Patogénesis de la osteoporosis: papel de los estrógenos

  • Oswaldo Rincón-Sierra
  • Ivonne Díaz-Yamal
  • Luis Ernesto Pérez-Agudelo

Resumen

Introducción: la osteoporosis es una enfermedad en la que la pérdida de fortaleza ósea conduce a fracturas por fragilidad. Las fracturas de cadera tienen alta morbilidad y mortalidad, igualmente existen resultados similares para las fracturas vertebrales.  La prevalencia creciente y los tremendos costos de este desorden resaltan la importancia de desarrollar nuevos tratamientos, por ello identificar los mecanismos moleculares que controlan la masa ósea es de suma importancia.

La resorción ósea por los osteoclastos se acopla con la formación por los osteoblastos, proceso equilibrado que remodela y adapta el esqueleto. La fragilidad ósea es consecuencia de una adaptación fallida. Durante la menopausia, la remodelación del hueso pierde su equilibrio y se produce pérdida ósea.

La deficiencia de estrógenos conduce a un aumento global en producción de IL-7, en parte a través de disminución en TGF-ß y aumento de IGF-1, lo que lleva a activación de células T. Las células T activadas liberan IFN-g, el cual incrementa la presentación antigénica.

La deficiencia de estrógenos también amplifica la activación de células T y la osteoclastogénesis, regulando a la baja las vías antioxidantes. El aumento resultante en los oxidantes estimula la presentación antigénica y la producción de TNF por los osteoclastos maduros. El efecto combinado de IFN-g y oxidantes promueve la liberación de los factores osteoclastogénicos RANKL y TNF.

El TNF estimula la producción de RANKL y MCSF por células pluripotenciales y osteoblastos, incrementando la producción de estos últimos. TNF e IL-7 alteran la formación ósea a través de efectos represivos directos en los osteoblastos.

Descargas

La descarga de datos todavía no está disponible.

Biografía del autor/a

Oswaldo Rincón-Sierra
Especialista en Endocrinología. Departamento de Medicina Interna, Hospital Militar Central.
Ivonne Díaz-Yamal
Especialista en Ginecología y Obstetricia. Jefe de la Unidad de Infertilidad y Endocrinología Reproductiva, Hospital Militar Central. Directora Científica Unidad de Fertilidad Clínica Marly (Bogotá). 
Luis Ernesto Pérez-Agudelo
Especialista en Ginecología y Obstetricia. Profesor asistente Universidad Militar Nueva Granada.

Referencias bibliográficas

Kanis JA. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: synopsis of a WHO report. WHO Study Group. Osteoporos Int 1994;4:368-81.

NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001;285:785-95.

Hodgson SF, Watts NB, Bilezikian JP, Clarke BL, Gray TK, Harris DW, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003. Endocr Pract 2003;9:544-64.

North American Menopause Society. Management of osteoporosis in postmenopausal women: 2006 position statement of The North American Menopause Society. Menopause 2006;13:340-67.

Looker AC, Wahner HW, Dunn WL, Calvo MS, Harris TB, Heyse SP, et al. Updated data on proximal femur bone mineral levels of US adults. Osteoporos Int 1998;8:468-89.

Looker AC, Orwoll ES, Johnston CC, Lindsay RL, Wahner HW, Dunn WL, et al. Prevalence of low femoral bone density in older U.S. adults from NHANES III. J Bone Miner Res 1997;12:1761-8.

Melton LJ, Thamer M, Ray NF, Chan JK, Chesnut CH, Einhorn TA, et al. Fractures attributable to osteoporosis: report from the National Osteoporosis Foundation. J Bone Miner Res 1997;12:16-23.

Johnell O, Kanis J. Epidemiology of osteoporotic fractures. Osteoporos Int 2005;16 Suppl 2:S3-7.

Cauley JA, Thompson DE, Ensrud KC, Scott JC, Black D. Risk of mortality following clinical fractures. Osteoporos Int 2000;11:556-61.

Russell GR, Espina B, Hulley P. Bone biology and the pathogenesis of osteoporosis. Curr Opin Rheumatol 2006;18 Suppl 1:S3-10.

Raisz LG. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest 2005;115:3318-25.

Riggs BL, Khosla S, Melton LJ. Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 2002;23:279-302.

Davies JH, Evans BA, Gregor y JW. Bone mass acquisition in healthy children. Arch Dis Child 2005;90:373-8.

Kronenberg HM. Developmental regulation of the growth plate. Nature 2003;423:332-6.

Komm BS, Terpening CM, Benz DJ, Graeme KA, Gallegos A, Korc M, et al. Estrogen binding, receptor mRNA, and biologic response in osteoblast-like osteosarcoma cells. Science 1988;241:81-4.

Tomkinson A, Gevers EF, Wit JM, Reeve J, Noble BS. The role of estrogen in the control of rat osteocyte apoptosis. J Bone Miner Res 1998;13:1243-50.

