Although it has long been recognized that inflammation, a consequence of immune-driven processes, significantly impacts bone turnover, the degree of centralization of skeletal and immune functions has begun to be dissected only recently. It is now recognized that formation of osteoclasts, the bone resorbing cells of the body, is centered on the key osteoclastogenic cytokine, receptor activator of NF-κB ligand (RANKL). Although numerous inflammatory cytokines are now recognized to promote osteoclast formation and skeletal degradation, with just a few exceptions, RANKL is now considered to be the final downstream effector cytokine that drives osteoclastogenesis and regulates osteoclastic bone resorption. The biological activity of RANKL is moderated by its physiological decoy receptor, osteoprotegerin (OPG). New discoveries concerning the sources and regulation of RANKL and OPG in physiological bone turnover as well as under pathological (osteoporotic) conditions continue to be made, opening a window to the complex regulatory processes that control skeletal integrity and the depth of integration of the skeleton within the immune response. This paper will examine the interconnection between bone turnover and the immune system and the implications thereof for physiological and pathological bone turnover. 1. Introduction Mineralized bone consists of a protein matrix comprising predominantly, but not exclusively, collagen type I fibers that are layered down in oriented linear bundles. This protein matrix scaffold is coated with a layer of mineral, predominantly calcium phosphate in the form of crystals of hydroxyapatite [1]. The skeleton forms in early life, mainly through endochondral ossification in which bone is initially patterned in mineralized cartilage followed by replacement of the cartilage template by mineralized bone. Some skeletal components including certain bones of the skull such as the calvaria are formed without a cartilage intermediate through direct matrix and mineralization deposition, a process referred to as intramembranous ossification [2]. The skeleton achieves its final shape and ultimate form through bone modeling, a process involving the coordinated activity of bone synthesizing osteoblasts and bone resorbing osteoclasts. This process of selective bone deposition and removal sculpts the skeleton to achieve final shape and optimal load bearing capacity [3, 4]. Bone modeling continues until early adulthood in humans at which time peak bone mineral density (BMD) and bone size are achieved. Thereafter, the skeleton undergoes a process
References
[1]
S. Weiner and W. Traub, “Bone structure: from angstroms to microns,” The FASEB Journal, vol. 6, no. 3, pp. 879–885, 1992.
[2]
T. A. Franz-Odendaal, “Induction and patterning of intramembranous bone,” Frontiers in Bioscience, vol. 16, no. 7, pp. 2734–2746, 2011.
[3]
S. C. Manolagas, “Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis,” Endocrine Reviews, vol. 21, no. 2, pp. 115–137, 2000.
[4]
S. C. Manolagas and R. L. Jilka, “Mechanisms of disease: bone marrow, cytokines, and bone remodeling—emerging insights into the pathophysiology of osteoporosis,” The New England Journal of Medicine, vol. 332, no. 5, pp. 305–311, 1995.
[5]
S. Khosla, S. Amin, and E. Orwoll, “Osteoporosis in men,” Endocrine Reviews, vol. 29, no. 4, pp. 441–464, 2008.
[6]
J. A. Eisman, E. R. Bogoch, R. Dell et al., “Making the first fracture the last fracture: ASBMR task force report on secondary fracture prevention,” Journal of Bone and Mineral Research, vol. 27, no. 10, pp. 2039–2046, 2012.
[7]
O. Johnell and J. A. Kanis, “An estimate of the worldwide prevalence and disability associated with osteoporotic fractures,” Osteoporosis International, vol. 17, no. 12, pp. 1726–1733, 2006.
[8]
C. J. Todd, C. J. Freeman, C. Camilleri-Ferrante et al., “Differences in mortality after fracture of hip: the East Anglian audit,” British Medical Journal, vol. 310, no. 6984, pp. 904–908, 1995.
[9]
D. M. Black, L. Palermo, M. C. Nevitt et al., “Comparison of methods for defining prevalent vertebral deformities: the study of osteoporotic fractures,” Journal of Bone and Mineral Research, vol. 10, no. 6, pp. 890–902, 1995.
[10]
“Prevention and management of osteoporosis,” World Health Organization Technical Report Series, vol. 921, pp. 1–164, 2003.
[11]
J. R. Lewis, S. K. Z. Hassan, R. T. Wenn, and C. G. Moran, “Mortality and serum urea and electrolytes on admission for hip fracture patients,” Injury, vol. 37, no. 8, pp. 698–704, 2006.
[12]
A. Brainsky, H. Glick, E. Lydick et al., “The economic cost of hip fractures in community-dwelling older adults: a prospective study,” Journal of the American Geriatrics Society, vol. 45, no. 3, pp. 281–287, 1997.
[13]
R. Burge, B. Dawson-Hughes, D. H. Solomon, J. B. Wong, A. King, and A. Tosteson, “Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025,” Journal of Bone and Mineral Research, vol. 22, no. 3, pp. 465–475, 2007.
[14]
M. C. Horowitz and J. A. Lorenzo, “The origins of osteoclasts,” Current Opinion in Rheumatology, vol. 16, no. 4, pp. 464–468, 2004.
[15]
M. N. Weitzmann and R. Pacifici, “The role of T lymphocytes in bone metabolism,” Immunological Reviews, vol. 208, pp. 154–168, 2005.
[16]
H. Takayanagi, “Mechanistic insight into osteoclast differentiation in osteoimmunology,” Journal of Molecular Medicine, vol. 83, no. 3, pp. 170–179, 2005.
[17]
M. N. Weitzmann and R. Pacifici, “Estrogen deficiency and bone loss: an inflammatory tale,” Journal of Clinical Investigation, vol. 116, no. 5, pp. 1186–1194, 2006.
[18]
J. Lorenzo, M. Horowitz, and Y. Choi, “Osteoimmunology: interactions of the bone and immune system,” Endocrine Reviews, vol. 29, no. 4, pp. 403–440, 2008.
[19]
I. Ofotokun and M. N. Weitzmann, “HIV-1 infection and antiretroviral therapies: risk factors for osteoporosis and bone fracture,” Current Opinion in Endocrinology, Diabetes and Obesity, vol. 17, no. 6, pp. 523–529, 2010.
[20]
A. Leibbrandt and J. M. Penninger, “Novel functions of RANK(L) signaling in the immune system,” Advances in Experimental Medicine and Biology, vol. 658, pp. 77–94, 2010.
[21]
I. Ofotokun and M. N. Weitzmann, “HIV and bone metabolism,” Discovery Medicine, vol. 11, pp. 385–393, 2011.
[22]
I. Ofotokun, E. McIntosh, and M. N. Weitzmann, “HIV: inflammation and bone,” Current HIV/AIDS Reports, vol. 9, pp. 16–25, 2012.
[23]
R. Pacifici, “Role of T cells in ovariectomy induced bone loss—revisited,” Journal of Bone and Mineral Research, vol. 27, pp. 231–239, 2012.
[24]
R. Baron, L. Neff, W. Brown, D. Louvard, and P. J. Courtoy, “Selective internalization of the apical plasma membrane and rapid redistribution of lysosomal enzymes and mannose 6-phosphate receptors during osteoclast inactivation by calcitonin,” Journal of Cell Science, vol. 97, no. 3, pp. 439–447, 1990.
[25]
S. L. Teitelbaum, “Bone resorption by osteoclasts,” Science, vol. 289, no. 5484, pp. 1504–1508, 2000.
[26]
R. Pacifici, C. Brown, E. Puscheck et al., “Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 12, pp. 5134–5138, 1991.
[27]
S. C. Manolagas, T. Bellido, and R. L. Jilka, “New insights into the cellular, biochemical, and molecular basis of postmenopausal and senile osteoporosis: roles of IL-6 and gp130,” International Journal of Immunopharmacology, vol. 17, no. 2, pp. 109–116, 1995.
[28]
N. Takahashi, T. Akatsu, N. Udagawa et al., “Osteoblastic cells are involved in osteoclast formation,” Endocrinology, vol. 123, no. 5, pp. 2600–2602, 1988.
[29]
W. S. Simonet, D. L. Lacey, C. R. Dunstan et al., “Osteoprotegerin: a novel secreted protein involved in the regulation of bone density,” Cell, vol. 89, no. 2, pp. 309–319, 1997.
[30]
E. Tsuda, M. Goto, S. I. Mochizuki et al., “Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis,” Biochemical and Biophysical Research Communications, vol. 234, no. 1, pp. 137–142, 1997.
[31]
D. L. Lacey, E. Timms, H. L. Tan et al., “Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation,” Cell, vol. 93, no. 2, pp. 165–176, 1998.
[32]
K. Matsuzaki, N. Udagawa, N. Takahashi et al., “Osteoclast differentiation factor (ODF) induces osteoclast-like cell formation in human peripheral blood mononuclear cell cultures,” Biochemical and Biophysical Research Communications, vol. 246, no. 1, pp. 199–204, 1998.
[33]
D. M. Anderson, E. Maraskovsky, W. L. Billingsley et al., “A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function,” Nature, vol. 390, no. 6656, pp. 175–179, 1997.
[34]
B. R. Wong, R. Josien, S. Y. Lee 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,” The Journal of Experimental Medicine, vol. 186, no. 12, pp. 2075–2080, 1997.
[35]
H. Hsu, D. L. Lacey, C. R. Dunstan et al., “Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 7, pp. 3540–3545, 1999.
