedCrossRef Ortoft G, Oxlund H, Jorgensen PH, Andreassen TT (1992) Glucocorticoid treatment of food deprivation counteracts the simulation effect of growth hormone on rat cortical bone strength. Acta Paediatr 81:912–917PubMedCrossRef
22.
Zurück zum Zitat Banu J, Wang L, Kalu DN (2002) Age-related changes in bone mineral content and density in intact male F344 rats. Bone 30:125–130PubMedCrossRef Banu J, Wang L, Kalu DN (2002) Age-related changes in bone mineral content and density in intact male F344 rats. Bone 30:125–130PubMedCrossRef
23.
Zurück zum Zitat Wang L, Banu J, McMahan CA, Kalu DN (2001) Male rodent model of age-related bone loss in men. Bone 29:141–148PubMedCrossRef Wang L, Banu J, McMahan CA, Kalu DN (2001) Male rodent model of age-related bone loss in men. Bone 29:141–148PubMedCrossRef
24.
Zurück zum Zitat Iida H, Fukuda S (2002) Age-related changes in bone mineral density, cross-sectional area and strength at different skeletal sites in male rats. J Vet Med Sci 64:29–34PubMedCrossRef Iida H, Fukuda S (2002) Age-related changes in bone mineral density, cross-sectional area and strength at different skeletal sites in male rats. J Vet Med Sci 64:29–34PubMedCrossRef
25.
Zurück zum Zitat Chen H, Zhou X, Emura, Shoumura S (2009) Site-specific bone loss in senescence-accelerated mouse (SAMP6): a murine model for senile osteoporosis. Exp Gerontol 44:792–798PubMedCrossRef Chen H, Zhou X, Emura, Shoumura S (2009) Site-specific bone loss in senescence-accelerated mouse (SAMP6): a murine model for senile osteoporosis. Exp Gerontol 44:792–798PubMedCrossRef
26.
Zurück zum Zitat Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL et al (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending lifespan. Cell Metab 8:157–168PubMedCentralPubMedCrossRef Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL et al (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending lifespan. Cell Metab 8:157–168PubMedCentralPubMedCrossRef
27.
Zurück zum Zitat Jee WS, Ma Y (1999) Animal models of immobilization osteopenia. Morphologie 83:25–34PubMed Jee WS, Ma Y (1999) Animal models of immobilization osteopenia. Morphologie 83:25–34PubMed
28.
Zurück zum Zitat Perrien DS, Akel NS, Dupont-Versteegden EE, Skinner RA, Siegel ER, Suva LJ, Gaddy D (2007) Aging alters the skeletal response to disuse in the rat. Am J Physiol Regul Integr Comp Physiol 292:988–996CrossRef Perrien DS, Akel NS, Dupont-Versteegden EE, Skinner RA, Siegel ER, Suva LJ, Gaddy D (2007) Aging alters the skeletal response to disuse in the rat. Am J Physiol Regul Integr Comp Physiol 292:988–996CrossRef
29.
Zurück zum Zitat Juan ME, González-Pons E, Munuera T, Ballester J, Rodríguez-Gil JE, Planas JM (2005) Trans-RES, a natural antioxidant from grapes, increases sperm output in healthy rats. J Nutr 135:757–760PubMed Juan ME, González-Pons E, Munuera T, Ballester J, Rodríguez-Gil JE, Planas JM (2005) Trans-RES, a natural antioxidant from grapes, increases sperm output in healthy rats. J Nutr 135:757–760PubMed
30.
Zurück zum Zitat Vico L, Collet P, Guignandon A, Lafage-Proust MH, Thomas T, Rehaillia M, Alexandre C (2000) Effects of long-term microgravity exposure on cancellous and cortical weight-bearing bones of cosmonauts. Lancet 355:1607–1611PubMedCrossRef Vico L, Collet P, Guignandon A, Lafage-Proust MH, Thomas T, Rehaillia M, Alexandre C (2000) Effects of long-term microgravity exposure on cancellous and cortical weight-bearing bones of cosmonauts. Lancet 355:1607–1611PubMedCrossRef
31.
Zurück zum Zitat Li XJ, Jee WS, Ke HZ, Mori S, Akamine T (1991) Age-related changes of cancellous and cortical bone histomorphometry in female Sprague-Dawley rats. Cells Mater (Suppl) 1:25–37 Li XJ, Jee WS, Ke HZ, Mori S, Akamine T (1991) Age-related changes of cancellous and cortical bone histomorphometry in female Sprague-Dawley rats. Cells Mater (Suppl) 1:25–37
32.
Zurück zum Zitat Bloomfield SA, Allen MR, Hogan HA, Delp MD (2003) Site and compartment specific changes in bone with hindlimb unloading in mature adult rats. Bone 31:149–157CrossRef Bloomfield SA, Allen MR, Hogan HA, Delp MD (2003) Site and compartment specific changes in bone with hindlimb unloading in mature adult rats. Bone 31:149–157CrossRef
33.
Zurück zum Zitat Hayes DP (2011) Resveratrol and vitamin D: significant potential interpretive problems arising from their mutual processes, interactions and effects. Med Hypotheses 77:765–772PubMedCrossRef Hayes DP (2011) Resveratrol and vitamin D: significant potential interpretive problems arising from their mutual processes, interactions and effects. Med Hypotheses 77:765–772PubMedCrossRef
34.
