Estrogen deficiency and bone loss: an inflammatory tale.

Estrogen plays a fundamental role in skeletal growth and bone homeostasis in both men and women. Although remarkable progress has been made in our understanding of how estrogen deficiency causes bone loss, the mechanisms involved have proven to be complex and multifaceted. Although estrogen is established to have direct effects on bone cells, recent animal studies have identified additional unexpected regulatory effects of estrogen centered at the level of the adaptive immune response. Furthermore, a potential role for reactive oxygen species has now been identified in both humans and animals. One major challenge is the integration of a multitude of redundant pathways and cytokines, each apparently capable of playing a relevant role, into a comprehensive model of postmenopausal osteoporosis. This Review presents our current understanding of the process of estrogen deficiency-mediated bone destruction and explores some recent findings and hypotheses to explain estrogen action in bone. Due to the inherent difficulties associated with human investigation, many of the lessons learned have been in animal models. Consequently, many of these principles await further validation in humans.

[1]  T. Fry,et al.  IL-7 increases both thymic-dependent and thymic-independent T-cell regeneration after bone marrow transplantation. , 2001, Blood.

[2]  M. Nanes Tumor necrosis factor-alpha: molecular and cellular mechanisms in skeletal pathology. , 2003, Gene.

[3]  G. Gronowicz,et al.  Interleukin‐7 Influences Osteoclast Function In Vivo but Is Not a Critical Factor in Ovariectomy‐Induced Bone Loss , 2006, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[4]  G. Mundy,et al.  Estrogen promotes apoptosis of murine osteoclasts mediated by TGF–β , 1996, Nature Medicine.

[5]  J. Bijlsma,et al.  Interleukin 7 stimulates tumour necrosis factor α and Th1 cytokine production in joints of patients with rheumatoid arthritis , 2003, Annals of the rheumatic diseases.

[6]  R. Pacifici,et al.  The role of T lymphocytes in bone metabolism , 2005, Immunological reviews.

[7]  J. Compston,et al.  Bone Remodeling and Structure in Postmenopausal Women Treated with Long-Term, High-Dose Estrogen Therapy , 1999, Osteoporosis International.

[8]  S. Teitelbaum,et al.  Bone resorption by osteoclasts. , 2000, Science.

[9]  M. Nanes Tumor necrosis factor-α: molecular and cellular mechanisms in skeletal pathology , 2003 .

[10]  R. Koup,et al.  Evidence for thymic function in the elderly. , 2000, Vaccine.

[11]  Wei-Ping Qian,et al.  An IL-7-dependent rebound in thymic T cell output contributes to the bone loss induced by estrogen deficiency. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[12]  P. Jensen,et al.  Transcriptional regulation of the MHC class II antigen presentation pathway. , 2003, Current opinion in immunology.

[13]  M. Almeida,et al.  Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids. , 2003, The Journal of clinical investigation.

[14]  P. Marrack,et al.  Reactive oxygen species regulate activation-induced T cell apoptosis. , 1999, Immunity.

[15]  S. Khosla,et al.  Minireview: the OPG/RANKL/RANK system. , 2001, Endocrinology.

[16]  Sundeep Khosla,et al.  Sex steroids and the construction and conservation of the adult skeleton. , 2002, Endocrine reviews.

[17]  T. Martin,et al.  Activated T lymphocytes support osteoclast formation in vitro. , 1999, Biochemical and biophysical research communications.

[18]  J. Pfeilschifter,et al.  Changes in proinflammatory cytokine activity after menopause. , 2002, Endocrine reviews.

[19]  R. Ceredig,et al.  Prelymphomatous B cell hyperplasia in the bone marrow of interleukin-7 transgenic mice: precursor B cell dynamics, microenvironmental organization and osteolysis. , 1996, Experimental hematology.

[20]  S. Manolagas,et al.  Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. , 2000, Endocrine reviews.

[21]  F. Pei,et al.  Different Doses of Nitric Oxide Donor Prevent Osteoporosis in Ovariectomized Rats , 2005, Clinical orthopaedics and related research.

[22]  Chendong Yang,et al.  Generation and Function of Reactive Oxygen Species in Dendritic Cells During Antigen Presentation 1 , 2003, The Journal of Immunology.

[23]  M. Nagarkatti,et al.  Evidence for estradiol-induced apoptosis and dysregulated T cell maturation in the thymus. , 2001, Toxicology.