Hall JM, McDonnell DP. The estrogen receptor betaisoform (ERbeta) of the human estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology 1999;140:5566-78.

Deroo BJ, Korach KS. Estrogen receptors and human disease. J Clin Invest 2006;116:561-70.

Srivastava S, Weitzmann MN, Kimble RB, Rizzo M, Zahner M, Milbrandt J, et al. Estrogen blocks M-CSF gene expression and osteoclast formation by regulating phosphorylation of Egr-1 and its interaction with Sp-1. J Clin Invest 1998;102:1850-9.

Srivastava S, Weitzmann MN, Cenci S, Ross FP, Adler S, Pacifici R. Estrogen decreases TNF gene expression by blocking JNK activity and the resulting production of c-Jun and JunD. J Clin Invest 1999;104:503-13.

Kousteni S, Han L, Chen JR, Almeida M, Plotkin LI, Bellido T, et al. Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids. J Clin Invest 2003;111:1651-64.

Weitzmann MN, Pacifici R. The role of T lymphocytes in bone metabolism. Immunol Rev 2005;208:154-68.

Kousteni S, Bellido T, Plotkin LI, O’Brien CA, Bodenner DL, Han L, et al. Nongenotropic, sexnonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 2001;104:719-30.

Weitzmann MN, Roggia C, Toraldo G, Weitzmann L, Pacifici R. Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency. J Clin Invest 2002;110:1643-50.

Eriksen EF, Langdahl B, Vesterby A, Rungby J, Kassem M. Hormone replacement therapy prevents osteoclastic hyperactivity: a histomorphometric study in early postmenopausal women. J Bone Miner Res 1999;14:1217-21.

Manolagas SC. Birth and death of bone cells: basic regulator y mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 2000;21:115-37.

Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology 2001;142:5050-5.

Hofbauer LC, Lacey DL, Dunstan CR, Spelsberg TC, Riggs BL, Khosla S. Interleukin-1beta and tumor necrosis factor-alpha, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. Bone 1999;25:255-9.

Cenci S, Weitzmann MN, Roggia C, Namba N, Novack D, Woodring J, et al. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J Clin Invest 2000;106:1229-37.

Zhang YH, Heulsmann A, Tondravi MM, Mukherjee A, Abu-Amer Y. Tumor necrosis factor-alpha (TNF) stimulates RANKL-induced osteoclastogenesis via coupling of TNF type 1 receptor and RANK signaling pathways. J Biol Chem 2001;276:563-8.

Nanes MS. Tumor necrosis factor-alpha: molecular and cellular mechanisms in skeletal pathology. Gene 2003;321:1-15.

Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL. TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest 2000;106:1481-8.

Weitzmann MN, Pacifici R. Estrogen deficiency and bone loss: an inflammatory tale. J Clin Invest 2006;116:1186-94.

Ammann P, Rizzoli R, Bonjour JP, Bourrin S, Meyer JM, Vassalli P, et al. Transgenic mice expressing soluble tumor necrosis factor-receptor are protected against bone loss caused by estrogen deficiency. J Clin Invest 1997;99:1699-703.

Ralston SH, Russell RG, Gowen M. Estrogen inhibits release of tumor necrosis factor from peripheral blood mononuclear cells in postmenopausal women. J Bone Miner Res 1990;5:983-8.

Abrahamsen B, Bendtzen K, Beck-Nielsen H. Cytokines and T-lymphocyte subsets in healthy post-menopausal women: estrogen retards bone loss without affecting the release of IL-1 or IL-1ra. Bone 1997;20:251-8.

Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature 2000;408:600-5.

Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999;402:304-9.

Cenci S, Toraldo G, Weitzmann MN, Roggia C, Gao Y, Qian WP, et al. Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-gamma-induced class II transactivator. Proc Natl Acad Sci U S A 2003;100:10405-10.

Roggia C, Gao Y, Cenci S, Weitzmann MN, Toraldo G, Isaia G, et al. Up-regulation of TNF-producing T cells in the bone marrow: a key mechanism by which estrogen deficiency induces bone loss in vivo. Proc Natl Acad Sci U S A 2001;98:13960-5.

Kotake S, Nanke Y, Mogi M, Kawamoto M, Furuya T, Yago T, et al. IFN-gamma-producing human T cells directly induce osteoclastogenesis from human monocytes via the expression of RANKL. Eur J Immunol 2005;35:3353-63.

Yang NN, Venugopalan M, Hardikar S, Glasebrook A. Identification of an estrogen response element activated by metabolites of 17beta-estradiol and raloxifene. Science 1996;273:1222-5.

Gao Y, Qian WP, Dark K, Toraldo G, Lin AS, Guldberg RE, et al. Estrogen prevents bone loss through transforming growth factor beta signaling in T cells. Proc Natl Acad Sci U S A 2004;101:16618-23.

