Perspective
You have free access to this content
Role of T cells in ovariectomy induced bone loss—revisited
Article first published online: 23 JAN 2012
DOI: 10.1002/jbmr.1500
Copyright © 2012 American Society for Bone and Mineral Research
Additional Information
How to Cite
Pacifici, R. (2012), Role of T cells in ovariectomy induced bone loss—revisited. J Bone Miner Res, 27: 231–239. doi: 10.1002/jbmr.1500
Publication History
- Issue published online: 23 JAN 2012
- Article first published online: 23 JAN 2012
- Manuscript Accepted: 7 DEC 2011
- Manuscript Revised: 28 NOV 2011
- Manuscript Received: 13 OCT 2011
References
- 1, , , , , , . Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J Clin Invest. 2000; 106(10): 1229–37.
- 2, , . Sex steroids and bone. Recent Prog Horm Res. 2002; 57: 385–409.
- 3, . Estrogen deficiency and bone loss: an inflammatory tale. J Clin Invest. 2006; 116(5): 1186–94.
- 4, , , , , , . Attenuation of the self-renewal of transit-amplifying osteoblast progenitors in the murine bone marrow by 17 beta-estradiol. J Clin Invest. 2001; 107(7): 803–12.
- 5, , , , , , , , , , , , , , , , , , . Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell. 2007; 130(5): 811–23.
- 6, , , , , , . Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival. EMBO J. 2008; 27(3): 535–45.
- 7, , , , , , , , . The estrogen receptor-alpha in osteoclasts mediates the protective effects of estrogens on cancellous but not cortical bone. Mol Endocrinol. 2010; 24(2): 323–34.
- 8, , , , , , , . Transient versus sustained phosphorylation and nuclear accumulation of ERKs underlie anti-versus pro-apoptotic effects of estrogens. J Biol Chem. 2005; 280(6): 4632–8.
- 9. Skeletal remodeling in health and disease. Nat Med. 2007; 13(7): 791–801.
- 10. From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. Endocr Rev. 2010; 31(3): 266–300.
- 11, , , , , . Loss of estrogen upregulates osteoblastogenesis in the murine bone marrow. Evidence for autonomy from factors released during bone resorption. J Clin Invest. 1998; 101(9): 1942–50.
- 12, , , , , , , , , , , , , . Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell. 2001; 104(5): 719–30.
- 13, , , , , , . Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids. J Clin Invest. 2003; 111(11): 1651–64.
- 14, , , , . Estrogen deficiency increases the ability of stromal cells to support murine osteoclastogenesis via an interleukin-1and tumor necrosis factor- mediated stimulation of macrophage colony-stimulating factor production. J Biol Chem. 1996; 271(46): 28890–7.
- 15, , , , , , . 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(24): 13960–5.
- 16, , , , , , , , . Estrogen prevents bone loss through transforming growth factor beta signaling in T cells. Proc Natl Acad Sci U S A. 2004; 101(47): 16618–23.
- 17, , , , , , , . IFN-gamma stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation. J Clin Invest. 2007; 117(1): 122–32.
- 18, , , , , , , , . Ovariectomy disregulates osteoblast and osteoclast formation through the T-cell receptor CD40 ligand. Proc Natl Acad Sci U S A. 2011; 108(2): 768–73.
- 19, , , , , , , , , . Oxidative stress causes bone loss in estrogen-deficient mice through enhanced bone marrow dendritic cell activation. Proc Natl Acad Sci U S A. 2007; 104(38): 15087–92.
- 20, , . Abatacept. Nat Rev Drug Discov. 2006; 5(3): 185–6.
- 21, . The evolving clinical profile of abatacept (CTLA4-Ig): a novel co-stimulatory modulator for the treatment of rheumatoid arthritis. Arthritis Res Ther. 2005; 7(Suppl 2): S21–5.
- 22, , , , , , , , , , , , , . Pharmacologic stem cell based intervention as a new approach to osteoporosis treatment in rodents. PLoS One. 2008; 3(7): e2615.
- 23, , , , , , , , , . T lymphocyte-deficient mice lose trabecular bone mass with ovariectomy. J Bone Miner Res. 2006; 21(11): 1704–2.Direct Link:
- 24, , , . Lymphocytes and the Dap12 adaptor are key regulators of osteoclast activation associated with gonadal failure. PLoS One. 2007; 2(7): e585.
- 25, , . IL-7 drives T cell-mediated bone loss following ovariectomy. Ann N Y Acad Sci. 2006; 1068: 348–51.Direct Link:
- 26, , , , , , . IL-17 mediates estrogen-deficient osteoporosis. J Bone Miner Res. 2011; 27(Abstract FR0299).
- 27, , , , , , . Cutting edge: estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment. J Immunol. 2004; 173(4): 2227–30.
- 28, , , , , , , , , , , . Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006; 203(12): 2673–82.
- 29, , , , , , , , . Estrogen receptor alpha signaling in T lymphocytes is required for estradiol-mediated inhibition of Th1 and Th17 cell differentiation and protection against experimental autoimmune encephalomyelitis. J Immunol. 2011; 187(5): 2386–93.
- 30, , , . A bone-protective role for IL-17 receptor signaling in ovariectomy-induced bone loss. Eur J Immunol. 2009; 39(10): 2831–9.Direct Link:
- 31, , , , , . Human CD4+CD25+ regulatory T cells inhibit the differentiation of osteoclasts from peripheral blood mononuclear cells. Biochem Biophys Res Commun. 357(4): 1046–52.
- 32, , , , , , , . 2010 Regulatory T cells as a potent target for controlling bone loss. Biochem Biophys Res Commun. 2007; 402(2): 173–6.
- 33, , , . Estrogen enhances the functions of CD4(+)CD25(+)Foxp3(+) regulatory T cells that suppress osteoclast differentiation and bone resorption in vitro. Cell Mol Immunol. 2011; 8(1): 50–8.
- 34, , , , , , , , , , , , . Induction of regulatory T cells by physiological level estrogen. J Cell Physiol. 2008; 214(2): 456–64.Direct Link:
- 35, , , , , , , , . Increased bone density and resistance to ovariectomy-induced bone loss in FoxP3-transgenic mice based on impaired osteoclast differentiation. Arthritis Rheum. 2010; 62(8): 2328–38.Direct Link:
- 36, . Homeostasis of naive and memory T cells. Immunity. 2008; 29(6): 848–62.
- 37, , , , . The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery. Immunity. 1999; 11(2): 173–81.
- 38, , , , . Human nutrition, the gut microbiome and the immune system. Nature. 2011; 474(7351): 327–36.
- 39, , , , . Absence of gut microbiota leads to increased bone mass associated with low serum serotonin levels. J Bone Miner Res. 2010; 25: Abstract 1170.
- 40, , , , , . Daidzein prevents the increase in CD4CD28null T cells and B lymphopoesis in ovariectomized mice: a key mechanism for anti-osteoclastogenic effect. PLoS One. 2011; 6(6): e21216.
- 41, , , , , , , , . Premature T cell senescence in Ovx mice is inhibited by repletion of estrogen and medicarpin: a possible mechanism for alleviating bone loss. Osteoporos Int. Epub 2011 May 12.
- 42, , , , , , , , , . Estrogen deficiency increases osteoclastogenesis up-regulating T cells activity: a key mechanism in osteoporosis. Bone. 2008; 43(1): 92–100.
- 43, , , , , . Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest. 2003; 111(8): 1221–30.
- 44, , , , , , . Transgenic mice expressing soluble tumor necrosis factor-receptor are protected against bone loss caused by estrogen deficiency. J Clin Invest. 1997; 99: 1699–703.
- 45, , . The functional block of TNF but not of IL-6 prevents bone loss in ovariectomized mice. J Bone Miner Res. 1997; 12: 935–41.Direct Link:
- 46, , , , , , , . 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(18): 10405–10.
- 47, . Ovariectomy increases the formation of T cell niches at the resorption surfaces. J Bone Miner Res. 2005; 20(Suppl 1):Abs.
- 48, , , . The human thymus during aging. Immunol Res. 2000; 22(2–3): 253–61.
- 49, . Evidence for thymic function in the elderly. Vaccine. 2000; 18(16): 1638–41.
- 50, , , , , , , , . Generation of functional thymocytes in the human adult. Immunity. 1999; 10(5): 569–75.
- 51, , . The involution of the ageing human thymic epithelium is independent of puberty. A morphometric study. Scand J Immunol. 1985; 22(5): 563–75.Direct Link:
- 52, , , , , , , , , , . Age-dependent incidence, time course, and consequences of thymic renewal in adults. J Clin Invest. 2005; 115(4): 930–9.
- 53, , , , , . IL-7 increases both thymic-dependent and thymic-independent T-cell regeneration after bone marrow transplantation. Blood. 2001; 97(5): 1491–7.
- 54, . Age-associated remodeling of thymopoiesis: role for gonadal hormones and catecholamines. Neuroimmunomodulation. 2008; 15(4–6): 290–322.
- 55, , , , , , . Neonatal testosterone imprinting affects thymus development and leads to phenotypic rejuvenation and masculinization of the peripheral blood T-cell compartment in adult female rats. Brain Behav Immun. 2009; 23(2): 294–304.
- 56, . Hypertrophy of the thymus and restoration of immune functions in mice and rats by gonadectomy. Mech Ageing Dev. 1989; 47(3): 175–85.
- 57, , , , , . Evidence for estradiol-induced apoptosis and dysregulated T cell maturation in the thymus. Toxicology. 2001; 163(1): 49–62.
