Physiological and pathophysiological bone turnover-role of the immune system

Nature Reviews Endocrinology

Volumn 12, Issue 9, 2016, Pages 518-532

  Weitzmann, M Neale ^a,b   Ofotokun, Ighovwerha ^b,c  

^a ATLANTA VA MEDICAL CENTER   (United States)

^b EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c Grady Healthcare System   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ABATACEPT; ANTIRETROVIRUS AGENT; OSTEOCLAST DIFFERENTIATION FACTOR; OSTEOPROTEGERIN; PARATHYROID HORMONE;

ADAPTIVE IMMUNITY; B LYMPHOCYTE; BONE DESTRUCTION; BONE TURNOVER; ESTROGEN DEFICIENCY; FRACTURE; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; HYPERPARATHYROIDISM; IMMUNE SYSTEM; NONHUMAN; OSSIFICATION; OSTEOCLASTOGENESIS; OSTEOLYSIS; OSTEOPOROSIS; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; RHEUMATOID ARTHRITIS; T LYMPHOCYTE; ANIMAL; BONE DENSITY; BONE REMODELING; IMMUNOLOGY; METABOLIC BONE DISEASE; METABOLISM; PHYSIOLOGY;

ANIMALS; BONE DENSITY; BONE DISEASES, METABOLIC; BONE REMODELING; BONE RESORPTION; FRACTURES, BONE; HUMANS; IMMUNE SYSTEM; OSTEOPOROSIS;

EID: 84975748660     PISSN: 17595029     EISSN: 17595037     Source Type: Journal    
DOI: 10.1038/nrendo.2016.91     Document Type: Review

References (182)

1. Eisman, J. A. et al. Making the first fracture the last fracture: ASBMR task force report on secondary fracture prevention. J. Bone Miner. Res. 27, 2039-2046 (2012).
2. World Health Organization. Prevention and management of osteoporosis (WHO, 2003).
3. Kates, S. L., Kates, O. S. & Mendelson, D. A. Advances in the medical management of osteoporosis. Injury 38, S17-S23 (2007).
4. Johnell, O. & Kanis, J. A. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos. Int. 17, 1726-1733 (2006).
5. Bass, E., French, D. D., Bradham, D. D. & Rubenstein, L. Z. Risk-adjusted mortality rates of elderly veterans with hip fractures. Ann. Epidemiol. 17, 514-519 (2007).
6. Lewis, J. R., Hassan, S. K., Wenn, R. T. & Moran, C. G. Mortality and serum urea and electrolytes on admission for hip fracture patients. Injury 37, 698-704 (2006).
7. Ofotokun, I., McIntosh, E. & Weitzmann, M. N. HIV: inflammation and bone. Curr. HIV/AIDS Rep. 9, 16-25 (2012).
8. Weitzmann, M. N. & Pacifici, R. Estrogen deficiency and bone loss: An inflammatory tale. J. Clin. Invest. 116, 1186-1194 (2006).
9. Titanji, K. et al. Dysregulated B cell expression of RANKL and OPG correlates with loss of bone mineral density in HIV infection. PLoS Pathog. 10, e1004497 (2014).
10. Vikulina, T. et al. Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats. Proc. Natl Acad. Sci. USA 107, 13848-13853 (2010).
11. Robinson, J. W. et al. T cell expressed CD40L potentiates the bone anabolic activity of intermittent PTH treatment. J. Bone Miner. Res. 30, 695-705 (2014).
12. Li, J. Y. et al. The sclerostin-independent bone anabolic activity of intermittent PTH treatment is mediated by T-cell-produced Wnt10b. J. Bone Miner. Res. 29, 43-54 (2014).
13. Bedi, B. et al. Silencing of parathyroid hormone (PTH) receptor 1 in T cells blunts the bone anabolic activity of PTH. Proc. Natl Acad. Sci. USA 109, E725-E733 (2012).
14. Terauchi, M. et al. T lymphocytes amplify the anabolic activity of parathyroid hormone through Wnt10b signaling. Cell Metab. 10, 229-240 (2009).
15. Roser-Page, S., Vikulina, T., Zayzafoon, M. & Weitzmann, M. N. CTLA-4Ig-induced T cell anergy promotes Wnt-10b production and bone formation in a mouse model. Arthritis Rheumatol. 66, 990-999 (2014).