Zurück zum Zitat Gropper SS, Smith JL, Groff JL (2009) The fat-soluble vitamins. In: Gropper SS, Smith JL, Groff JL (eds) Advanced nutrition and human metabolism, 5th edn. Wadsworth, Belmont, pp 373–428 Gropper SS, Smith JL, Groff JL (2009) The fat-soluble vitamins. In: Gropper SS, Smith JL, Groff JL (eds) Advanced nutrition and human metabolism, 5th edn. Wadsworth, Belmont, pp 373–428
35.
Zurück zum Zitat Duque G (2008) Bone and fat connection in aging bone. Curr Opin Rheum 20:429–434CrossRef Duque G (2008) Bone and fat connection in aging bone. Curr Opin Rheum 20:429–434CrossRef
36.
Zurück zum Zitat Morey E, Baylink DJ (1978) Inhibition of bone formation during space flight. Science 201:1138–1141PubMedCrossRef Morey E, Baylink DJ (1978) Inhibition of bone formation during space flight. Science 201:1138–1141PubMedCrossRef
37.
Zurück zum Zitat Pietschmann P, Skalicky M, Kneissel M, Rauner M, Hofbauer G, Stupphann D, Viidik A (2007) Bone structure and metabolism in a rodent model of male senile osteoporosis. Exp Gerontol 42:1099–1108PubMedCrossRef Pietschmann P, Skalicky M, Kneissel M, Rauner M, Hofbauer G, Stupphann D, Viidik A (2007) Bone structure and metabolism in a rodent model of male senile osteoporosis. Exp Gerontol 42:1099–1108PubMedCrossRef
38.
Zurück zum Zitat Almeida M, Han L, Martin-Millan M, Plotkin LI, Stewart SA, Roberson PK, Kousteni S, O’Brien CA, Bellido T, Parfitt AM, Weinstein RS, Jilka RL, Manolagas SC (2007) Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J Biol Chem 282:27285–27297PubMedCentralPubMedCrossRef Almeida M, Han L, Martin-Millan M, Plotkin LI, Stewart SA, Roberson PK, Kousteni S, O’Brien CA, Bellido T, Parfitt AM, Weinstein RS, Jilka RL, Manolagas SC (2007) Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J Biol Chem 282:27285–27297PubMedCentralPubMedCrossRef
39.
Zurück zum Zitat Xu H, Watkins BA, Seifert MF (1995) Vitamin E stimulates trabecular bone formation and alters epiphyseal cartilage morphometry. Calcif Tissue Int 57:293–300PubMedCrossRef Xu H, Watkins BA, Seifert MF (1995) Vitamin E stimulates trabecular bone formation and alters epiphyseal cartilage morphometry. Calcif Tissue Int 57:293–300PubMedCrossRef
40.
Zurück zum Zitat la Lastra De, Villegas I (2005) Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications. Mol Nutr Food Res 49:405–430PubMedCrossRef la Lastra De, Villegas I (2005) Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications. Mol Nutr Food Res 49:405–430PubMedCrossRef
41.
Zurück zum Zitat Franceschi C, Valensin S, Bonafè M, Paolisso G, Yashin AI, Monti D, De Benedictis G (2000) The network and remodeling theories of aging: historical background and new perspectives. Exp Gerontol 35:879–896PubMedCrossRef Franceschi C, Valensin S, Bonafè M, Paolisso G, Yashin AI, Monti D, De Benedictis G (2000) The network and remodeling theories of aging: historical background and new perspectives. Exp Gerontol 35:879–896PubMedCrossRef
42.
Zurück zum Zitat Cauley JA, Danielson ME, Boudreau RM, Forrest KY, Zmuda JM, Pahor M, Tylaysky FA, Cummings SR, Harris TB, Newman AB (2007) Inflammatory markers and incident fracture risk in older men and women: the health aging and body composition study. J Bone Miner Res 222:1088–1095CrossRef Cauley JA, Danielson ME, Boudreau RM, Forrest KY, Zmuda JM, Pahor M, Tylaysky FA, Cummings SR, Harris TB, Newman AB (2007) Inflammatory markers and incident fracture risk in older men and women: the health aging and body composition study. J Bone Miner Res 222:1088–1095CrossRef
43.
Zurück zum Zitat Gilbert L, He X, Farmer P, Boden S, Kozlowski M, Rubin J, Nanes MS (2000) Inhibition of osteoblast differentiation by tumor necrosis factor-alpha. Endocrinology 141:3956–3964PubMed Gilbert L, He X, Farmer P, Boden S, Kozlowski M, Rubin J, Nanes MS (2000) Inhibition of osteoblast differentiation by tumor necrosis factor-alpha. Endocrinology 141:3956–3964PubMed
46.
Zurück zum Zitat Weinreb M, Rodan GA, Thompson DD (1989) Osteopenia in the immobilized rat hind limb is associated with increased bone resorption and decreased bone formation. Bone 10:187–194PubMedCrossRef Weinreb M, Rodan GA, Thompson DD (1989) Osteopenia in the immobilized rat hind limb is associated with increased bone resorption and decreased bone formation. Bone 10:187–194PubMedCrossRef
Metadaten
Titel
Resveratrol supplementation preserves long bone mass, microstructure, and strength in hindlimb-suspended old male rats
verfasst von
Stephanie M. Durbin
Janna R. Jackson
Michael J. Ryan
Joseph C. Gigliotti
Stephan E. Alway
Janet C. Tou
Publikationsdatum
01.01.2014
Verlag
Springer Japan
Erschienen in
Journal of Bone and Mineral Metabolism / Ausgabe 1/2014
Print ISSN: 0914-8779
Elektronische ISSN: 1435-5604
DOI
https://doi.org/10.1007/s00774-013-0469-2

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