[24]  S. Cummings,et al.  Isosorbide Mononitrate Increases Bone Formation and Decreases Bone Resorption in Postmenopausal Women: A Randomized Trial , 2004, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[25]  R. Pacifici,et al.  Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency. , 2002, The Journal of clinical investigation.

[26]  Xiaofei He,et al.  Inhibition of Osteoblast Differentiation by Tumor Necrosis Factor-α. , 2000, Endocrinology.

[27]  Oscar L. Sierra,et al.  Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-γ-induced class II transactivator , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Wei-Ping Qian,et al.  IL-7 induces bone loss in vivo by induction of receptor activator of nuclear factor κB ligand and tumor necrosis factor α from T cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[29]  N. Kamatani,et al.  IFN‐γ‐producing human T cells directly induce osteoclastogenesis from human monocytes via the expression of RANKL , 2005, European journal of immunology.

[30]  Hong-Hee Kim,et al.  Reactive oxygen species mediate RANK signaling in osteoclasts. , 2004, Experimental cell research.

[31]  F. Ross,et al.  Estrogen Decreases Osteoclast Formation by Down-regulating Receptor Activator of NF-κB Ligand (RANKL)-induced JNK Activation* , 2001, The Journal of Biological Chemistry.

[32]  Masaki Noda,et al.  Leptin regulation of bone resorption by the sympathetic nervous system and CART , 2005, Nature.

[33]  W. McBride,et al.  Down-regulation of murine fibrosarcoma transforming growth factor-beta 1 expression by interleukin 7. , 1995, Journal of the National Cancer Institute.

[34]  H. Beck-Nielsen,et al.  Cytokines and T-lymphocyte subsets in healthy post-menopausal women: estrogen retards bone loss without affecting the release of IL-1 or IL-1ra. , 1997, Bone.

[35]  M. Bouxsein,et al.  Ovariectomy‐Induced Bone Loss Varies Among Inbred Strains of Mice , 2005, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[36]  T. Taniguchi,et al.  T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. , 2000, Nature.

[37]  S. Ralston,et al.  Estrogen inhibits release of tumor necrosis factor from peripheral blood mononuclear cells in postmenopausal women , 1990, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[38]  A. Marušić,et al.  Depletion of CD4 and CD8 T Lymphocytes in Mice In Vivo Enhances 1,25-Dihydroxyvitamin D3-Stimulated Osteoclast-Like Cell Formation In Vitro by a Mechanism That Is Dependent on Prostaglandin Synthesis1 , 2000, The Journal of Immunology.

[39]  J. Wit,et al.  The Role of Estrogen in the Control of Rat Osteocyte Apoptosis , 1998, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[40]  D. Roopenian,et al.  CD4+ T Cells and the Proinflammatory Cytokines Gamma Interferon and Interleukin-6 Contribute to Alveolar Bone Loss in Mice , 1999, Infection and Immunity.

[41]  M. Tohkin,et al.  Comparative study of inhibitory effects by murine interferon γ and a new bisphosphonate (alendronate) in hypercalcemic, nude mice bearing human tumor (LJC-1-JCK) , 1994, Cancer Immunology, Immunotherapy.

[42]  R. Pacifici,et al.  Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. , 2000, The Journal of clinical investigation.

[43]  Z. Urry,et al.  Thioredoxin-1 mediates osteoclast stimulation by reactive oxygen species. , 2004, Biochemical and biophysical research communications.

[44]  J. Gustafsson,et al.  Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. , 1998, Molecular pharmacology.

[45]  D. Lacey,et al.  Interleukin-1beta and tumor necrosis factor-alpha, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. , 1999, Bone.

[46]  J. Milbrandt,et al.  Estrogen blocks M-CSF gene expression and osteoclast formation by regulating phosphorylation of Egr-1 and its interaction with Sp-1. , 1998, The Journal of clinical investigation.

[47]  B. Komm,et al.  Estrogen binding, receptor mRNA, and biologic response in osteoblast-like osteosarcoma cells. , 1988, Science.

[48]  A. Martini,et al.  Elevated circulating interleukin-7 levels in patients with systemic juvenile rheumatoid arthritis. , 1995, The Journal of rheumatology.

[49]  H. Fox,et al.  Estrogen regulates the IFN-gamma promoter. , 1991, Journal of immunology.