16. Manolagas, S. C. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr. Rev. 21, 115-137 (2000).
17. Walker, D. G. Bone resorption restored in osteopetrotic mice by transplants of normal bone marrow and spleen cells. Science 190, 784-785 (1975).
18. Walker, D. G. Congenital osteopetrosis in mice cured by parabiotic union with normal siblings. Endocrinology 91, 916-920 (1972).
19. Buring, K. On the origin of cells in heterotopic bone formation. Clin. Orthop. Relat. Res. 110, 293-301 (1975).
20. Simonet, W. S. et al. Osteoprotegerin: A novel secreted protein involved in the regulation of bone density. Cell 89, 309-319 (1997).
21. Tsuda, E. et al. Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochem. Biophys. Res. Commun. 234, 137-142 (1997).
22. Lacey, D. L. et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165-176 (1998).
23. Matsuzaki, K. et al. Osteoclast differentiation factor (ODF) induces osteoclast-like cell formation in human peripheral blood mononuclear cell cultures. Biochem. Biophys. Res. Commun. 246, 199-204 (1998).
24. Wong, B. R. et al. TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. J. Exp. Med. 186, 2075-2080 (1997).
25. Wong, B. R. et al. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J. Biol. Chem. 272, 25190-25194 (1997).
26. Anderson, D. M. et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390, 175-179 (1997).
27. Teitelbaum, S. L. Bone resorption by osteoclasts. Science 289, 1504-1508 (2000).
28. Khosla, S. Minireview: The OPG/RANKL/RANK system. Endocrinology 142, 5050-5055 (2001).
29. Xiong, J. et al. Matrix-embedded cells control osteoclast formation. Nat. Med. 17, 1235-1241 (2011).
30. Nakashima, T. et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat. Med. 17, 1231-1234 (2011).
31. McClung, M. R. et al. Romosozumab in postmenopausal women with low bone mineral density. N. Engl. J. Med. 370, 412-420 (2014).
32. Yun, T. J. et al. OPG/FDCR-1, a TNF receptor family member, is expressed in lymphoid cells and is up-regulated by ligating CD40. J. Immunol. 161, 6113-6121 (1998).
33. Li, Y. et al. B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo. Blood 109, 3839-3848 (2007).
34. Surh, C. D. & Sprent, J. Homeostasis of naive and memory T cells. Immunity 29, 848-862 (2008).
35. Gyarmati, J. et al. Alterations of the connective tissue in nude mice. Thymus 5, 383-392 (1983).
36. Horowitz, M., Vignery, A., Gershon, R. K. & Baron, R. Thymus-derived lymphocytes and their interactions with macrophages are required for the production of osteoclast-activating factor in the mouse. Proc. Natl Acad. Sci. USA 81, 2181-2185 (1984).
37. Grcevic, D., Lee, S. K., Marusic, A. & Lorenzo, J. A. 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 synthesis. J. Immunol. 165, 4231-4238 (2000).
38. Klausen, B., Hougen, H. P. & Fiehn, N. E. Increased periodontal bone loss in temporarily B lymphocyte-deficient rats. J. Periodontal Res. 24, 384-390 (1989).
39. Pineda, B., Laporta, P., Hermenegildo, C., Cano, A. & Garcia-Perez, M. A. A C>T polymorphism located at position-1 of the Kozak sequence of CD40 gene is associated with low bone mass in Spanish postmenopausal women. Osteoporos. Int. 19, 1147-1152 (2007).
40. Lopez-Granados, E. et al. Osteopenia in X-linked hyper-IgM syndrome reveals a regulatory role for CD40 ligand in osteoclastogenesis. Proc. Natl Acad. Sci. USA 104, 5056-5061 (2007).
41. Axmann, R. et al. CTLA-4 directly inhibits osteoclast formation. Ann. Rheum. Dis. 67, 1603-1609 (2008).
42. Bozec, A. et al. T cell costimulation molecules CD80/86 inhibit osteoclast differentiation by inducing the IDO/tryptophan pathway. Sci. Transl Med. 6, 235ra260 (2014).
43. Moir, S. & Fauci, A. S. B cells in HIV infection and disease. Nat. Rev. Immunol. 9, 235-245 (2009).
44. Moir, S. et al. Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals. J. Exp. Med. 205, 1797-1805 (2008).
45. Aukrust, P. et al. Decreased bone formative and enhanced resorptive markers in human immunodeficiency virus infection: indication of normalization of the bone-remodeling process during highly active antiretroviral therapy. J. Clin. Endocrinol. Metab. 84, 145-150 (1999).