[36]
S. Khosla, “Minireview: the OPG/RANKL/RANK system,” Endocrinology, vol. 142, no. 12, pp. 5050–5055, 2001.
[37]
T. Suda, N. Takahashi, N. Udagawa, E. Jimi, M. T. Gillespie, and T. J. Martin, “Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families,” Endocrine Reviews, vol. 20, no. 3, pp. 345–357, 1999.
[38]
H. J. Choi, Y. R. Park, M. Nepal et al., “Inhibition of osteoclastogenic differentiation by Ikarisoside A in RAW 264.7 cells via JNK and NF-κB signaling pathways,” European Journal of Pharmacology, vol. 636, no. 1–3, pp. 28–35, 2010.
[39]
T. Maruyama, H. Fukushima, K. Nakao et al., “Processing of the NF-κB2 precursor p100 to p52 is critical for RANKL-induced osteoclast differentiation,” Journal of Bone and Mineral Research, vol. 25, no. 5, pp. 1058–1067, 2010.
[40]
T. Ogasawara, M. Katagiri, A. Yamamoto et al., “Osteoclast differentiation by RANKL requires NF-κB-mediated downregulation of cyclin-dependent kinase 6 (Cdk6),” Journal of Bone and Mineral Research, vol. 19, no. 7, pp. 1128–1136, 2004.
[41]
S. Vaira, M. Alhawagri, I. Anwisye, H. Kitaura, R. Faccio, and D. V. Novack, “RelA/p65 promotes osteoclast differentiation by blocking a RANKL-induced apoptotic JNK pathway in mice,” Journal of Clinical Investigation, vol. 118, no. 6, pp. 2088–2097, 2008.
[42]
S. Srivastava, M. N. Weitzmann, S. Cenci, F. P. Ross, S. Adler, and R. Pacifici, “Estrogen decreases TNF gene expression by blocking JNK activity and the resulting production of c-Jun and JunD,” Journal of Clinical Investigation, vol. 104, no. 4, pp. 503–513, 1999.
[43]
S. Srivastava, G. Toraldo, M. N. Weitzmann, S. Cenci, F. P. Ross, and R. Pacifici, “Estrogen decreases osteoclast formation by down-regulating receptor activator of NF-κB ligand (RANKL)-induced JNK activation,” Journal of Biological Chemistry, vol. 276, no. 12, pp. 8836–8840, 2001.
[44]
H. Hirotani, N. A. Tuohy, J. T. Woo, P. H. Stern, and N. A. Clipstone, “The calcineurin/nuclear factor of activated T cells signaling pathway regulates osteoclastogenesis in RAW264.7 cells,” Journal of Biological Chemistry, vol. 279, no. 14, pp. 13984–13992, 2004.
[45]
K. Matsuo, D. L. Galson, C. Zhao et al., “Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos,” Journal of Biological Chemistry, vol. 279, no. 25, pp. 26475–26480, 2004.
[46]
H. Takayanagi, “The role of NFAT in osteoclast formation,” Annals of the New York Academy of Sciences, vol. 1116, pp. 227–237, 2007.
[47]
M. H. Helfrich, C. W. Thesingh, R. H. P. Mieremet, and A. S. van Iperen-van Gent, “Osteoclast generation from human fetal bone marrow in cocultures with murine fetal long bones. A model for in vitro study of human osteoclast formation and function,” Cell and Tissue Research, vol. 249, no. 1, pp. 125–136, 1987.
[48]
T. Inaoka, G. Bilbe, O. Ishibashi, K. I. Tezuka, M. Kumegawa, and T. Kokubo, “Molecular cloning of human cDNA for cathepsin K: novel cysteine proteinase predominantly expressed in bone,” Biochemical and Biophysical Research Communications, vol. 206, no. 1, pp. 89–96, 1995.
[49]
B. F. Boyce, T. Yoneda, C. Lowe, P. Soriano, and G. R. Mundy, “Requirement of pp60(c-src) expression for osteoclasts to form ruffled borders and resorb bone in mice,” Journal of Clinical Investigation, vol. 90, no. 4, pp. 1622–1627, 1992.
[50]
T. A. Hentunen, S. H. Jackson, H. Chung et al., “Characterization of immortalized osteoclast precursors developed from mice transgenic for both bcl-X(L) and simian virus 40 large T antigen,” Endocrinology, vol. 140, no. 7, pp. 2954–2961, 1999.
[51]
J. Clover, R. A. Dodds, and M. Gowen, “Integrin subunit expression by human osteoblasts and osteoclasts in situ and in culture,” Journal of Cell Science, vol. 103, no. 1, pp. 267–271, 1992.
[52]
S. L. Teitelbaum, “The osteoclast and its unique cytoskeleton,” Annals of the New York Academy of Sciences, vol. 1240, pp. 14–17, 2011.
[53]
M. J. Oursler, L. V. Bell, B. Clevinger, and P. Osdoby, “Identification of osteoclast-specific monoclonal antibodies,” Journal of Cell Biology, vol. 100, no. 5, pp. 1592–1600, 1985.
[54]
Y. Y. Kong, H. Yoshida, I. Sarosi et al., “OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis,” Nature, vol. 397, no. 6717, pp. 315–323, 1999.
[55]
N. Bucay, I. Sarosi, C. R. Dunstan et al., “Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification,” Genes and Development, vol. 12, no. 9, pp. 1260–1268, 1998.
[56]
H. Min, S. Morony, I. Sarosi et al., “Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis,” The Journal of Experimental Medicine, vol. 192, no. 4, pp. 463–474, 2000.
[57]
A. E. Hughes, S. H. Ralston, J. Marken et al., “Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis,” Nature Genetics, vol. 24, no. 1, pp. 45–48, 2000.
[58]
M. P. Whyte, S. E. Obrecht, P. M. Finnegan et al., “Osteoprotegerin deficiency and juvenile Paget's disease,” The New England Journal of Medicine, vol. 347, no. 3, pp. 175–184, 2002.
[59]
M. P. Whyte, P. N. Singhellakis, M. B. Petersen, M. Davies, W. G. Totty, and S. Mumm, “Juvenile Paget's disease: the second reported, oldest patient is homozygous for the TNFRSF11B “Balkan” mutation (966_969delTGACinsCTT), which elevates circulating immunoreactive osteoprotegerin levels,” Journal of Bone and Mineral Research, vol. 22, no. 6, pp. 938–946, 2007.
[60]
M. P. Whyte and S. Mumm, “Heritable disorders of the RANKL/OPG/RANK signaling pathway,” Journal of Musculoskeletal Neuronal Interactions, vol. 4, no. 3, pp. 254–267, 2004.
[61]
M. P. Whyte, W. G. Totty, D. V. Novack, X. Zhang, D. Wenkert, and S. Mumm, “Camurati-engelmann disease: unique variant featuring a novel mutation in TGFβ1 encoding transforming growth factor beta 1 and a missense change in TNFSF11 encoding RANK ligand,” Journal of Bone and Mineral Research, vol. 26, no. 5, pp. 920–933, 2011.
[62]
B. Bolon, C. Carter, M. Daris et al., “Adenoviral delivery of osteoprotegerin ameliorates bone resorption in a mouse ovariectomy model of osteoporosis,” Molecular Therapy, vol. 3, no. 2, pp. 197–205, 2001.
[63]
C. Capparelli, S. Morony, K. Warmington et al., “Sustained antiresorptive effects after a single treatment with human recombinant osteoprotegerin (OPG): a pharmacodynamic and pharmacokinetic analysis in rats,” Journal of Bone and Mineral Research, vol. 18, no. 5, pp. 852–858, 2003.
[64]
M. S. Ominsky, P. J. Kostenuik, P. Cranmer, S. Y. Smith, and J. E. Atkinson, “The RANKL inhibitor OPG-Fc increases cortical and trabecular bone mass in young gonad-intact cynomolgus monkeys,” Osteoporosis International, vol. 18, no. 8, pp. 1073–1082, 2007.
[65]
P. J. Bekker, D. Holloway, A. Nakanishi, M. Arrighi, P. T. Leese, and C. R. Dunstan, “The effect of a single dose of osteoprotegerin in postmenopausal women,” Journal of Bone and Mineral Research, vol. 16, no. 2, pp. 348–360, 2001.
[66]
M. R. McClung, E. M. Lewiecki, S. B. Cohen et al., “Denosumab in postmenopausal women with low bone mineral density,” The New England Journal of Medicine, vol. 354, no. 8, pp. 821–831, 2006.
[67]
S. R. Cummings, J. S. Martin, M. R. McClung et al., “Denosumab for prevention of fractures in postmenopausal women with osteoporosis,” The New England Journal of Medicine, vol. 361, no. 8, pp. 756–765, 2009.
[68]
L. C. Hofbauer, D. L. Lacey, C. R. Dunstan, T. C. Spelsberg, B. L. Riggs, and S. Khosla, “Interleukin-1β and tumor necrosis factor-κ, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells,” Bone, vol. 25, no. 3, pp. 255–259, 1999.
[69]
S. Wei, H. Kitaura, P. Zhou, F. Patrick Ross, and S. L. Teitelbaum, “IL-1 mediates TNF-induced osteoclastogenesis,” Journal of Clinical Investigation, vol. 115, no. 2, pp. 282–290, 2005.
[70]
M. N. Weitzmann, C. Roggia, G. Toraldo, L. Weitzmann, and R. Pacifici, “Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency,” Journal of Clinical Investigation, vol. 110, no. 11, pp. 1643–1650, 2002.
[71]
F. Arai, T. Miyamoto, O. Ohneda et al., “Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor κB (RANK) receptors,” The Journal of Experimental Medicine, vol. 190, no. 12, pp. 1741–1754, 1999.