- 58, , , , , , , , , , , . Augmentation of T cell levels and responses induced by androgen deprivation. J Immunol. 2004; 173(10): 6098–108.
- 59, , , , , , , , , , . Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol. 2005; 175(4): 2741–53.
- 60, , , , , , . Role of ovarian hormones in age-associated thymic involution revisited. Immunobiology. 215(4): 275–93.
- 61, , , , , , , , , . 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(46): 16735–40.
- 62, , , . Effects of natural menopause, hysterectomy, and oophorectomy on lumbar spine and femoral neck bone densities. Obstet Gynecol. 1988; 72(4): 631–8.
- 63, , Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev. 2002; 23(3): 279–302.
- 64, , , , , , , . A crucial role for thiol antioxidants in estrogen-deficiency bone loss. J Clin Invest. 2003; 112(6): 915–23.
- 65, , , , , , , . Ovariectomy induces oxidative stress and impairs bone antioxidant system in adult rats. Clin Chim Acta. 2005; 360(1–2): 81–6.
- 66, , , , . Association between oxidative stress and bone mineral density. Biochem Biophys Res Commun. 2001; 288(1): 275–9.
- 67, , , , , , , , . Marked decrease in plasma antioxidants in aged osteoporotic women: results of a cross-sectional study. J Clin Endocrinol Metab. 2003; 88(4): 1523–7.
- 68. Oxidant signals and oxidative stress. Curr Opin Cell Biol. 2003; 15(2): 247–54.
- 69
- 70, , , , , , , , , , , , . Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J Biol Chem. 2007; 282(37): 27285–97.
- 71, , , , , , , , , , . Estrogens attenuate oxidative stress and the differentiation and apoptosis of osteoblasts by DNA-binding-independent actions of the ERalpha. J Bone Miner Res. 2010; 25(4): 769–81.
- 72, , , . Redox imbalance induced by contact sensitizers triggers the maturation of dendritic cells. J Invest Dermatol. 2005; 124(3): 579–86.
- 73, , , . Reactive oxygen species activate human peripheral blood dendritic cells. Free Radic Biol Med. 1999; 26(1–2): 232–8.
- 74, , , , , , , , . Reactive oxygen species are essential mediators in antigen presentation by Kupffer cells. Immunol Cell Biol. 2005; 83(4): 336–43.
- 75, , , , , . Dendritic cells exposed to nacystelyn are refractory to maturation and promote the emergence of alloreactive regulatory t cells. Transplantation. 2003; 75(3): 383–9.
- 76, , , , , . N-acetyl-L-cysteine inhibits primary human T cell responses at the dendritic cell level: association with NF-kappaB inhibition. J Immunol. 1999; 162(5): 2569–74.
- 77, , , . Tumor necrosis factor-alpha mediates osteopenia caused by depletion of antioxidants. Endocrinology. 2005; 146(1): 113–8.
- 78, , , . Identification of an estrogen response element activated by metabolites of 17b-estradiol and raloxifene. Science. 1996; 273: 1222–5.
- 79, . Transcriptional regulation of the MHC class II antigen presentation pathway. Curr Opin Immunol. 2003; 15(1): 105–11.
- 80, , , , , , , , , , , . T-cell-mediated regulation of osteoclastogenesis by signalling cross- talk between RANKL and IFN-gamma. Nature. 2000; 408(6812): 600–5.
- 81, , , , , . Accelerated collagen-induced arthritis in IFN-gamma receptor-deficient mice. J Immunol. 1997; 158(11): 5507–13.
- 82, , , , , , , , . Prolonged decrease of serum calcium concentration by murine gamma-interferon in hypercalcemic, human tumor (EC-GI)-bearing nude mice. Cancer Res. 1992; 52(2): 444–9.
- 83, , , . Comparative study of inhibitory effects by murine interferon gamma and a new bisphosphonate (alendronate) in hypercalcemic, nude mice bearing human tumor (LJC-1-JCK). Cancer Immunol Immunother. 1994; 39(3): 155–60.
- 84, , , , , , , . IFN-gamma directly inhibits TNF-alpha-induced osteoclastogenesis in vitro and in vivo and induces apoptosis mediated by Fas/Fas ligand interactions. Immunol Lett. 2011; 137(1–2): 53–61.
- 85, , , , , , . Inhibition of RANK expression and osteoclastogenesis by TLRs and IFN-gamma in human osteoclast precursors. J Immunol. 2009; 183(11): 7223–33.
- 86, , , , , , , , . Long-term treatment of osteopetrosis with recombinant human interferon gamma. N Engl J Med. 1995; 332(24): 1594–9.