46. Tebas, P. et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS 14, F63-F67 (2000).
47. Jain, R. G. & Lenhard, J. M. Select HIV protease inhibitors alter bone and fat metabolism ex vivo. J. Biol. Chem. 277, 19247-19250 (2002).
48. Mora, S. et al. Bone mineral loss through increased bone turnover in HIV-infected children treated with highly active antiretroviral therapy. AIDS 15, 1823-1829 (2001).
49. Huang, J. S., Wilkie, S. J., Sullivan, M. P. & Grinspoon, S. Reduced bone density in androgen-deficient women with acquired immune deficiency syndrome wasting. J. Clin. Endocrinol. Metab. 86, 3533-3539 (2001).
50. Mondy, K. & Tebas, P. Emerging bone problems in patients infected with human immunodeficiency virus. Clin. Infect. Dis. 36, S101-S105 (2003).
51. Brown, T. T. & Qaqish, R. B. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: A meta-analytic review. AIDS 20, 2165-2174 (2006).
52. Bonjoch, A. et al. High prevalence of and progression to low bone mineral density in HIV-infected patients: A longitudinal cohort study. AIDS 24, 2827-2833 (2010).
53. Sharma, A., Flom, P. L., Weedon, J. & Klein, R. S. Prospective study of bone mineral density changes in aging men with or at risk for HIV infection. AIDS 24, 2337-2345 (2010).
54. Triant, V. A., Brown, T. T., Lee, H. & Grinspoon, S. K. Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U. S. healthcare system. J. Clin. Endocrinol. Metab. 93, 3499-3504 (2008).
55. Prior, J. et al. Fragility fractures and bone mineral density in HIV positive women: A case-control population-based study. Osteoporos. Int. 18, 1345-1353 (2007).
56. Young, B., Dao, C. N., Buchacz, K., Baker, R. & Brooks, J. T. Increased rates of bone fracture among HIV-infected persons in the HIV Outpatient Study (HOPS) compared with the US general population, 2000-2006. Clin. Infect. Dis. 52, 1061-1068 (2011).
57. Womack, J. A. et al. Increased risk of fragility fractures among HIV infected compared to uninfected male veterans. PLoS ONE 6, e17217 (2011).
58. Guerri-Fernandez, R. et al. HIV infection is strongly associated with hip fracture risk, independently of age, gender, and comorbidities: A population-based cohort study. J. Bone Miner. Res. 28, 1259-1263 (2013).
59. Prieto-Alhambra, D. et al. HIV infection and its association with an excess risk of clinical fractures: A nationwide case-control study. J. Acquir. Immune Def. Syndr. 66, 90-95 (2014).
60. Sharma, A. et al. Increased fracture incidence in middle-aged HIV-infected and HIV-uninfected women: updated results from the women's interagency HIV study. J. Acquir. Immune Defic. Syndr. 70, 54-61 (2015).
61. Yin, M. T. et al. Fracture incidence in HIV-infected women: results from the Women's Interagency HIV Study. AIDS 24, 2679-2686 (2010).
62. Vance, D. E., McGuinness, T., Musgrove, K., Orel, N. A. & Fazeli, P. L. Successful aging and the epidemiology of HIV. Clin. Interv. Aging 6, 181-192 (2011).
63. Amorosa, V. & Tebas, P. Bone disease and HIV infection. Clin. Infect. Dis. 42, 108-114 (2006).
64. Ofotokun, I. & Weitzmann, M. N. HIV-1 infection and antiretroviral therapies: risk factors for osteoporosis and bone fracture. Curr. Opin. Endocrinol. Diabetes Obes. 17, 523-529 (2010).
65. Ofotokun, I. & Weitzmann, M. N. HIV and bone metabolism. Discov. Med. 11, 385-393 (2011).
66. Bruera, D., Luna, N., David, D. O., Bergoglio, L. M. & Zamudio, J. Decreased bone mineral density in HIV-infected patients is independent of antiretroviral therapy. AIDS 17, 1917-1923 (2003).
67. Dube, M. P. et al. Prospective, intensive study of metabolic changes associated with 48 weeks of amprenavir-based antiretroviral therapy. Clin. Infect. Dis. 35, 475-481 (2002).
68. Knobel, H., Guelar, A., Vallecillo, G., Nogues, X. & Diez, A. Osteopenia in HIV-infected patients: is it the disease or is it the treatment? AIDS 15, 807-808 (2001).