[72]
R. Pacifici, J. L. Vannice, L. Rifas, and R. B. Kimble, “Monocytic secretion of interleukin-1 receptor antagonist in normal and osteoporotic women: effects of menopause and estrogen/progesterone therapy,” Journal of Clinical Endocrinology and Metabolism, vol. 77, no. 5, pp. 1135–1141, 1993.
[73]
R. B. Kimble, J. L. Vannice, D. C. Bloedow et al., “Interleukin-1 receptor antagonist decreases bone loss and bone resorption in ovariectomized rats,” Journal of Clinical Investigation, vol. 93, no. 5, pp. 1959–1967, 1994.
[74]
R. Kitazawa, R. B. Kimble, J. L. Vannice, V. T. Kung, and R. Pacifici, “Interleukin-1 receptor antagonist and tumor necrosis factor binding protein decrease osteoclast formation and bone resorption in ovariectomized mice,” Journal of Clinical Investigation, vol. 94, no. 6, pp. 2397–2406, 1994.
[75]
R. B. Kimble, A. B. Matayoshi, J. L. Vannice, V. T. Kung, C. Williams, and R. Pacifici, “Simultaneous block of interleukin-1 and tumor necrosis factor is required to completely prevent bone loss in the early postovariectomy period,” Endocrinology, vol. 136, no. 7, pp. 3054–3061, 1995.
[76]
R. B. Kimble, S. Srivastava, F. Patrick Ross, A. Matayoshi, and R. Pacifici, “Estrogen deficiency increases the ability of stromal cells to support murine osteoclastogenesis via an interleukin-1-and tumor necrosis factor-mediated stimulation of macrophage colony-stimulating factor production,” Journal of Biological Chemistry, vol. 271, no. 46, pp. 28890–28897, 1996.
[77]
S. Cenci, M. N. Weitzmann, C. Roggia et al., “Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-α,” Journal of Clinical Investigation, vol. 106, no. 10, pp. 1229–1237, 2000.
[78]
J. Lam, S. Takeshita, J. E. Barker, O. Kanagawa, F. P. Ross, and S. L. Teitelbaum, “TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand,” Journal of Clinical Investigation, vol. 106, no. 12, pp. 1481–1488, 2000.
[79]
K. Fuller, C. Murphy, B. Kirstein, S. W. Fox, and T. J. Chambers, “TNFα potently activates osteoclasts, through a direct action independent of and strongly synergistic with RANKL,” Endocrinology, vol. 143, no. 3, pp. 1108–1118, 2002.
[80]
Y. H. Zhang, A. Heulsmann, M. M. Tondravi, A. Mukherjee, and Y. Abu-Amer, “Tumor necrosis factor-α (TNF) stimulates RANKL-induced osteoclastogenesis via coupling of TNF type 1 receptor and RANK signaling pathways,” Journal of Biological Chemistry, vol. 276, no. 1, pp. 563–568, 2001.
[81]
K. Kobayashi, N. Takahashi, E. Jimi et al., “Tumor necrosis factor α stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction,” The Journal of Experimental Medicine, vol. 191, no. 2, pp. 275–285, 2000.
[82]
K. Redlich, B. G？rtz, S. Hayer 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,” American Journal of Pathology, vol. 164, no. 2, pp. 543–555, 2004.
[83]
N. Saidenberg-Kermanac'H, A. Corrado, D. Lemeiter, M. C. deVernejoul, M. C. Boissier, and M. E. Cohen-Solal, “TNF-α antibodies and osteoprotegerin decrease systemic bone loss associated with inflammation through distinct mechanisms in collagen-induced arthritis,” Bone, vol. 35, no. 5, pp. 1200–1207, 2004.
[84]
A. M. Reimold, “New indications for treatment of chronic inflammation by TNF-α blockade,” American Journal of the Medical Sciences, vol. 325, no. 2, pp. 75–92, 2003.
[85]
B. F. Boyce, L. Xing, G. Franzoso, and U. Siebenlist, “Required and nonessential functions of nuclear factor-kappa B in bone cells,” Bone, vol. 25, no. 1, pp. 137–139, 1999.
[86]
T. J. Hall, M. Schaeublin, H. Jeker, K. Fuller, and T. J. Chambers, “The role of reactive oxygen intermediates in osteoclastic bone resorption,” Biochemical and Biophysical Research Communications, vol. 207, no. 1, pp. 280–287, 1995.
[87]
S. Vaira, T. Johnson, A. C. Hirbe et al., “RelB is the NF-κB subunit downstream of NIK responsible for osteoclast differentiation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 10, pp. 3897–3902, 2008.
[88]
J. Liu, S. Wang, P. Zhang, N. Said-Al-Naief, S. M. Michalek, and X. Feng, “Molecular mechanism of the bifunctional role of lipopolysaccharide in osteoclastogenesis,” Journal of Biological Chemistry, vol. 284, no. 18, pp. 12512–12523, 2009.
[89]
V. Iotsova, J. Caama？o, J. Loy, Y. Yang, A. Lewin, and R. Bravo, “Osteopetrosis in mice lacking NF-κB1 and NF-κB2,” Nature Medicine, vol. 3, no. 11, pp. 1285–1289, 1997.
[90]
K. Strait, Y. Li, D. L. Dillehay, and M. N. Weitzmann, “Suppression of NF-κB activation blocks osteoclastic bone resorption during estrogen deficiency,” International Journal of Molecular Medicine, vol. 21, no. 4, pp. 521–525, 2008.
[91]
R. Feng, G. Anderson, G. Xiao et al., “SDX-308, a nonsteroidal anti-inflammatory agent, inhibits NF-κB activity, resulting in strong inhibition of osteoclast formation/activity and multiple myeloma cell growth,” Blood, vol. 109, no. 5, pp. 2130–2138, 2007.
[92]
J. C. Clohisy, T. Hirayama, E. Frazier, S. K. Han, and Y. Abu-Amer, “NF-κB signaling blockade abolishes implant particle-induced osteoclastogenesis,” Journal of Orthopaedic Research, vol. 22, no. 1, pp. 13–20, 2004.
[93]
S. Dai, T. Hirayama, S. Abbas, and Y. Abu-Amer, “The IκB kinase (IKK) inhibitor, NEMO-binding domain peptide, blocks osteoclastogenesis and bone erosion in inflammatory arthritis,” Journal of Biological Chemistry, vol. 279, no. 36, pp. 37219–37222, 2004.
[94]
X. Lu, P. Farmer, J. Rubin, and M. S. Nanes, “Integration of the NfκB p65 subunit into the vitamin D receptor transcriptional complex: identification of p65 domains that inhibit 1,25-dihydroxyvitamin D3-stimulated transcription,” Journal of Cellular Biochemistry, vol. 92, no. 4, pp. 833–848, 2004.
[95]
L. Gilbert, X. He, P. Farmer et al., “Inhibition of osteoblast differentiation by tumor necrosis factor-α,” Endocrinology, vol. 141, no. 11, pp. 3956–3964, 2000.
[96]
M. S. Nanes, “Tumor necrosis factor-κ: molecular and cellular mechanisms in skeletal pathology,” Gene, vol. 321, no. 1-2, pp. 1–15, 2003.
[97]
E. C. Wahl, J. Aronson, L. Liu et al., “Restoration of regenerative osteoblastogenesis in aged mice: modulation of TNF,” Journal of Bone and Mineral Research, vol. 25, no. 1, pp. 114–123, 2010.
[98]
Y. Li, A. Li, K. Strait, H. Zhang, M. S. Nanes, and M. N. Weitzmann, “Endogenous TNFα lowers maximum peak bone mass and inhibits osteoblastic smad activation through NF-κB,” Journal of Bone and Mineral Research, vol. 22, no. 5, pp. 646–655, 2007.
[99]
M. Wan and X. Cao, “BMP signaling in skeletal development,” Biochemical and Biophysical Research Communications, vol. 328, no. 3, pp. 651–657, 2005.
[100]
E. J. Moerman, K. Teng, D. A. Lipschitz, and B. Lecka-Czernik, “Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: the role of PPAR-γ2 transcription factor and TGF-β/BMP signaling pathways,” Aging Cell, vol. 3, no. 6, pp. 379–389, 2004.
[101]
F. Zhang, T. Qiu, X. Wu et al., “Sustained BMP signaling in osteoblasts stimulates bone formation by promoting angiogenesis and osteoblast differentiation,” Journal of Bone and Mineral Research, vol. 24, no. 7, pp. 1224–1233, 2009.
[102]
S. D. Boden, “The ABCs of BMPs,” Orthop Nurs, vol. 24, pp. 49–52, 2005.
[103]
K. Janssens, P. Ten Dijke, S. Janssens, and W. Van Hul, “Transforming growth factor-β1 to the bone,” Endocrine Reviews, vol. 26, no. 6, pp. 743–774, 2005.
[104]
Y. Tang, X. Wu, W. Lei et al., “TGF-β1-induced migration of bone mesenchymal stem cells couples bone resorption with formation,” Nature Medicine, vol. 15, no. 7, pp. 757–765, 2009.
[105]
N. Selvamurugan, S. Kwok, T. Alliston, M. Reiss, and N. C. Partridge, “Transforming growth factor-β1 regulation of collagenase-3 expression in osteoblastic cells by cross-talk between the Smad and MAPK signaling pathways and their components, Smad2 and Runx2,” Journal of Biological Chemistry, vol. 279, no. 18, pp. 19327–19334, 2004.
