Abstract
Age-related bone loss has been associated with high levels of marrow adipogenesis. Estrogens (E2) are known to regulate the differentiation of marrow precursors into osteoblasts, however, their role in bone marrow adipogenesis remain unknown. E2 regulate adipocyte differentiation in subcutaneous and visceral fat through interaction with other nuclear receptors. This interaction has not been assessed in bone marrow adipocytes in vivo. In this study, we compared two groups of animals, young and old, after either oophorectomy (OVX) or oophorectomy plus E2 (OVX + E2) replacement. We found that absence of E2 was associated with higher levels of PPARγ and lower levels of Sirt1 most significantly in the old group. In addition, old mice responded better to E2 replacement in terms of reducing adipogenesis and PPARγ expression as well as increasing levels of Sirt1 expression. Our findings represent a new understanding of the role of E2 in age-related bone loss, which could be mediated through the regulation of Sirt1 expression within the bone marrow. In addition, this evidence suggests that old individuals may show a better response to E2 administration in terms of reverting the high levels of marrow fat seen in age-related bone loss.
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References
Akune T, Ohba S, Kamekura S et al (2004) PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest 113:846–855
Bäckesjö CM, Li Y, Lindgren U et al (2006) Activation of Sirt1 decreases adipocyte formation during osteoblast differentiation of mesenchymal stem cells. J Bone Miner Res 21:993–1002. doi:10.1359/jbmr.060415
Chaiamnuay S, Saag KG (2006) Postmenopausal osteoporosis. What have we learned since the introduction of bisphosphonates? Rev Endocr Metab Disord 7:101–112. doi:10.1007/s11154-006-9008-y
Duque G, Troen BR (2008) Understanding the mechanisms of senile osteoporosis: new facts for a major geriatric syndrome. J Am Geriatr Soc 56:935–941. doi:10.1111/j.1532-5415.2008.01764.x
Duque G, El Abdaimi K, Macoritto M et al (2002) Estrogens (E2) regulate expression and response of 1, 25-dihydroxyvitamin D3 receptors in bone cells: changes with aging and hormone deprivation. Biochem Biophys Res Commun 299:446–454. doi:10.1016/S0006-291X(02)02657-8
Duque G, Macoritto M, Kremer R (2004a) Vitamin D treatment of senescence accelerated mice (SAM-P/6) induces several regulators of stromal cell plasticity. Biogerontology 5:421–429. doi:10.1007/s10522-004-3192-5
Duque G, Macoritto M, Kremer R (2004b) 1,25(OH)2D3 inhibits bone marrow adipogenesis in senescence accelerated mice (SAM-P/6) by decreasing the expression of peroxisome proliferator-activated receptor gamma 2 (PPARgamma2). Exp Gerontol 39:333–338. doi:10.1016/j.exger.2003.11.008
Ferguson VL, Ayers RA, Bateman TA et al (2003) Bone development and age-related bone loss in male C57BL/6J mice. Bone 33(3):387–389. doi:10.1016/S8756-3282(03)00199-6
Foryst-Ludwig A, Clemenz M, Hohmann S et al (2008) Metabolic actions of estrogen receptor beta (ERbeta) are mediated by a negative cross-talk with PPARgamma. PLoS Genet 4:e1000108. doi:10.1371/journal.pgen.1000108
Hong L, Colpan A, Peptan IA (2006) Modulations of 17-beta estradiol on osteogenic and adipogenic differentiations of human mesenchymal stem cells. Tissue Eng 12:2747–2753. doi:10.1089/ten.2006.12.2747
Kalu DN, Chen C (1999) Ovariectomized murine model of postmenopausal calcium malabsorption. J Bone Miner Res 14:593–601. doi:10.1359/jbmr.1999.14.4.593
Kumar R, Thompson EB (1999) The structure of the nuclear hormone receptors. Steroids 64:310–319. doi:10.1016/S0039-128X(99)00014-8
Liao QC, Li YL, Qin YF et al (2008) Inhibition of adipocyte differentiation by phytoestrogen genistein through a potential downregulation of extracellular signal-regulated kinases 1/2 activity. J Cell Biochem 104:1853–1864. doi:10.1002/jcb.21753
Lund KJ (2008) Menopause and the menopausal transition. Med Clin North Am 92:1253–1271. doi:10.1016/j.mcna.2008.04.009
Moerman EJ, Teng K, Lipschitz DA et al (2004) Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: the role of PPAR-gamma2 transcription factor and TGF-beta/BMP signaling pathways. Aging Cell 3:379–389. doi:10.1111/j.1474-9728.2004.00127.x
Picard F, Kurtev M, Chung N et al (2004) Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 429:771–776. doi:10.1038/nature02583
Raisz LG, Seeman E (2001) Causes of age-related bone loss and bone fragility: an alternative view. J Bone Miner Res 16:1948–1952. doi:10.1359/jbmr.2001.16.11.1948
Rasbach KA, Schnellmann RG (2008) Isoflavones promote mitochondrial biogenesis. J Pharmacol Exp Ther 325:536–543. doi:10.1124/jpet.107.134882
Rayalam S, Yang JY, Ambati S et al (2008) Resveratrol induces apoptosis and inhibits adipogenesis in 3T3–L1 adipocytes. Phytother Res 22:1367–1371. doi:10.1002/ptr.2503
Shockley KR, Rosen CJ, Churchill GA et al (2007) PPARgamma2 regulates a molecular signature of marrow mesenchymal stem cells. PPAR Res 2007:81219. doi:10.1155/2007/81219
Sottile V, Seuwen K, Kneissel M (2004) Enhanced marrow adipogenesis and bone resorption in estrogen-deprived rats treated with the PPARgamma agonist BRL49653 (rosiglitazone). Calcif Tissue Int 75:329–337. doi:10.1007/s00223-004-0224-8
Syed FA, Oursler MJ, Hefferanm TE et al (2008) Effects of estrogen therapy on bone marrow adipocytes in postmenopausal osteoporotic women. Osteoporos Int 19:1323–1330. doi:10.1007/s00198-008-0574-6
Zallone A (2006) Direct and indirect estrogen actions on osteoblasts and osteoclasts. Ann N Y Acad Sci 1068:173–179. doi:10.1196/annals.1346.019
Acknowledgments
This work was supported by grants from the Canadian Institutes of Health Research and the Nepean Medical Research Foundation. Dr. Duque holds a Fellowship from the University of Sydney-Medical Research Foundation. The authors would like to thank Mrs. Leigh Bambury for preparation of the manuscript.
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Elbaz, A., Rivas, D. & Duque, G. Effect of estrogens on bone marrow adipogenesis and Sirt1 in aging C57BL/6J mice. Biogerontology 10, 747–755 (2009). https://doi.org/10.1007/s10522-009-9221-7
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DOI: https://doi.org/10.1007/s10522-009-9221-7