69. Reid, W. et al. An HIV-1 transgenic rat that develops HIV-related pathology and immunologic dysfunction. Proc. Natl Acad. Sci. USA 98, 9271-9276 (2001).
70. Lafferty, M. K. et al. Elevated suppressor of cytokine signaling-1 (SOCS-1): A mechanism for dysregulated osteoclastogenesis in HIV transgenic rats. Pathog. Dis. 71, 81-89 (2014).
71. Brown, T. T. et al. Body composition, soluble markers of inflammation, and bone mineral density in antiretroviral therapy-naive HIV-1-infected individuals. J. Acquir. Immune Defic. Syndr. 63, 323-330 (2013).
72. Thomas, J. & Doherty, S. M. HIV infection - a risk factor for osteoporosis. J. Acquir. Immune Defic. Syndr. 33, 281-291 (2003).
73. McComsey, G. A. et al. Bone disease in HIV infection: A practical review and recommendations for HIV care providers. Clin. Infect. Dis. 51, 937-946 (2010).
74. Yin, M. T. et al. Short-term bone loss in HIV-infected premenopausal women. J. Acquir. Immune Defic. Syndr. 53, 202-208 (2010).
75. Bolland, M. J. & Grey, A. HIV and low bone density: responsible party, or guilty by association? IBMS BoneKEy 8, 7-15 (2011).
76. Nolan, D. et al. Stable or increasing bone mineral density in HIV-infected patients treated with nelfinavir or indinavir. AIDS 15, 1275-1280 (2001).
77. Bolland, M. J. et al. Stable bone mineral density over 6 years in HIV-infected men treated with highly active antiretroviral therapy (HAART). Clin. Endocrinol. (Oxf.) 76, 643-648 (2012).
78. Gibellini, D. et al. Analysis of the effects of specific protease inhibitors on OPG/RANKL regulation in an osteoblast-like cell line. New Microbiol. 33, 109-115 (2010).
79. Grigsby, I. F., Pham, L., Gopalakrishnan, R., Mansky, L. M. & Mansky, K. C. Downregulation of Gnas, Got2 and Snord32a following tenofovir exposure of primary osteoclasts. Biochem. Biophys. Res. Commun. 391, 1324-1329 (2010).
80. Grigsby, I. F. et al. Tenofovir treatment of primary osteoblasts alters gene expression profiles: implications for bone mineral density loss. Biochem. Biophys. Res. Commun. 394, 48-53 (2010).
81. Wang, M. W. et al. The HIV protease inhibitor ritonavir blocks osteoclastogenesis and function by impairing RANKL-induced signaling. J. Clin. Invest. 114, 206-213 (2004).
82. Brown, T. T. et al. Loss of bone mineral density after antiretroviral therapy initiation, independent of antiretroviral regimen. J. Acquir. Immune Defic. Syndr. 51, 554-561 (2009).
83. Piso, R. J., Rothen, M., Rothen, J. P. & Stahl, M. Markers of bone turnover are elevated in patients with antiretroviral treatment independent of the substance used. J. Acquir. Immune Defic. Syndr. 56, 320-324 (2011).
84. Deeks, S. G., Tracy, R. & Douek, D. C. Systemic effects of inflammation on health during chronic HIV infection. Immunity 39, 633-645 (2013).
85. Hofbauer, L. C. et al. Interleukin-1? and tumor necrosis factor-?, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. Bone 25, 255-259 (1999).
86. Cenci, S. et al. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-?. J. Clin. Invest. 106, 1229-1237 (2000).
87. Fuller, K., Murphy, C., Kirstein, B., Fox, S. W. & Chambers, T. J. TNF? potently activates osteoclasts, through a direct action independent of and strongly synergistic with RANKL. Endocrinology 143, 1108-1118 (2002).
88. Ofotokun, I. et al. Antiretroviral therapy induces a rapid increase in bone resorption that is positively associated with the magnitude of immune reconstitution in HIV infection. AIDS 30, 405-414 (2016).
89. Brown, T. T., Ross, A. C., Storer, N., Labbato, D. & McComsey, G. A. Bone turnover, osteoprotegerin/ RANKL and inflammation with antiretroviral initiation: Tenofovir versus non-tenofovir regimens. Antivir. Ther. 16, 1063-1072 (2011).
90. Hui, S. L., Slemenda, C. W. & Johnston, C. C. Jr Age and bone mass as predictors of fracture in a prospective study. J. Clin. Invest. 81, 1804-1809 (1988).