- 87, , . Combination macrophage-colony stimulating factor and interferon-gamma administration ameliorates the osteopetrotic condition in microphthalmic (mi/mi) mice. Pediatr Res. 1993; 33(4 Pt 1): 384–9.
- 88, , , , , . CD4(+) T cells and the proinflammatory cytokines gamma interferon and interleukin-6 contribute to alveolar bone loss in mice. Infect Immun. 1999; 67(6): 2804–9.
- 89, , . Immunohistologic assessment of cytokine production of infiltrating cells in various forms of leprosy. Am J Pathol. 1990; 137(4): 749–53.
- 90, , , , , , , , , , et al. Double-blind trial of recombinant gamma-interferon versus placebo in the treatment of rheumatoid arthritis. Arthritis Rheum. 1989; 32(8): 964–73.Direct Link:
- 91, , , , , , , , . Interferon-gamma causes loss of bone volume in vivo and fails to ameliorate cyclosporin A-induced osteopenia. Endocrinology. 1994; 135: 1077–83.
- 92, , , , , , , , , , , , , , . Interferon-gamma plays a role in bone formation in vivo and rescues osteoporosis in ovariectomized mice. J Bone Miner Res. 2011; 26(7): 1472–83.Direct Link:
- 93
- 94, , , , , , . Autocrine regulation of interferon gamma in mesenchymal stem cells plays a role in early osteoblastogenesis. Stem Cells. 2009; 27(3): 550–8.Direct Link:
- 95, , , , , , . 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; 19: 9360–5.
- 96, , , , . Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency. J Clin Invest. 2002; 110(11): 1643–50.
- 97, , , , , , , , , , , , . IL-7 inhibits fibroblast TGF-beta production and signaling in pulmonary fibrosis. J Clin Invest. 2002; 109(7): 931–7.
- 98, , , , , , , , . Down-regulation of murine fibrosarcoma transforming growth factor-beta 1 expression by interleukin 7. J Natl Cancer Inst. 1995; 87(8): 593–7.
- 99, . CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol. 1998; 16: 111–35.
- 100, , , . CD40/CD154 interactions at the interface of tolerance and immunity. Annu Rev Immunol. 2004; 22: 307–28.
- 101, , , , , , , . CD40L stabilizes arterial thrombi by a beta3 integrin–dependent mechanism. Nat Med. 2002; 8(3): 247–52.
- 102, , , , , , , , , , . CD40 ligand binds to alpha5beta1 integrin and triggers cell signaling. J Biol Chem. 2007; 282(8): 5143–51.
- 103, , , , , . CD40 ligand blocks apoptosis induced by tumor necrosis factor alpha, glucocorticoids, and etoposide in osteoblasts and the osteocyte-like cell line murine long bone osteocyte-Y4. Endocrinology. 2003; 144(5): 1761–9.
- 104, , , , , , . B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo. Blood. 2007; 109(9): 3839–48.
- 105, , , , , , , , . Osteopenia in X-linked hyper-IgM syndrome reveals a regulatory role for CD40 ligand in osteoclastogenesis. Proc Natl Acad Sci U S A. 2007; 104(12): 5056–61.
- 106, , , , , , , , . T cells potentiate PTH-induced cortical bone loss through CD40L signaling. Cell Metab. 2008; 8(2): 132–45.
- 107, , , , , , , , . Dlk1/FA1 is a novel endocrine regulator of bone and fat mass and its serum level is modulated by growth hormone. Endocrinology. 2007; 148(7): 3111–21.
- 108, , , , , , , , . dlk1/FA1 regulates the function of human bone marrow mesenchymal stem cells by modulating gene expression of pro-inflammatory cytokines and immune response-related factors. J Biol Chem. 2007; 282(10): 7339–51.
- 109, , , , , , , , , . DLK1 is a novel regulator of bone mass that mediates estrogen deficiency-induced bone loss in mice. J Bone Miner Res. 2011; 26(7): 1457–71.Direct Link:
- 110, , , , , , , , , , , , . The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell. 2000; 103(1): 41–50.
- 111, , , . Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform. Proc Natl Acad Sci U S A. 2003; 100(17): 9744–9.
- 112, , . RANKL and RANK in sex hormone-induced breast cancer and breast cancer metastasis. Trends Endocrinol Metab. 2011; 22(5): 188–94.
- 113, , . Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol. 2004; 5(3): 266–71.
- 114, , , , , , , , . Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), TRAIL receptors, and the soluble receptor osteoprotegerin in human gestational membranes and amniotic fluid during pregnancy and labor at term and preterm. J Clin Endocrinol Metab. 2003; 88(8): 3835–44.

1523-4681/asset/olbannerleft.gif?v=1&s=d7e4c0e37904a489128d3a4e58ba94214db307a9)
1523-4681/asset/olbannerright.gif?v=1&s=854ee0e4d351ead9faaca8bfab3e50b1c7c9d03d)