[106]
S. Spinella-Jaegle, S. Roman-Roman, C. Faucheu et al., “Opposite effects of bone morphogenetic protein-2 and transforming growth factor-β1 on osteoblast differentiation,” Bone, vol. 29, no. 4, pp. 323–330, 2001.
[107]
J. Gebken, A. Feydt, J. Brinckmann, H. Notbohm, P. K. Müller, and B. B？tge, “Ligand-induced downregulation of receptors for TGF-β in human osteoblast-like cells from adult donors,” Journal of Endocrinology, vol. 161, no. 3, pp. 503–510, 1999.
[108]
Y. Takeuchi, M. Suzawa, T. Kikuchi, E. Nishida, T. Fujita, and T. Matsumoto, “Differentiation and transforming growth factor-β receptor down-regulation by collagen-α2β1 integrin interaction is mediated by focal adhesion kinase and its downstream signals in murine osteoblastic cells,” Journal of Biological Chemistry, vol. 272, no. 46, pp. 29309–29316, 1997.
[109]
R. A. Eliseev, E. M. Schwarz, M. J. Zuscik, R. J. O'Keefe, H. Drissi, and R. N. Rosier, “Smad7 mediates inhibition of Saos2 osteosarcoma cell differentiation by NFκB,” Experimental Cell Research, vol. 312, no. 1, pp. 40–50, 2006.
[110]
R. Guo, M. Yamashita, Q. Zhang et al., “Ubiquitin ligase Smurf1 mediates tumor necrosis factor-induced systemic bone loss by promoting proteasomal degradation of bone morphogenetic signaling proteins,” Journal of Biological Chemistry, vol. 283, no. 34, pp. 23084–23092, 2008.
[111]
T. Mukai, F. Otsuka, H. Otani et al., “TNF-α inhibits BMP-induced osteoblast differentiation through activating SAPK/JNK signaling,” Biochemical and Biophysical Research Communications, vol. 356, no. 4, pp. 1004–1010, 2007.
[112]
M. Yamaguchi and M. N. Weitzmann, “The estrogen 17β-estradiol and phytoestrogen genistein mediate differential effects on osteoblastic NF-κB activity,” International Journal of Molecular Medicine, vol. 23, no. 2, pp. 297–301, 2009.
[113]
J. Chang, Z. Wang, E. Tang et al., “Inhibition of osteoblastic bone formation by nuclear factor-κB,” Nature Medicine, vol. 15, no. 6, pp. 682–689, 2009.
[114]
M. Yamaguchi and M. N. Weitzmann, “Vitamin K2 stimulates osteoblastogenesis and suppresses osteoclastogenesis by suppressing NF-κB activation,” International Journal of Molecular Medicine, vol. 27, no. 1, pp. 3–14, 2011.
[115]
M. Yamaguchi, J. L. Arbiser, and M. N. Weitzmann, “Honokiol stimulates osteoblastogenesis by suppressing NF-κB activation,” International Journal of Molecular Medicine, vol. 28, pp. 1049–1053, 2011.
[116]
M. Yamaguchi and M. N. Weitzmann, “Zinc stimulates osteoblastogenesis and suppresses osteoclastogenesis by antagonizing NF-κB activation,” Molecular and Cellular Biochemistry, vol. 355, pp. 179–186, 2011.
[117]
M. Yamaguchi and M. N. Weitzmann, “The bone anabolic carotenoids p-hydroxycinnamic acid and β-cryptoxanthin antagonize NF-κB activation in MC3T3 preosteoblasts,” Molecular Medicine Reports, vol. 2, no. 4, pp. 641–644, 2009.
[118]
M. Yamaguchi and M. N. Weitzmann, “The bone anabolic carotenoid p-hydroxycinnamic acid promotes osteoblast mineralization and suppresses osteoclast differentiation by antagonizing NF-κB activation,” International Journal of Molecular Medicine, vol. 30, no. 3, pp. 708–712, 2012.
[119]
J. Xiong, M. Onal, R. L. Jilka, R. S. Weinstein, S. C. Manolagas, and C. A. O'Brien, “Matrix-embedded cells control osteoclast formation,” Nature Medicine, vol. 17, pp. 1235–1241, 2011.
[120]
D. A. Corral, M. Amling, M. Priemel et al., “Dissociation between bone resorption and bone formation in osteopenic transgenic mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 23, pp. 13835–13840, 1998.
[121]
M. C. Horowitz, A. L. M. Bothwell, D. G. T. Hesslein, D. L. Pflugh, and D. G. Schatz, “B cells and osteoblast and osteoclast development,” Immunological Reviews, vol. 208, pp. 141–153, 2005.
[122]
M. Onal, J. Xiong, X. Chen et al., “Receptor activator of nuclear factor kappaB ligand (RANKL) protein expression by B lymphocytes contributes to ovariectomy-induced bone loss,” The Journal of Biological Chemistry, vol. 287, pp. 29851–29860, 2012.
[123]
T. Nakashima, M. Hayashi, T. Fukunaga et al., “Evidence for osteocyte regulation of bone homeostasis through RANKL expression,” Nature Medicine, vol. 17, pp. 1231–1234, 2011.
[124]
M. N. Weitzmann, S. Cenci, L. Rifas, J. Haug, J. Dipersio, and R. Pacifici, “T cell activation induces human osteoclast formation via receptor activator of nuclear factor κB ligand-dependent and -independent mechanisms,” Journal of Bone and Mineral Research, vol. 16, no. 2, pp. 328–337, 2001.
[125]
M. N. Weitzmann, S. Cenci, L. Rifas, C. Brown, and R. Pacifici, “Interleukin-7 stimulates osteoclast formation by up-regulating the T-cell production of soluble osteoclastogenic cytokines,” Blood, vol. 96, no. 5, pp. 1873–1878, 2000.
[126]
L. Rifas and M. N. Weitzmann, “A novel T cell cytokine, secreted osteoclastogenic factor of activated T cells, induces osteoclast formation in a RANKL-independent manner,” Arthritis and Rheumatism, vol. 60, no. 11, pp. 3324–3335, 2009.
[127]
L. Rifas, R. Civitelli, and L. V. Avioli, “Activated T cells stimulate IL-6 production by human osteoblasts via soluble factors and cell contact,” Journal of Bone and Mineral Research, vol. 12, p. S436, 1998.
[128]
J. R. Edwards, S. G. Sun, R. Locklin et al., “LIGHT (TNFSF14), a novel mediator of bone resorption, is elevated in rheumatoid arthritis,” Arthritis and Rheumatism, vol. 54, no. 5, pp. 1451–1462, 2006.
[129]
D. M. Shinar and G. A. Rodan, “Biphasic effects of transforming growth factor-β on the production of osteoclast-like cells in mouse bone marrow cultures: the role of prostaglandins in the generation of these cells,” Endocrinology, vol. 126, no. 6, pp. 3153–3158, 1990.
[130]
R. J. Sells Galvin, C. L. Gatlin, J. W. Horn, and T. R. Fuson, “TGF-β enhances osteoclast differentiation in hematopoietic cell cultures stimulated with RANKL and M-CSF,” Biochemical and Biophysical Research Communications, vol. 265, no. 1, pp. 233–239, 1999.
[131]
N. J. Horwood, V. Kartsogiannis, J. M. W. Quinn, E. Romas, T. J. Martin, and M. T. Gillespie, “Activated T lymphocytes support osteoclast formation in vitro,” Biochemical and Biophysical Research Communications, vol. 265, no. 1, pp. 144–150, 1999.
[132]
C. Chenu, J. Pfeilschifter, G. R. Mundy, and G. D. Roodman, “Transforming growth factor β inhibits formation of osteoclast-like cells in long-term human marrow cultures,” Proceedings of the National Academy of Sciences of the United States of America, vol. 85, no. 15, pp. 5683–5687, 1988.
[133]
D. E. Hughes, A. Dai, J. C. Tiffee, H. H. Li, G. R. Munoy, and B. F. Boyce, “Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-β,” Nature Medicine, vol. 2, no. 10, pp. 1132–1135, 1996.
[134]
M. N. Weitzmann, S. Cenci, J. Haug, C. Brown, J. DiPersio, and R. Pacifici, “B lymphocytes inhibit human osteoclastogenesis by secretion of TGFbeta,” Journal of Cellular Biochemistry, vol. 78, pp. 318–324, 2000.
[135]
H. Takai, M. Kanematsu, K. Yano et al., “Transforming growth factor-β stimulates the production of osteoprotegerin/osteoclastogenesis inhibitory factor by bone marrow stromal cells,” Journal of Biological Chemistry, vol. 273, no. 42, pp. 27091–27096, 1998.
[136]
J. M. W. Quinn, K. Itoh, N. Udagawa et al., “Transforming growth factor β affects osteoclast differentiation via direct and indirect actions,” Journal of Bone and Mineral Research, vol. 16, no. 10, pp. 1787–1794, 2001.
[137]
Y. Gao, W. P. Qian, K. Dark et al., “Estrogen prevents bone loss through transforming growth factor β signaling in T cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 47, pp. 16618–16623, 2004.
[138]
I. Itonaga, A. Sabokbar, S. G. Sun et al., “Transforming growth factor-β induces osteoclast formation in the absence of RANKL,” Bone, vol. 34, no. 1, pp. 57–64, 2004.
[139]
T. J. Yun, P. M. Chaudhary, G. L. Shu et al., “OPG/FDCR-1, a TNF receptor family member, is expressed in lymphoid cells and is up-regulated by ligating CD40,” Journal of Immunology, vol. 161, no. 11, pp. 6113–6121, 1998.