91. Bolland, M. J. et al. Annual zoledronate increases bone density in highly active antiretroviral therapy-treated human immunodeficiency virus-infected men: A randomized controlled trial. J. Clin. Endocrinol. Metab. 92, 1283-1288 (2007).
92. Bolland, M. J. et al. Effects of intravenous zoledronate on bone turnover and bone density persist for at least five years in HIV-infected men. J. Clin. Endocrinol. Metab. 97, 1922-1928 (2012).
93. McComsey, G. A. et al. Alendronate with calcium and vitamin D supplementation is safe and effective for the treatment of decreased bone mineral density in HIV. AIDS 21, 2473-2482 (2007).
94. Brown, T. T. et al. Recommendations for evaluation and management of bone disease in HIV. Clin. Infect. Dis. 60, 1242-1251 (2015).
95. McClung, M. R. et al. Denosumab in postmenopausal women with low bone mineral density. N. Engl. J. Med. 354, 821-831 (2006).
96. Reid, I. R. et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N. Engl. J. Med. 346, 653-661 (2002).
97. Ofotokun, I. et al. Role of T-cell reconstitution in HIV-1 antiretroviral therapy-induced bone loss. Nat. Commun. 6, 8282 (2015).
98. Ofotokun, I. et al. A single dose zoledronic acid infusion prevents antiretroviral therapy-induced bone loss in treatment-naive HIV-infected patients: A phase IIb trial. Clin. Infect. Dis. http://dx. doi. org/10. 1093/ cid/ciw331 (2016).
99. Chopin, F. et al. Long term effects of Infliximab on bone and cartilage turnover markers in patients with rheumatoid arthritis. Ann. Rheum. Dis. 67, 353-357 (2007).
100. Seriolo, B., Paolino, S., Sulli, A., Ferretti, V. & Cutolo, M. Bone metabolism changes during anti-TNF-? therapy in patients with active rheumatoid arthritis. Ann. NY Acad. Sci. 1069, 420-427 (2006).
101. Wheater, G. et al. Suppression of bone turnover by B-cell depletion in patients with rheumatoid arthritis. Osteoporos. Int. 22, 3067-3072 (2011).
102. Genovese, M. C. et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor ? inhibition. N. Engl. J. Med. 353, 1114-1123 (2005).
103. Edwards, J. C. et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N. Engl. J. Med. 350, 2572-2581 (2004).
104. Schett, G. & David, J. P. The multiple faces of autoimmune-mediated bone loss. Nat. Rev. Endocrinol. 6, 698-706 (2010).
105. Fournier, C. Where do T cells stand in rheumatoid arthritis? Joint Bone Spine 72, 527-532 (2005).
106. Kong, Y. Y. et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402, 304-309 (1999).
107. He, X., Kang, A. H. & Stuart, J. M. Anti-human type II collagen CD19+ B cells are present in patients with rheumatoid arthritis and healthy individuals. J. Rheumatol. 28, 2168-2175 (2001).
108. Yanaba, K. et al. B cell depletion delays collagen-induced arthritis in mice: Arthritis induction requires synergy between humoral and cell-mediated immunity. J. Immunol. 179, 1369-1380 (2007).
109. Li, P. & Schwarz, E. M. The TNF-? transgenic mouse model of inflammatory arthritis. Springer Semin. Immunopathol. 25, 19-33 (2003).
110. Schett, G. et al. Osteoprotegerin protects against generalized bone loss in tumor necrosis factor-transgenic mice. Arthritis Rheum. 48, 2042-2051 (2003).
111. Fry, T. J. & Mackall, C. L. Interleukin-7: master regulator of peripheral T-cell homeostasis? Trends Immunol. 22, 564-571 (2001).
112. De Benedetti, F. et al. Elevated circulating interleukin-7 levels in patients with systemic juvenile rheumatoid arthritis. J. Rheumatol. 22, 1581-1585 (1995).
113. Hartgring, S. A., Willis, C. R., Bijlsma, J. W., Lafeber, F. P. & van Roon, J. A. Interleukin-7-aggravated joint inflammation and tissue destruction in collagen-induced arthritis is associated with T-cell and B-cell activation. Arthritis Res. Ther. 14, R137 (2012).
114. Hartgring, S. A. et al. Blockade of the interleukin-7 receptor inhibits collagen-induced arthritis and is associated with reduction of T cell activity and proinflammatory mediators. Arthritis Rheum. 62, 2716-2725 (2010).