[50]  K. Michaëlsson,et al.  Association between oxidative stress and bone mineral density. , 2001, Biochemical and biophysical research communications.

[51]  G. Haegeman,et al.  N-acetyl-L-cysteine inhibits primary human T cell responses at the dendritic cell level: association with NF-kappaB inhibition. , 1999, Journal of immunology.

[52]  J. Haug,et al.  T Cell Activation Induces Human Osteoclast Formation via Receptor Activator of Nuclear Factor κB Ligand‐Dependent and ‐Independent Mechanisms , 2001 .

[53]  M. Catani,et al.  Marked decrease in plasma antioxidants in aged osteoporotic women: results of a cross-sectional study. , 2003, The Journal of clinical endocrinology and metabolism.

[54]  C. Murphy,et al.  TNFalpha potently activates osteoclasts, through a direct action independent of and strongly synergistic with RANKL. , 2002, Endocrinology.

[55]  R. Koup,et al.  Generation of functional thymocytes in the human adult. , 1999, Immunity.

[56]  J. Gustafsson,et al.  Cloning of a novel receptor expressed in rat prostate and ovary. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[57]  W. V. Berghe,et al.  N-Acetyl-l-Cysteine Inhibits Primary Human T Cell Responses at the Dendritic Cell Level: Association with NF-κB Inhibition , 1999, The Journal of Immunology.

[58]  Z. Grossman,et al.  Self-tolerance: context dependent tuning of T cell antigen recognition. , 2000, Seminars in immunology.

[59]  F. Lemonnier,et al.  Differential requirements for survival and proliferation of CD8 naïve or memory T cells. , 1997, Science.

[60]  R. Guldberg,et al.  Estrogen prevents bone loss through transforming growth factor beta signaling in T cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[61]  R. Maki,et al.  Quantitative analysis of cytokine gene expression in rheumatoid arthritis. , 1990, Journal of immunology.

[62]  S. Takao,et al.  Reactive oxygen species are essential mediators in antigen presentation by Kupffer cells , 2005, Immunology and cell biology.

[63]  C. Murphy,et al.  TNFα Potently Activates Osteoclasts, through a Direct Action Independent of and Strongly Synergistic with RANKL. , 2002, Endocrinology.

[64]  Ilangovan Ramachandran,et al.  Ovariectomy induces oxidative stress and impairs bone antioxidant system in adult rats. , 2005, Clinica chimica acta; international journal of clinical chemistry.

[65]  S. Nakagawa,et al.  Redox imbalance induced by contact sensitizers triggers the maturation of dendritic cells. , 2005, The Journal of investigative dermatology.

[66]  H. Müller-Hermelink,et al.  The Involution of the Ageing Human Thymic Epithelium is Independent of Puberty , 1985, Scandinavian journal of immunology.

[67]  R. Rodriguiz,et al.  Combination Macrophage-Colony Stimulating Factor and Interferon-γ Administration Ameliorates the Osteopetrotic Condition in Microphthalmic (mi/mi) Mice , 1993, Pediatric Research.

[68]  F. Ross,et al.  Estrogen decreases TNF gene expression by blocking JNK activity and the resulting production of c-Jun and JunD. , 1999, The Journal of clinical investigation.

[69]  M. Sorci-Thomas,et al.  Estrogen modulates the expression of tumor necrosis factor alpha mRNA in phorbol ester-stimulated human monocytic THP-1 cells. , 1994, Lymphokine and cytokine research.

[70]  T. Chambers,et al.  Tumor Necrosis Factor-α Mediates Osteopenia Caused by Depletion of Antioxidants , 2005 .

[71]  Wei-Ping Qian,et al.  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. , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[72]  D. Lacey,et al.  Interleukin-1β and tumor necrosis factor-α, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells , 1999 .

[73]  B. Chain,et al.  Reactive oxygen species activate human peripheral blood dendritic cells. , 1999, Free radical biology & medicine.

[74]  A. Billiau,et al.  Accelerated collagen-induced arthritis in IFN-gamma receptor-deficient mice. , 1997, Journal of immunology.

[75]  N. Andersson,et al.  Liver-derived IGF-I is permissive for ovariectomy-induced trabecular bone loss. , 2006, Bone.