[140]
Y. Li, G. Toraldo, A. Li et al., “B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo,” Blood, vol. 109, no. 9, pp. 3839–3848, 2007.
[141]
D. Grcevic, S. K. Lee, A. Marusic, and J. A. Lorenzo, “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,” Journal of Immunology, vol. 165, no. 8, pp. 4231–4238, 2000.
[142]
E. Lopez-Granados, S. T. Temmerman, L. Wu et al., “Osteopenia in X-linked hyper-IgM syndrome reveals a regulatory role for CD40 ligand in osteoclastogenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 12, pp. 5056–5061, 2007.
[143]
P. Tebas, W. G. Powderly, S. Claxton et al., “Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy,” AIDS, vol. 14, no. 4, pp. F63–F67, 2000.
[144]
K. Mondy and P. Tebas, “Emerging bone problems in patients infected with human immunodeficiency virus,” Clinical Infectious Diseases, vol. 36, no. 2, pp. S101–S105, 2003.
[145]
K. Mondy, K. Yarasheski, W. G. Powderly et al., “Longitudinal evolution of bone mineral density and bone markers in human immunodeficiency virus-infected individuals,” Clinical Infectious Diseases, vol. 36, no. 4, pp. 482–490, 2003.
[146]
J. S. Huang, S. J. Wilkie, M. P. Sullivan, and S. Grinspoon, “Reduced bone density in androgen-deficient women with acquired immune deficiency syndrome wasting,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 8, pp. 3533–3539, 2001.
[147]
M. J. Bolland and A. Grey, “HIV and low bone density: responsible party, or guilty by association?” IBMS BoneKEy, vol. 8, pp. 7–15, 2011.
[148]
S. E. Dolan, J. S. Huang, K. M. Killilea, M. P. Sullivan, N. Aliabadi, and S. Grinspoon, “Reduced bone density in HIV-infected women,” AIDS, vol. 18, no. 3, pp. 475–483, 2004.
[149]
J. Thomas and S. M. Doherty, “HIV infection—a risk factor for osteoporosis,” Journal of Acquired Immune Deficiency Syndromes, vol. 33, no. 3, pp. 281–291, 2003.
[150]
G. A. McComsey, P. Tebas, E. Shane et al., “Bone disease in HIV infection: a practical review and recommendations for HIV care providers,” Clinical Infectious Diseases, vol. 51, no. 8, pp. 937–946, 2010.
[151]
T. T. Brown and R. B. Qaqish, “Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review,” AIDS, vol. 20, no. 17, pp. 2165–2174, 2006.
[152]
S. L. Hui, C. W. Slemenda, and C. C. Johnston, “Age and bone mass as predictors of fracture in a prospective study,” Journal of Clinical Investigation, vol. 81, no. 6, pp. 1804–1809, 1988.
[153]
World Health Organization, “Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group,” World Health Organization Technical Report Series, vol. 843, pp. 1–129, 1994.
[154]
S. H. Abbasi-Jahromi, A. Matayoshi, R. Kimble, A. Dimarogonas, and R. Pacifici, “Bone quality factor analysis: a new noninvasive technique for the measurement of bone density and bone strength,” Journal of Bone and Mineral Research, vol. 11, no. 5, pp. 594–599, 1996.
[155]
V. Amorosa and P. Tebas, “Bone disease and HIV infection,” Clinical Infectious Diseases, vol. 42, no. 1, pp. 108–114, 2006.
[156]
G. Guaraldi, P. Ventura, M. Albuzza et al., “Pathological fractures in AIDS patients with osteopenia and osteoporosis induced by antiretroviral therapy,” AIDS, vol. 15, no. 1, pp. 137–138, 2001.
[157]
V. A. Triant, T. T. Brown, H. Lee, and S. K. Grinspoon, “Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 9, pp. 3499–3504, 2008.
[158]
J. H. Arnsten, R. Freeman, A. A. Howard, M. Floris-Moore, Y. Lo, and R. S. Klein, “Decreased bone mineral density and increased fracture risk in aging men with or at risk for HIV infection,” AIDS, vol. 21, no. 5, pp. 617–623, 2007.
[159]
J. Prior, D. Burdge, E. Maan et al., “Fragility fractures and bone mineral density in HIV positive women: a case-control population-based study,” Osteoporosis International, vol. 18, no. 10, pp. 1345–1353, 2007.
[160]
J. A. Womack, J. L. Goulet, C. Gibert et al., “Increased risk of fragility fractures among HIV infected compared to uninfected male veterans,” PLoS ONE, vol. 6, no. 2, Article ID e17217, 2011.
[161]
B. Young, C. N. Dao, K. Buchacz, R. Baker, and J. T. Brooks, “Increased rates of bone fracture among HIV-infected persons in the HIV outpatient study (HOPS) compared with the US general population, 2000-2006,” Clinical Infectious Diseases, vol. 52, no. 8, pp. 1061–1068, 2011.
[162]
M. T. Yin, Q. Shi, D. R. Hoover et al., “Fracture incidence in HIV-infected women: results from the Women's Interagency HIV Study,” AIDS, vol. 24, no. 17, pp. 2679–2686, 2010.
[163]
S. Desai and A. Landay, “Early immune senescence in HIV disease,” Current HIV/AIDS Reports, vol. 7, no. 1, pp. 4–10, 2010.
[164]
A. De Milito, “B lymphocyte dysfunctions in HIV infection,” Current HIV Research, vol. 2, no. 1, pp. 11–21, 2004.
[165]
S. Moir, J. Ho, A. Malaspina et al., “Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals,” The Journal of Experimental Medicine, vol. 205, no. 8, pp. 1797–1805, 2008.
[166]
M. Morrow, A. Valentin, R. Little, R. Yarchoan, and G. N. Pavlakis, “A splenic marginal zone-like peripheral blood CD27+B220？ B cell population is preferentially depleted in HIV type 1-infected individuals,” AIDS Research and Human Retroviruses, vol. 24, no. 4, pp. 621–633, 2008.
[167]
W. Reid, M. Sadowska, F. Denaro et al., “An HIV-1 transgenic rat that develops HIV-related pathology and immunologic dysfunction,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 16, pp. 9271–9276, 2001.
[168]
N. Manabe, H. Kawaguchi, H. Chikuda et al., “Connection between B lymphocyte and osteoclast differentiation pathways,” Journal of Immunology, vol. 167, no. 5, pp. 2625–2631, 2001.
[169]
T. Kawai, T. Matsuyama, Y. Hosokawa et al., “B and T lymphocytes are the primary sources of RANKL in the bone resorptive lesion of periodontal disease,” American Journal of Pathology, vol. 169, no. 3, pp. 987–998, 2006.
[170]
M. Kanematsu, T. Sato, H. Takai, K. Watanabe, K. Ikeda, and Y. Yamada, “Prostaglandin E2 induces expression of receptor activator of nuclear factor-κB ligand/osteoprotegrin ligand on pre-B cells: implications for accelerated osteoclastogenesis in estrogen deficiency,” Journal of Bone and Mineral Research, vol. 15, no. 7, pp. 1321–1329, 2000.
[171]
T. Vikulina, X. Fan, M. Yamaguchi et al., “Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 31, pp. 13848–13853, 2010.
[172]
S. G. Deeks, “HIV infection, inflammation, immunosenescence, and aging,” Annual Review of Medicine, vol. 62, pp. 141–155, 2011.
[173]
S. G. Deeks, “Immune dysfunction, inflammation, and accelerated aging in patients on antiretroviral therapy,” Topics in HIV Medicine, vol. 17, no. 4, pp. 118–123, 2009.
[174]
J. M. Brenchley, D. A. Price, T. W. Schacker et al., “Microbial translocation is a cause of systemic immune activation in chronic HIV infection,” Nature Medicine, vol. 12, no. 12, pp. 1365–1371, 2006.
[175]
W. Zou and Z. Bar-Shavit, “Dual modulation of osteoclast differentiation by lipopolysaccharide,” Journal of Bone and Mineral Research, vol. 17, no. 7, pp. 1211–1218, 2002.
[176]
C. Duvivier, S. Kolta, L. Assoumou et al., “Greater decrease in bone mineral density with protease inhibitor regimens compared with nonnucleoside reverse transcriptase inhibitor regimens in HIV-1 infected naive patients,” AIDS, vol. 23, no. 7, pp. 817–824, 2009.
[177]
A. B. Hansen, N. Obel, H. Nielsen, C. Pedersen, and J. Gerstoft, “Bone mineral density changes in protease inhibitor-sparing vs. nucleoside reverse transcriptase inhibitor-sparing highly active antiretroviral therapy: data from a randomized trial,” HIV Medicine, vol. 12, no. 3, pp. 157–165, 2011.
[178]
K. Briot, S. Kolta, P. Flandre et al., “Prospective one-year bone loss in treatment-na？ve HIV+ men and women on single or multiple drug HIV therapies,” Bone, vol. 48, pp. 1133–1139, 2011.
[179]
M. G. A. van Vonderen, P. Lips, M. A. van Agtmael et al., “First line zidovudine/lamivudine/lopinavir/ritonavir leads to greater bone loss compared to nevirapine/lopinavir/ritonavir,” AIDS, vol. 23, no. 11, pp. 1367–1376, 2009.
[180]
P. Rivas, M. Górgolas, R. García-Delgado, M. Díaz-Curiel, A. Goyenechea, and M. L. Fernández-Guerrero, “Evolution of bone mineral density in AIDS patients on treatment with zidovudine/lamivudine plus abacavir or lopinavir/ritonavir,” HIV Medicine, vol. 9, no. 2, pp. 89–95, 2008.