115. Buchwald, Z. S. et al. Osteoclast-induced Foxp3+ CD8 T-cells limit bone loss in mice. Bone 56, 163-173 (2013).
116. Glowacki, A. J. et al. Prevention of inflammation-mediated bone loss in murine and canine periodontal disease via recruitment of regulatory lymphocytes. Proc. Natl Acad. Sci. USA 110, 18525-18530 (2013).
117. Zaiss, M. M. et al. Regulatory T cells protect from local and systemic bone destruction in arthritis. J. Immunol. 184, 7238-7246 (2010).
118. Kim, Y. G. et al. Human CD4+CD25+ regulatory T cells inhibit the differentiation of osteoclasts from peripheral blood mononuclear cells. Biochem. Biophys. Res. Commun. 357, 1046-1052 (2007).
119. Zaiss, M. M. et al. Treg cells suppress osteoclast formation: A new link between the immune system and bone. Arthritis Rheum. 56, 4104-4112 (2007).
120. Zaiss, M. M. et al. Increased bone density and resistance to ovariectomy-induced bone loss in FoxP3-transgenic mice based on impaired osteoclast differentiation. Arthritis Rheum. 62, 2328-2338 (2010).
121. Rifas, L. & Weitzmann, M. N. A novel T cell cytokine, secreted osteoclastogenic factor of activated T cells, induces osteoclast formation in a RANKL-independent manner. Arthritis Rheumatol. 60, 3324-3335 (2009).
122. Jarry, C. R. et al. Secreted osteoclastogenic factor of activated T cells (SOFAT), a novel osteoclast activator, in chronic periodontitis. Hum. Immunol. 74, 861-866 (2013).
123. Redlich, K. et al. Repair of local bone erosions and reversal of systemic bone loss upon therapy with anti-tumor necrosis factor in combination with osteoprotegerin or parathyroid hormone in tumor necrosis factor-mediated arthritis. Am. J. Pathol. 164, 543-555 (2004).
124. Garlet, G. P. et al. Regulatory T cells attenuate experimental periodontitis progression in mice. J. Clin. Periodontol. 37, 591-600 (2010).
125. Araujo-Pires, A. C. et al. IL-4/CCL22/CCR4 axis controls regulatory T-cell migration that suppresses inflammatory bone loss in murine experimental periodontitis. J. Bone Miner. Res. 30, 412-422 (2015).
126. Zhu, L. L. et al. Blocking antibody to the ?-subunit of FSH prevents bone loss by inhibiting bone resorption and stimulating bone synthesis. Proc. Natl Acad. Sci. USA 109, 14574-14579 (2012).
127. Clowes, J. A., Riggs, B. L. & Khosla, S. The role of the immune system in the pathophysiology of osteoporosis. Immunol. Rev. 208, 207-227 (2005).
128. Di Gregorio, G. B. et al. Attenuation of the self-renewal of transit-amplifying osteoblast progenitors in the murine bone marrow by 17 ?-estradiol. J. Clin. Invest. 107, 803-812 (2001).
129. Szulc, P., Hofbauer, L. C., Heufelder, A. E., Roth, S. & Delmas, P. D. Osteoprotegerin serum levels in men: correlation with age, estrogen, and testosterone status. J. Clin. Endocrinol. Metab. 86, 3162-3165 (2001).
130. Srivastava, S. 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. 102, 1850-1859 (1998).
131. Srivastava, S. et al. Estrogen decreases osteoclast formation by down-regulating receptor activator of NF-?B ligand (RANKL)-induced JNK activation. J. Biol. Chem. 276, 8836-8840 (2001).
132. Kim, B. J. et al. TNF-? mediates the stimulation of sclerostin expression in an estrogen-deficient condition. Biochem. Biophys. Res. Commun. 424, 170-175 (2012).
133. Salem, M. L. Estrogen, a double-edged sword: modulation of TH1-and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production. Curr. Drug Targets Inflamm. Allergy 3, 97-104 (2004).
134. Eghbali-Fatourechi, G. et al. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J. Clin. Invest. 111, 1221-1230 (2003).
135. Masuzawa, T. et al. Estrogen deficiency stimulates B lymphopoiesis in mouse bone marrow. J. Clin. Invest. 94, 1090-1097 (1994).
136. Miyaura, C. 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. USA 94, 9360-9365 (1997).
137. Onal, M. et al. Receptor activator of nuclear factor ?B ligand (RANKL) protein expression by B lymphocytes contributes to ovariectomy-induced bone loss. J. Biol. Chem. 287, 29851-29860 (2012).