[76]  R. Bataille,et al.  Human myeloma cells stimulate the receptor activator of nuclear factor-kappa B ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease. , 2002, Blood.

[77]  R. Rodriguiz,et al.  Long-term treatment of osteopetrosis with recombinant human interferon gamma. , 1995, The New England journal of medicine.

[78]  Josef M. Penninger,et al.  Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand , 1999, Nature.

[79]  T. Heng,et al.  Activation of Thymic Regeneration in Mice and Humans following Androgen Blockade , 2005, The Journal of Immunology.

[80]  Min Huang,et al.  IL-7 inhibits fibroblast TGF-β production and signaling in pulmonary fibrosis , 2002 .

[81]  Gregory D. Sempowski,et al.  The human thymus during aging , 2000, Immunologic research.

[82]  S. Nozawa,et al.  Estrogen deficiency stimulates B lymphopoiesis in mouse bone marrow. , 1994, The Journal of clinical investigation.

[83]  Bert W O'Malley,et al.  Coregulator function: a key to understanding tissue specificity of selective receptor modulators. , 2004, Endocrine reviews.

[84]  J. Gerdes,et al.  Immunohistologic assessment of cytokine production of infiltrating cells in various forms of leprosy. , 1990, The American journal of pathology.

[85]  K. Ikeda,et al.  Generation of Bone‐Resorbing Osteoclasts from B220+ Cells: Its Role in Accelerated Osteoclastogenesis due to Estrogen Deficiency * , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[86]  C. Yallampalli,et al.  Nitric oxide donor alleviates ovariectomy-induced bone loss. , 1996, Bone.

[87]  R. Kimble,et al.  The Functional Block of TNF but Not of IL‐6 Prevents Bone Loss in Ovariectomized Mice , 1997, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[88]  T. Chambers,et al.  Hydrogen peroxide is essential for estrogen-deficiency bone loss and osteoclast formation. , 2005, Endocrinology.

[89]  B. L. Riggs,et al.  Drugs Used to Treat Osteoporosis: The Critical Need for a Uniform Nomenclature Based on Their Action on Bone Remodeling , 2004, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[90]  N. Takahashi,et al.  Prolonged decrease of serum calcium concentration by murine gamma-interferon in hypercalcemic, human tumor (EC-GI)-bearing nude mice. , 1992, Cancer research.

[91]  E. Benveniste,et al.  17beta-Estradiol inhibits class II major histocompatibility complex (MHC) expression: influence on histone modifications and cbp recruitment to the class II MHC promoter. , 2004, Molecular endocrinology.

[92]  T. Chambers,et al.  Tumor necrosis factor-alpha mediates osteopenia caused by depletion of antioxidants. , 2005, Endocrinology.

[93]  J. Rungby,et al.  Hormone Replacement Therapy Prevents Osteoclastic Hyperactivity: A Histomorphometric Study in Early Postmenopausal Women , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[94]  B. Katzenellenbogen,et al.  Nongenotropic, Sex-Nonspecific Signaling through the Estrogen or Androgen Receptors Dissociation from Transcriptional Activity , 2001, Cell.

[95]  M. Karnovsky,et al.  NADPH-oxidase expression and in situ production of superoxide by osteoclasts actively resorbing bone , 1994, The Journal of cell biology.

[96]  A. Glasebrook,et al.  Identification of an Estrogen Response Element Activated by Metabolites of 17β-Estradiol and Raloxifene , 1996, Science.

[97]  J. Rubin,et al.  Inhibition of osteoblast differentiation by tumor necrosis factor-alpha. , 2000, Endocrinology.

[98]  Hiroshi Takayanagi,et al.  T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ , 2000, Nature.

[99]  P. Roberson,et al.  Loss of estrogen upregulates osteoblastogenesis in the murine bone marrow. Evidence for autonomy from factors released during bone resorption. , 1998, The Journal of clinical investigation.

[100]  S. Takeshita,et al.  TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. , 2000, The Journal of clinical investigation.

[101]  D. Kioussis,et al.  A self-reactive T cell population that is not subject to negative selection. , 1992, International immunology.

[102]  D. McDonnell,et al.  The Estrogen Receptor ␤-isoform (er␤) of the Human Estrogen Receptor Modulates Er␣ Transcriptional Activity and Is a Key Regulator of the Cellular Response to Estrogens and Antiestrogens* , 2022 .