[181]
J. Fernández-Rivera, R. García, F. Lozano et al., “Relationship between low bone mineral density and highly active antiretroviral therapy including protease inhibitors in HIV-infected patients,” HIV Clinical Trials, vol. 4, no. 5, pp. 337–346, 2003.
[182]
M. W. H. Wang, S. Wei, R. Faccio et al., “The HIV protease inhibitor ritonavir blocks osteoclastogenesis and function by impairing RANKL-induced signaling,” Journal of Clinical Investigation, vol. 114, no. 2, pp. 206–213, 2004.
[183]
J. M. Fakruddin and J. Laurence, “HIV envelope gp120-mediated regulation of osteoclastogenesis via receptor activator of nuclear factor κB ligand (RANKL) secretion and its modulation by certain HIV protease inhibitors through interferon-γ/RANKL cross-talk,” Journal of Biological Chemistry, vol. 278, no. 48, pp. 48251–48258, 2003.
[184]
D. P. Wanner, A. Tyndall, and U. A. Walker, “Tenofovir-induced osteomalacia,” Clinical and Experimental Rheumatology, vol. 27, no. 6, pp. 1001–1003, 2009.
[185]
G. Pan, X. Wu, M. A. McKenna, X. Feng, T. R. Nagy, and J. M. McDonald, “AZT enhances osteoclastogenesis and bone loss,” AIDS Research and Human Retroviruses, vol. 20, no. 6, pp. 608–620, 2004.
[186]
G. Pan, M. Kilby, and J. M. McDonald, “Modulation of osteoclastogenesis induced by nucleoside reverse transcriptase inhibitors,” AIDS Research and Human Retroviruses, vol. 22, no. 11, pp. 1131–1141, 2006.
[187]
T. T. Brown, G. A. McComsey, M. S. King, R. B. Qaqish, B. M. Bernstein, and B. A. Da Silva, “Loss of bone mineral density after antiretroviral therapy initiation, independent of antiretroviral regimen,” Journal of Acquired Immune Deficiency Syndromes, vol. 51, no. 5, pp. 554–561, 2009.
[188]
D. Bruera, N. Luna, D. O. David, L. M. Bergoglio, and J. Zamudio, “Decreased bone mineral density in HIV-infected patients is independent of antiretroviral therapy,” AIDS, vol. 17, no. 13, pp. 1917–1923, 2003.
[189]
J. E. Gallant, S. Staszewski, A. L. Pozniak et al., “Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial,” Journal of the American Medical Association, vol. 292, no. 2, pp. 191–201, 2004.
[190]
H. J. Stellbrink, C. Orkin, J. R. Arribas et al., “Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study,” Clinical Infectious Diseases, vol. 51, no. 8, pp. 963–972, 2010.
[191]
J. M. Franco, A. Rubio, M. Martínez-Moya et al., “T-cell repopulation and thymic volume in HIV-1-infected adult patients after highly active antiretroviral therapy,” Blood, vol. 99, no. 10, pp. 3702–3706, 2002.
[192]
R. C. Kalayjian, J. Spritzler, M. Pu et al., “Distinct mechanisms of T cell reconstitution can be identified by estimating thymic volume in adult HIV-1 disease,” Journal of Infectious Diseases, vol. 192, no. 9, pp. 1577–1587, 2005.
[193]
M. R. Ryan, R. Shepherd, J. K. Leavey et al., “An IL-7-dependent rebound in thymic T cell output contributes to the bone loss induced by estrogen deficiency,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 46, pp. 16735–16740, 2005.
[194]
J. Wactawski-Wende, S. G. Grossi, M. Trevisan et al., “The role of osteopenia in oral bone loss and periodontal disease,” Journal of Periodontology, vol. 67, no. 10, pp. 1076–1084, 1996.
[195]
B. Klausen, H. P. Hougen, and N. E. Fiehn, “Increased periodontal bone loss in temporarily B lymphocyte-deficient rats,” Journal of Periodontal Research, vol. 24, no. 6, pp. 384–390, 1989.
[196]
Y. Choi and J. J. Kim, “B cells activated in the presence of Th1 cytokines inhibit osteoclastogenesis,” Experimental and Molecular Medicine, vol. 35, no. 5, pp. 385–392, 2003.
[197]
M. A. Taubman and T. Kawai, “Involvement of T-lymphocytes in periodontal disease and in direct and indirect induction of bone resorption,” Critical Reviews in Oral Biology and Medicine, vol. 12, no. 2, pp. 125–135, 2001.
[198]
T. Crotti, M. D. Smith, R. Hirsch et al., “Receptor activator NF κB ligand (RANKL) and osteoprotegerin (OPG) protein expression in periodontitis,” Journal of Periodontal Research, vol. 38, no. 4, pp. 380–387, 2003.
[199]
G. Brunetti, S. Colucci, P. Pignataro et al., “T cells support osteoclastogenesis in an in vitro model derived from human periodontitis patients,” Journal of Periodontology, vol. 76, no. 10, pp. 1675–1680, 2005.
[200]
S. Colucci, G. Mori, G. Brunetti et al., “Interleukin-7 production by B lymphocytes affects the T cell-dependent osteoclast formation in an in vitro model derived from human periodontitis patients,” International Journal of Immunopathology and Pharmacology, vol. 18, no. 3, pp. 13–19, 2005.
[201]
G. Mori, G. Brunetti, S. Collucci et al., “Osteoblast apoptosis in periodontal disease: role of TNF-related apoptosis-inducing ligand,” International Journal of Immunopathology and Pharmacology, vol. 22, no. 1, pp. 95–103, 2009.
[202]
M. Feldmann, F. M. Brennan, and R. N. Maini, “Rheumatoid arthritis,” Cell, vol. 85, no. 3, pp. 307–310, 1996.
[203]
J. C. W. Edwards, L. Szczepański, J. Szechiński et al., “Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis,” The New England Journal of Medicine, vol. 350, no. 25, pp. 2572–2581, 2004.
[204]
G. Schett and J. P. David, “The multiple faces of autoimmune-mediated bone loss,” Nature Reviews Endocrinology, vol. 6, no. 12, pp. 698–706, 2010.
[205]
C. Fournier, “Where do T cells stand in rheumatoid arthritis?” Joint Bone Spine, vol. 72, no. 6, pp. 527–532, 2005.
[206]
Y. Y. Kong, U. Felge, I. Sarosi et al., “Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand,” Nature, vol. 402, no. 6759, pp. 304–309, 1999.
[207]
X. He, A. H. Kang, and J. M. Stuart, “Anti-human type II collagen CD19+ B cells are present in patients with rheumatoid arthritis and healthy individuals,” Journal of Rheumatology, vol. 28, no. 10, pp. 2168–2175, 2001.
[208]
K. Yanaba, Y. Hamaguchi, G. M. Venturi, D. A. Steeber, S. Clair, and T. F. Tedder, “B cell depletion delays collagen-induced arthritis in mice: arthritis induction requires synergy between humoral and cell-mediated immunity,” Journal of Immunology, vol. 179, no. 2, pp. 1369–1380, 2007.
[209]
P. Li and E. M. Schwarz, “The TNF-α transgenic mouse model of inflammatory arthritis,” Springer Seminars in Immunopathology, vol. 25, no. 1, pp. 19–33, 2003.
[210]
G. Schett, K. Redlich, S. Hayer et al., “Osteoprotegerin protects against generalized bone loss in tumor necrosis factor-transgenic mice,” Arthritis and Rheumatism, vol. 48, no. 7, pp. 2042–2051, 2003.
[211]
R. Fleischmann, I. Iqbal, P. Nandeshwar, and A. Quiceno, “Safety and efficacy of disease-modifying anti-rheumatic agents: focus on the benefits and risks of etanercept,” Drug Safety, vol. 25, no. 3, pp. 173–197, 2002.
[212]
J. K. Jenkins and K. J. Hardy, “Biological modifier therapy for the treatment of rheumatoid arthritis,” American Journal of the Medical Sciences, vol. 323, no. 4, pp. 197–205, 2002.
[213]
A. M. Reimold, “TNFalpha as therapeutic target: new drugs, more applications,” Current Drug Targets: Inflammation & Allergy, vol. 1, pp. 377–392, 2002.
[214]
N. T. Ilowite, “Update on biologics in juvenile idiopathic arthritis,” Current Opinion in Rheumatology, vol. 20, no. 5, pp. 613–618, 2008.
[215]
M. Natsumeda, K. Nishiya, and Z. Ota, “Stimulation by interleukin-7 of mononuclear cells in peripheral blood, synovial fluid and synovial tissue from patients with rheumatoid arthritis,” Acta Medica Okayama, vol. 47, no. 6, pp. 391–397, 1993.
[216]
F. De Benedetti, M. Massa, P. Pignatti, M. Kelley, C. R. Faltynek, and A. Martini, “Elevated circulating interleukin-7 levels in patients with systemic juvenile rheumatoid arthritis,” Journal of Rheumatology, vol. 22, no. 8, pp. 1581–1585, 1995.
[217]
L. Leistad, M. ？stensen, and A. Faxvaag, “Detection of cytokine mRNA in human, articular cartilage from patients with rheumatoid arthritis and osteoarthritis by reverse transcriptase-polymerase chain reaction,” Scandinavian Journal of Rheumatology, vol. 27, no. 1, pp. 61–67, 1998.