Miyaura C, Onoe Y, Inada M, Maki K, Ikuta K, Ito M, et al. Increased B-lymphopoiesis by interleukin 7 induces bone loss in mice with intact ovarian function: similarity to estrogen deficiency. Proc Natl Acad Sci U S A 1997;94:9360-5.

Valenzona HO, Pointer R, Ceredig R, Osmond DG. Prelymphomatous B cell hyperplasia in the bone marrow of interleukin-7 transgenic mice: precursor B cell dynamics, microenvironmental organization and osteolysis. Exp Hematol 1996;24:1521-9.

Toraldo G, Roggia C, Qian WP, Pacifici R, Weitzmann MN. IL-7 induces bone loss in vivo by induction of receptor activator of nuclear factor kappa B ligand and tumor necrosis factor alpha from T cells. Proc Natl Acad Sci U S A 2003;100:125-30.

Lee SK, Kalinowski JF, Jacquin C, Adams DJ, Gronowicz G, Lorenzo JA. Interleukin-7 influences osteoclast function in vivo but is not a critical factor in ovariectomy-induced bone loss. J Bone Miner Res 2006;21:695-702.

Huang M, Sharma S, Zhu LX, Keane MP, Luo J, Zhang L, et al. IL-7 inhibits fibroblast TGF-beta production and signaling in pulmonary fibrosis. J Clin Invest 2002;109:931-7.

Dubinett SM, Huang M, Dhanani S, Economou JS, Wang J, Lee P, et al. Down-regulation of murine fibrosarcoma transforming growth factor-beta 1 expression by interleukin 7. J Natl Cancer Inst 1995;87:593-7.

Sato T, Shibata T, Ikeda K, Watanabe K. Generation of bone-resorbing osteoclasts from B220+ cells: its role in accelerated osteoclastogenesis due to estrogen deficiency. J Bone Miner Res 2001;16:2215-21.

Okasha SA, Ryu S, Do Y, McKallip RJ, Nagarkatti M, Nagarkatti PS. Evidence for estradiol-induced apoptosis and dysregulated T cell maturation in the thymus. Toxicology 2001;163:49-62.

Utsuyama M, Hirokawa K. Hypertrophy of the thymus and restoration of immune functions in mice and rats by gonadectomy. Mech Ageing Dev 1989;47:175-85.

Ryan MR, Shepherd R, Leavey JK, Gao Y, Grassi F, Schnell FJ, et al. An IL-7-dependent rebound in thymic T cell output contributes to the bone loss induced by estrogen deficiency. Proc Natl Acad Sci U S A 2005;102:16735-40.

Muthusami S, Ramachandran I, Muthusamy B, Vasudevan G, Prabhu V, Subramaniam V, et al. Ovariectomy induces oxidative stress and impairs bone antioxidant system in adult rats. Clin Chim Acta 2005;360:81-6.

Lean JM, Davies JT, Fuller K, Jagger CJ, Kirstein B, Partington GA, et al. A crucial role for thiolantioxidants in estrogen-deficiency bone loss. J Clin Invest 2003;112:915-23.

Reth M. Hydrogen peroxide as second messenger in lymphocyte activation. Nat Immunol 2002;3:1129-34.

Lean J, Kirstein B, Urry Z, Chambers T, Fuller K. Thioredoxin-1 mediates osteoclast stimulation by reactive oxygen species. Biochem Biophys Res Commun 2004;321:845-50.

Lean JM, Jagger CJ, Kirstein B, Fuller K, Chambers TJ. Hydrogen peroxide is essential for estrogen-deficiency bone loss and osteoclast formation. Endocrinology 2005;146:728-35.

Wimalawansa SJ, De Marco G, Gangula P, Yallampalli C. Nitric oxide donor alleviates ovariectomy-induced bone loss. Bone 1996;18:301-4.

Hao YJ, Tang Y, Chen FB, Pei FX. Different doses of nitric oxide donor prevent osteoporosis in ovariectomized rats. Clin Orthop Relat Res 2005;226-31.

Jamal SA, Cummings SR, Hawker GA. Isosorbide mononitrate increases bone formation and decreases bone resorption in postmenopausal women: a randomized trial. J Bone Miner Res 2004;19:1512-7.

Jagger CJ, Lean JM, Davies JT, Chambers TJ. Tumor necrosis factor-alpha mediates osteopenia caused by depletion of antioxidants. Endocrinology 2005;146:113-8.

Publicado
2007-06-30
Cómo citar
1.
Rincón-Sierra O, Díaz-Yamal I, Pérez-Agudelo LE. Patogénesis de la osteoporosis: papel de los estrógenos. Rev. Colomb. Obstet. Ginecol. [Internet]. 30 de junio de 2007 [citado 17 de enero de 2022];58(2):142-50. Disponible en: https://revista.fecolsog.org/index.php/rcog/article/view/477
Sección
Artículo de Revisión
Crossref Cited-by logo

Artículos más leídos del mismo autor/a