138. Roggia, C. 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. USA 98, 13960-13965 (2001).
139. Grassi, F. et al. Oxidative stress causes bone loss in estrogen-deficient mice through enhanced bone marrow dendritic cell activation. Proc. Natl Acad. Sci. USA 104, 15087-15092 (2007).
140. Cenci, S. et al. Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-?-induced class II transactivator. Proc. Natl Acad. Sci. USA 100, 10405-10410 (2003).
141. Luo, C. Y., Wang, L., Sun, C. & Li, D. J. Estrogen enhances the functions of CD4+CD25+Foxp3+ regulatory T cells that suppress osteoclast differentiation and bone resorption in vitro. Cell. Mol. Immunol. 8, 50-58 (2011).
142. Gao, Y. et al. Estrogen prevents bone loss through transforming growth factor ? signaling in T cells. Proc. Natl Acad. Sci. USA 101, 16618-16623 (2004).
143. Li, H. et al. Cross talk between the bone and immune systems: osteoclasts function as antigen-presenting cells and activate CD4+ and CD8+ T cells. Blood 116, 210-217 (2010).
144. Britton, R. A. et al. Probiotic L. reuteri treatment prevents bone loss in a menopausal ovariectomized mouse model. J. Cell. Physiol. 229, 1822-1830 (2014).
145. Ohlsson, C. et al. Probiotics protect mice from ovariectomy-induced cortical bone loss. PLoS ONE 9, e92368 (2014).
146. Li, J. Y. et al. Sex steroid deficiency-associated bone loss is microbiota dependent and prevented by probiotics. J. Clin. Invest. http://dx. doi. org/10. 1172/ JCI86062 (2016).
147. Lindberg, M. K. et al. Liver-derived IGF-I is permissive for ovariectomy-induced trabecular bone loss. Bone 38, 85-92 (2006).
148. Weitzmann, M. N., Cenci, S., Rifas, L., Brown, C. & Pacifici, R. Interleukin-7 stimulates osteoclast formation by up-regulating the T-cell production of soluble osteoclastogenic cytokines. Blood 96, 1873-1878 (2000).
149. Toraldo, G., Roggia, C., Qian, W. P., Pacifici, R. & Weitzmann, M. N. IL-7 induces bone loss in vivo by induction of receptor activator of nuclear factor ?B ligand and tumor necrosis factor ? from T cells. Proc. Natl Acad. Sci. USA 100, 125-130 (2003).
150. Tyagi, A. M. et al. Estrogen deficiency induces the differentiation of IL-17 secreting Th17 cells: A new candidate in the pathogenesis of osteoporosis. PLoS ONE 7, e44552 (2012).
151. Liu, Y. et al. Transplantation of SHED prevents bone loss in the early phase of ovariectomy-induced osteoporosis. J. Dent. Res. 93, 1124-1132 (2014).
152. Tyagi, A. M. et al. Daidzein prevents the increase in CD4+CD28null T cells and B lymphopoesis in ovariectomized mice: A key mechanism for anti-osteoclastogenic effect. PLoS ONE 6, e21216 (2011).
153. Tyagi, A. M. et al. Enhanced immunoprotective effects by anti-IL-17 antibody translates to improved skeletal parameters under estrogen deficiency compared with anti-RANKL and anti-TNF-? antibodies. J. Bone Miner. Res. 29, 1981-1992 (2014).
154. Takayanagi, H. et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-?. Nature 408, 600-605 (2000).
155. Lee, S. K., Kalinowski, J. F., Jastrzebski, S. L., Puddington, L. & Lorenzo, J. A. Interleukin-7 is a direct inhibitor of in vitro osteoclastogenesis. Endocrinology 144, 3524-3531 (2003).
156. Valenzona, H. O., Pointer, R., Ceredig, R. & Osmond, D. G. Prelymphomatous B cell hyperplasia in the bone marrow of interleukin-7 transgenic mice: precursor B cell dynamics, microenvironmental organization and osteolysis. Exp. Hematol. 24, 1521-1529 (1996).
157. Aguila, H. L. et al. Osteoblast-specific overexpression of human interleukin-7 rescues the bone mass phenotype of interleukin-7-deficient female mice. J. Bone Miner. Res. 27, 1030-1042 (2012).