[218]
S. Harada, M. Yamamura, H. Okamoto et al., “Production of interleukin-7 and interleukin-15 by fibroblast-like synoviocytes from patients with rheumatoid arthritis,” Arthritis & Rheumatism, vol. 42, pp. 1508–1516, 1999.
[219]
S. Colucci, G. Brunetti, F. P. Cantatore et al., “Lymphocytes and synovial fluid fibroblasts support osteoclastogenesis through RANKL, TNFα, and IL-7 in an in vitro model derived from human psoriatic arthritis,” Journal of Pathology, vol. 212, no. 1, pp. 47–55, 2007.
[220]
S. M. Churchman and F. Ponchel, “Interleukin-7 in rheumatoid arthritis,” Rheumatology, vol. 47, no. 6, pp. 753–759, 2008.
[221]
S. A. Y. Hartgring, C. R. Willis, D. Alcorn 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 and Rheumatism, vol. 62, no. 9, pp. 2716–2725, 2010.
[222]
E. Lubberts, “IL-17/Th17 targeting: on the road to prevent chronic destructive arthritis?” Cytokine, vol. 41, no. 2, pp. 84–91, 2008.
[223]
S. Kotake, N. Udagawa, N. Takahashi et al., “IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis,” Journal of Clinical Investigation, vol. 103, no. 9, pp. 1345–1352, 1999.
[224]
E. Lubberts, L. Van den Bersselaar, B. Oppers-Walgreen et al., “IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of the receptor activator of NF-κB ligand/osteoprotegerin balance1,” Journal of Immunology, vol. 170, no. 5, pp. 2655–2662, 2003.
[225]
K. Zwerina, M. Koenders, A. Hueber et al., “Anti IL-17A therapy inhibits bone loss in TNF-α-mediated murine arthritis by modulation of the T-cell balance,” European Journal of Immunology, vol. 42, no. 2, pp. 413–423, 2012.
[226]
B. L. Riggs, S. Khosla, and L. J. Melton, “Sex steroids and the construction and conservation of the adult skeleton,” Endocrine Reviews, vol. 23, no. 3, pp. 279–302, 2002.
[227]
J. A. Clowes, B. L. Riggs, and S. Khosla, “The role of the immune system in the pathophysiology of osteoporosis,” Immunological Reviews, vol. 208, pp. 207–227, 2005.
[228]
C. Roggia, Y. Gao, S. Cenci 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,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 24, pp. 13960–13965, 2001.
[229]
S. Cenci, G. Toraldo, M. N. Weitzmann et al., “Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-γ-induced class II transactivator,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 18, pp. 10405–10410, 2003.
[230]
M. N. Weitzmann and R. Pacifici, “Role of the immune system in postmenopausal bone loss,” Current Osteoporosis Reports, vol. 3, no. 3, pp. 92–97, 2005.
[231]
M. N. Weitzmann and R. Pacifici, “Estrogen regulation of immune cell bone interactions,” Annals of the New York Academy of Sciences, vol. 1068, no. 1, pp. 256–274, 2006.
[232]
Y. Gao, F. Grassi, M. R. Ryan et al., “IFN-γ stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation,” Journal of Clinical Investigation, vol. 117, no. 1, pp. 122–132, 2007.
[233]
F. Grassi, G. Tell, M. Robbie-Ryan et al., “Oxidative stress causes bone loss in estrogen-deficient mice through enhanced bone marrow dendritic cell activation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 38, pp. 15087–15092, 2007.
[234]
M. N. Weitzmann and R. Pacifici, “T cells: unexpected players in the bone loss induced by estrogen deficiency and in basal bone homeostasis,” Annals of the New York Academy of Sciences, vol. 1116, pp. 360–375, 2007.
[235]
J. Y. Li, H. Tawfeek, B. Bedi et al., “Ovariectomy disregulates osteoblast and osteoclast formation through the T-cell receptor CD40 ligand,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 2, pp. 768–773, 2011.
[236]
T. Masuzawa, C. Miyaura, Y. Onoe et al., “Estrogen deficiency stimulates B lymphopoiesis in mouse bone marrow,” Journal of Clinical Investigation, vol. 94, no. 3, pp. 1090–1097, 1994.
[237]
M. C. Erlandsson, C. A. Jonsson, U. Islander, C. Ohlsson, and H. Carlsten, “Oestrogen receptor specificity in oestradiol-mediated effects on B lymphopoiesis and immunoglobulin production in male mice,” Immunology, vol. 108, no. 3, pp. 346–351, 2003.
[238]
C. Miyaura, Y. Onoe, M. Inada et al., “Increased B-lymphopoiesis by interleukin 7 induces bone loss in mice with intact ovarian function: similarity to estrogen deficiency,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 17, pp. 9360–9365, 1997.
[239]
T. Sato, T. Shibata, K. Ikeda, and K. Watanabe, “Generation of bone-resorbing osteoclasts from B220+ cells: its role in accelerated osteoclastogenesis due to estrogen deficiency,” Journal of Bone and Mineral Research, vol. 16, no. 12, pp. 2215–2221, 2001.
[240]
G. Toraldo, C. Roggia, W. P. Qian, R. Pacific, and M. N. Weitzmann, “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,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 1, pp. 125–130, 2003.
[241]
S. K. Lee, J. F. Kalinowski, S. L. Jastrzebski, L. Puddington, and J. A. Lorenzo, “Interleukin-7 is a direct inhibitor of in vitro osteoclastogenesis,” Endocrinology, vol. 144, no. 8, pp. 3524–3531, 2003.
[242]
G. Eghbali-Fatourechi, S. Khosla, A. Sanyal, W. J. Boyle, D. L. Lacey, and B. L. Riggs, “Role of RANK ligand in mediating increased bone resorption in early postmenopausal women,” Journal of Clinical Investigation, vol. 111, no. 8, pp. 1221–1230, 2003.
[243]
Y. Li, A. Li, X. Yang, and M. N. Weitzmann, “Ovariectomy-induced bone loss occurs independently of B cells,” Journal of Cellular Biochemistry, vol. 100, no. 6, pp. 1370–1375, 2007.
[244]
T. J. Fry and C. L. Mackall, “Interleukin-7: master regulator of peripheral T-cell homeostasis?” Trends in Immunology, vol. 22, no. 10, pp. 564–571, 2001.
[245]
M. Robbie-Ryan, R. Pacifici, and M. N. Weitzmann, “IL-7 drives T cell-mediated bone loss following ovariectomy,” Annals of the New York Academy of Sciences, vol. 1068, no. 1, pp. 348–351, 2006.
[246]
M. Utsuyama and K. Hirokawa, “Hypertrophy of the thymus and restoration of immune functions in mice and rats by gonadectomy,” Mechanisms of Ageing and Development, vol. 47, no. 3, pp. 175–185, 1989.
[247]
J. Pido-Lopez, N. Imami, and R. Aspinall, “Both age and gender affect thymic output: more recent thymic migrants in females than males as they age,” Clinical and Experimental Immunology, vol. 125, no. 3, pp. 409–413, 2001.
[248]
M. K. Lindberg, J. Svensson, K. Venken et al., “Liver-derived IGF-I is permissive for ovariectomy-induced trabecular bone loss,” Bone, vol. 38, no. 1, pp. 85–92, 2006.
[249]
S. K. Lee, J. F. Kalinowski, C. Jacquin, D. J. Adams, G. Gronowicz, and J. A. Lorenzo, “Interleukin-7 influences osteoclast function in vivo but is not a critical factor in ovariectomy-induced bone loss,” Journal of Bone and Mineral Research, vol. 21, no. 5, pp. 695–702, 2006.
[250]
H. L. Aguila, S. H. Mun, J. Kalinowski, D. J. Adams, J. A. Lorenzo, and S. K. Lee, “Osteoblast-specific overexpression of human interleukin-7 rescues the bone mass phenotype of interleukin-7-deficient female mice,” Journal of Bone and Mineral Research, vol. 27, pp. 1030–1042, 2012.
[251]
H. O. Valenzona, R. Pointer, R. Ceredig, and D. G. Osmond, “Prelymphomatous B cell hyperplasia in the bone marrow of interleukin-7 transgenic mice: precursor B cell dynamics, microenvironmental organization and osteolysis,” Experimental Hematology, vol. 24, no. 13, pp. 1521–1529, 1996.
[252]
D. Salopek, D. Gr？evi？, V. Katavi？, N. Kova？i？, I. K. Luki？, and A. Maru？i？, “Increased bone resorption and osteopenia are a part of the lymphoproliferative phenotype of mice with systemic over-expression of interleukin-7 gene driven by MHC class II promoter,” Immunology Letters, vol. 121, no. 2, pp. 134–139, 2008.
[253]
A. Huston and G. D. Roodman, “Role of the microenvironment in multiple myeloma bone disease,” Future Oncology, vol. 2, no. 3, pp. 371–378, 2006.
[254]
N. Giuliani, S. Colla, R. Sala et al., “Human myeloma cells stimulate the receptor activator of nuclear factor-κB ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease,” Blood, vol. 100, no. 13, pp. 4615–4621, 2002.
[255]
N. Giuliani, S. Colla, F. Morandi et al., “Myeloma cells block RUNX2/CBFA1 activity in human bone marrow osteoblast progenitors and inhibit osteoblast formation and differentiation,” Blood, vol. 106, no. 7, pp. 2472–2483, 2005.
[256]
S. D'Souza, D. del Prete, S. Jin et al., “Gfi1 expressed in bone marrow stromal cells is a novel osteoblast suppressor in patients with multiple myeloma bone disease,” Blood, vol. 118, no. 26, pp. 6871–6880, 2011.