[103]  J. Haug,et al.  T cell activation induces human osteoclast formation via receptor activator of nuclear factor kappaB ligand-dependent and -independent mechanisms. , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[104]  B. Riggs,et al.  Avian osteoclasts as estrogen target cells. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[105]  R. Jilka,et al.  Sex steroids and bone. , 2002, Recent progress in hormone research.

[106]  M. Perales,et al.  Administration of interleukin-7 after allogeneic bone marrow transplantation improves immune reconstitution without aggravating graft-versus-host disease. , 2001, Blood.

[107]  R. Baron,et al.  A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor-deficient mice. , 2003, The Journal of clinical investigation.

[108]  R. Pacifici,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 , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[109]  Z. Urry,et al.  A crucial role for thiol antioxidants in estrogen-deficiency bone loss. , 2003, The Journal of clinical investigation.

[110]  M. Eckhaus,et al.  Exogenous IL-7 increases recent thymic emigrants in peripheral lymphoid tissue without enhanced thymic function. , 2004, Blood.

[111]  Kozo Nakamura,et al.  Connection Between B Lymphocyte and Osteoclast Differentiation Pathways1 , 2001, The Journal of Immunology.

[112]  A. Mukherjee,et al.  Tumor Necrosis Factor-α (TNF) Stimulates RANKL-induced Osteoclastogenesis via Coupling of TNF Type 1 Receptor and RANK Signaling Pathways* , 2001, The Journal of Biological Chemistry.

[113]  E. Schwarz,et al.  Exposure to receptor-activator of NFκB ligand renders pre-osteoclasts resistant to IFN-γ by inducing terminal differentiation , 2002, Arthritis research & therapy.

[114]  B Stein,et al.  Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kappa B and C/EBP beta , 1995, Molecular and cellular biology.

[115]  V. Verhasselt,et al.  Dendritic cells exposed to nacystelyn are refractory to maturation and promote the emergence of alloreactive regulatory T cells , 2003, Transplantation.

[116]  Li Han,et al.  Transient Versus Sustained Phosphorylation and Nuclear Accumulation of ERKs Underlie Anti-Versus Pro-apoptotic Effects of Estrogens* , 2005, Journal of Biological Chemistry.

[117]  R. Rizzoli,et al.  Transgenic mice expressing soluble tumor necrosis factor-receptor are protected against bone loss caused by estrogen deficiency. , 1997, The Journal of clinical investigation.

[118]  K. Hirokawa,et al.  Hypertrophy of the thymus and restoration of immune functions in mice and rats by gonadectomy , 1989, Mechanisms of Ageing and Development.

[119]  K. Ikuta,et al.  Increased B-lymphopoiesis by interleukin 7 induces bone loss in mice with intact ovarian function: similarity to estrogen deficiency. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[120]  Y. Kadono,et al.  Osteoclast differentiation independent of the TRANCE–RANK–TRAF6 axis , 2005, The Journal of experimental medicine.

[121]  R. Eastell,et al.  Cancellous bone remodeling in type i (postmenopausal) osteoporosis: Quantitative assessment of rates of formation, resorption, and bone loss at tissue and cellular levels , 1990, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[122]  Shi Wei,et al.  IL-1 mediates TNF-induced osteoclastogenesis. , 2005, The Journal of clinical investigation.

[123]  Michael Reth,et al.  Hydrogen peroxide as second messenger in lymphocyte activation , 2002, Nature Immunology.

[124]  C. Mackall,et al.  Age-dependent incidence, time course, and consequences of thymic renewal in adults , 2005 .

[125]  M. Anbar,et al.  Effects of Natural Menopause, Hysterectomy, and Oophorectomy on Lumbar Spine and Femoral Neck Bone Densities , 1988, Obstetrics and gynecology.

[126]  R. Pacifici,et al.  Interleukin-7 stimulates osteoclast formation by up-regulating the T-cell production of soluble osteoclastogenic cytokines. , 2000, Blood.

[127]  B. Leibovich,et al.  Augmentation of T Cell Levels and Responses Induced by Androgen Deprivation1 , 2004, The Journal of Immunology.

[128]  H. Rammensee,et al.  Peptides naturally presented by MHC class I molecules. , 1993, Annual review of immunology.

[129]  E. Puscheck,et al.  Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells. , 1991, Proceedings of the National Academy of Sciences of the United States of America.