158. Weitzmann, M. N., 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. 110, 1643-1650 (2002).
159. Rodriguiz, R. M., Key, L. L. Jr & Ries, W. L. Combination macrophage-colony stimulating factor and interferon-? administration ameliorates the osteopetrotic condition in microphthalmic (mi/mi) mice. Pediatr. Res. 33, 384-389 (1993).
160. Alam, I. et al. Interferon ?, but not calcitriol improves the osteopetrotic phenotypes in ADO2 mice. J. Bone Miner. Res. 30, 2005-2013 (2015).
161. Key, L. L. Jr. et al. Long-term treatment of osteopetrosis with recombinant human interferon ?. N. Engl. J. Med. 332, 1594-1599 (1995).
162. Yamaza, T. et al. Pharmacologic stem cell based intervention as a new approach to osteoporosis treatment in rodents. PLoS ONE 3, e2615 (2008).
163. Sass, D. A. et al. The role of the T-lymphocyte in estrogen deficiency osteopenia. J. Bone Miner. Res. 12, 479-486 (1997).
164. Lee, S. K. et al. T Lymphocyte deficient mice lose trabecular bone mass with ovariectomy. J. Bone Miner. Res. 21, 1704-1712 (2006).
165. Cho, S. W. et al. Human adipose tissue-derived stromal cell therapy prevents bone loss in ovariectomized nude mouse. Tissue Eng. Part A 18, 1067-1078 (2012).
166. D'Amelio, P. et al. Estrogen deficiency increases osteoclastogenesis up-regulating T cells activity: A key mechanism in osteoporosis. Bone 43, 92-100 (2008).
167. Adeel, S. et al. Bone loss in surgically ovariectomized premenopausal women is associated with T lymphocyte activation and thymic hypertrophy. J. Investig. Med. 61, 1178-1183 (2013).
168. Kimble, R. B. et al. Simultaneous block of interleukin-1 and tumor necrosis factor is required to completely prevent bone loss in the early postovariectomy period. Endocrinology 136, 3054-3061 (1995).
169. Gao, Y. et al. IFN-? Stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation. J. Clin. Invest. 117, 122-132 (2007).
170. Lee, S. K. et al. Interleukin-7 influences osteoclast function in vivo but is not a critical factor in ovariectomy-induced bone loss. J. Bone Miner. Res. 21, 695-702 (2006).
171. Goswami, J., Hernandez-Santos, N., Zuniga, L. A. & Gaffen, S. L. A bone-protective role for IL-17 receptor signaling in ovariectomy-induced bone loss. Eur. J. Immunol. 39, 2831-2839 (2009).
172. Cummings, S. R. et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N. Engl. J. Med. 361, 756-765 (2009).
173. Pacifici, R. T cells: critical bone regulators in health and disease. Bone 47, 461-471 (2010).
174. Tawfeek, H. et al. Disruption of PTH receptor 1 in T cells protects against PTH-induced bone loss. PLoS ONE 5, e12290 (2010).
175. Hory, B. G. et al. Absence of response to human parathyroid hormone in athymic mice grafted with human parathyroid adenoma, hyperplasia or parathyroid cells maintained in culture. J. Endocrinol. Invest. 23, 273-279 (2000).
176. Gao, Y. et al. T cells potentiate PTH-induced cortical bone loss through CD40L signaling. Cell Metab. 8, 132-145 (2008).
177. Bedi, B. et al. Inhibition of antigen presentation and T cell costimulation blocks PTH-induced bone loss. Ann. NY Acad. Sci. 1192, 215-221 (2010).
178. Buchwald, Z. S. et al. A bone anabolic effect of RANKL in a murine model of osteoporosis mediated through FoxP3+ CD8 T-Cells. J. Bone Miner. Res. 30, 1508-1522 (2015).
179. Sayegh, M. H. Finally, CTLA4Ig graduates to the clinic. J. Clin. Invest. 103, 1223-1225 (1999).
180. Pacifici, R. Role of T cells in the modulation of PTH action: physiological and clinical significance. Endocrine 44, 576-582 (2013).
181. Li, Y. et al. Endogenous TNF? lowers maximum peak bone mass and inhibits osteoblastic Smad activation through NF-?B. J. Bone Miner. Res. 22, 646-655 (2007).
182. Gilbert, L. C., Chen, H., Lu, X. & Nanes, M. S. Chronic low dose tumor necrosis factor-? (TNF) suppresses early bone accrual in young mice by inhibiting osteoblasts without affecting osteoclasts. Bone 56, 174-183 (2013).