[257]
R. B. Kimble, S. Bain, and R. Pacifici, “The functional block of TNF but not of IL-6 prevents bone loss in ovariectomized mice,” Journal of Bone and Mineral Research, vol. 12, no. 6, pp. 935–941, 1997.
[258]
A. M. Tyagi, K. Srivastava, K. Sharan, D. Yadav, R. Maurya, and D. Singh, “Daidzein prevents the increase in CD4+CD28null T cells and B lymphopoesis in ovariectomized mice: a key mechanism for anti-osteoclastogenic effect,” PLoS ONE, vol. 6, no. 6, Article ID e21216, 2011.
[259]
F. Gori, L. C. Hofbauer, C. R. Dunstan, T. C. Spelsberg, S. Khosla, and B. Lawrence Riggs, “The expression of osteoprotegerin and RANK ligand and the support of osteoclast formation by stromal-osteoblast lineage cells is developmentally regulated,” Endocrinology, vol. 141, no. 12, pp. 4768–4776, 2000.
[260]
B. J. Kim, S. J. Bae, S. Y. Lee et al., “TNF-α mediates the stimulation of sclerostin expression in an estrogen-deficient condition,” Biochemical and Biophysical Research Communications, vol. 424, no. 1, pp. 170–175, 2012.
[261]
M. H. Sayegh, “Finally, CTLA4Ig graduates to the clinic,” Journal of Clinical Investigation, vol. 103, no. 9, pp. 1223–1225, 1999.
[262]
A. Muhlethaler-Mottet, W. D. Berardino, L. A. Otten, and B. Mach, “Activation of the MHC class II transactivator CIITA by interferon-γ requires cooperative interaction between Stat1 and USF-1,” Immunity, vol. 8, no. 2, pp. 157–166, 1998.
[263]
B. Ernst, D. S. Lee, J. M. Chang, J. Sprent, and C. D. Surh, “The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery,” Immunity, vol. 11, no. 2, pp. 173–181, 1999.
[264]
C. Tanchot, F. A. Lemonnier, B. Pérarnau, A. A. Freitas, and B. Rocha, “Differential requirements for survival and proliferation of CD8 naive or memory T cells,” Science, vol. 276, no. 5321, pp. 2057–2062, 1997.
[265]
C. D. Surh and J. Sprent, “Homeostasis of naive and memory T cells,” Immunity, vol. 29, no. 6, pp. 848–862, 2008.
[266]
H. Takayanagi, K. Ogasawara, S. Hida et al., “T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ,” Nature, vol. 408, no. 6812, pp. 600–605, 2000.
[267]
M. Pang, A. F. Martinez, J. Jacobs, W. Balkan, and B. R. Troen, “RANK ligand and interferon gamma differentially regulate cathepsin gene expression in pre-osteoclastic cells,” Biochemical and Biophysical Research Communications, vol. 328, no. 3, pp. 756–763, 2005.
[268]
G. N. Mann, T. W. Jacobs, F. J. Buchinsky et al., “Interferon-γ causes loss of bone volume in vivo and fails to ameliorate cyclosporin A-induced osteopenia,” Endocrinology, vol. 135, no. 3, pp. 1077–1083, 1994.
[269]
G. Duque, D. C. Huang, N. Dion et al., “Interferon-γ plays a role in bone formation in vivo and rescues osteoporosis in ovariectomized mice,” Journal of Bone and Mineral Research, vol. 26, no. 7, pp. 1472–1483, 2011.
[270]
R. M. Rodriguiz, L. L. Key, and W. L. Ries, “Combination macrophage-colony stimulating factor and interferon-γ administration ameliorates the osteopetrotic condition in microphthalmic (mi/mi) mice,” Pediatric Research, vol. 33, no. 4, pp. 384–389, 1993.
[271]
L. L. Key, R. M. Rodriguiz, S. M. Willi et al., “Long-term treatment of osteopetrosis with recombinant human interferon gamma,” The New England Journal of Medicine, vol. 332, no. 24, pp. 1594–1599, 1995.
[272]
P. R. Madyastha, S. U. Yang, W. L. Ries, and L. L. Key Jr., “IFN-γ enhances osteoclast generation cultures of peripheral blood from osteopetrotic patients and normalizes superoxide production,” Journal of Interferon and Cytokine Research, vol. 20, no. 7, pp. 645–652, 2000.
[273]
W. Huang, R. J. O'Keefe, and E. M. Schwarz, “Exposure to receptor-activator of NFκB ligand renders pre-osteoclasts resistant to IFN-γ by inducing terminal differentiation,” Arthritis Research & Therapy, vol. 5, no. 1, pp. R49–59, 2003.
[274]
T. Yamaza, Y. Miura, Y. Bi et al., “Pharmacologic stem cell based intervention as a new approach to osteoporosis treatment in rodents,” PLoS ONE, vol. 3, no. 7, Article ID e2615, 2008.
[275]
S. K. Lee, Y. Kadono, F. Okada et al., “T lymphocyte-deficient mice lose trabecular bone mass with ovariectomy,” Journal of Bone and Mineral Research, vol. 21, no. 11, pp. 1704–1712, 2006.
[276]
W. A. Goodman, K. D. Cooper, and T. S. McCormick, “Regulation generation: the suppressive functions of human regulatory T cells,” Critical Reviews in Immunology, vol. 32, no. 1, pp. 65–79, 2012.
[277]
Y. G. Kim, C. K. Lee, S. S. Nah, S. H. Mun, B. Yoo, and H. B. Moon, “Human CD4+CD25+ regulatory T cells inhibit the differentiation of osteoclasts from peripheral blood mononuclear cells,” Biochemical and Biophysical Research Communications, vol. 357, no. 4, pp. 1046–1052, 2007.
[278]
C. Y. Luo, L. Wang, C. Sun, and D. J. Li, “Estrogen enhances the functions of CD4+CD25+Foxp3+ regulatory T cells that suppress osteoclast differentiation and bone resorption in vitro,” Cellular and Molecular Immunology, vol. 8, no. 1, pp. 50–58, 2011.
[279]
K. Wing, T. Yamaguchi, and S. Sakaguchi, “Cell-autonomous and -non-autonomous roles of CTLA-4 in immune regulation,” Trends in Immunology, vol. 32, pp. 428–433, 2011.
[280]
M. M. Zaiss, R. Axmann, J. Zwerina et al., “Treg cells suppress osteoclast formation: a new link between the immune system and bone,” Arthritis and Rheumatism, vol. 56, no. 12, pp. 4104–4112, 2007.
[281]
R. Axmann, S. Herman, M. Zaiss et al., “CTLA-4 directly inhibits osteoclast formation,” Annals of the Rheumatic Diseases, vol. 67, no. 11, pp. 1603–1609, 2008.
[282]
J. Goswami, N. Hernández-Santos, L. A. Zuniga, and S. L. Gaffen, “A bone-protective role for IL-17 receptor signaling in ovariectomy-induced bone loss,” European Journal of Immunology, vol. 39, no. 10, pp. 2831–2839, 2009.
[283]
A. M. Tyagi, K. Srivastava, M. N. Mansoori, R. Trivedi, N. Chattopadhyay, and D. Singh, “Estrogen deficiency induces the differentiation of IL-17 secreting Th17 cells: a new candidate in the pathogenesis of osteoporosis,” PLoS ONE, vol. 7, Article ID e44552, 2012.
[284]
S. C. Manolagas, “From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis,” Endocrine Reviews, vol. 31, no. 3, pp. 266–300, 2010.
[285]
S. C. Manolagas and M. Almeida, “Gone with the Wnts: β-catenin, T-cell factor, forkhead box O, and oxidative stress in age-dependent diseases of bone, lipid, and glucose metabolism,” Molecular Endocrinology, vol. 21, no. 11, pp. 2605–2614, 2007.
[286]
J. M. Lean, J. T. Davies, K. Fuller et al., “A crucial role for thiol antioxidants in estrogen-deficiency bone loss,” Journal of Clinical Investigation, vol. 112, no. 6, pp. 915–923, 2003.
[287]
J. M. Lean, C. J. Jagger, B. Kirstein, K. Fuller, and T. J. Chambers, “Hydrogen peroxide is essential for estrogen-deficiency bone loss and osteoclast formation,” Endocrinology, vol. 146, no. 2, pp. 728–735, 2005.
[288]
S. Kantengwa, L. Jornot, C. Devenoges, and L. P. Nicod, “Superoxide anions induce the maturation of human dendritic cells,” American Journal of Respiratory and Critical Care Medicine, vol. 167, no. 3, pp. 431–437, 2003.
[289]
E. Bjorgo and K. Tasken, “Novel mechanism of signaling by CD28,” Immunology Letters, vol. 129, pp. 1–6, 2010.
[290]
P. D'Amelio, A. Grimaldi, S. Di Bella et al., “Estrogen deficiency increases osteoclastogenesis up-regulating T cells activity: a key mechanism in osteoporosis,” Bone, vol. 43, no. 1, pp. 92–100, 2008.
[291]
J. S. Lindberg and S. M. Moe, “Nephrology-specific issues in women's health osteoporosis in end-stage renal disease,” Seminars in Nephrology, vol. 19, no. 2, pp. 115–122, 1999.
[292]
H. Tawfeek, B. Bedi, J. Y. Li et al., “Disruption of PTH receptor 1 in t cells protects against PTH-induced bone loss,” PLoS ONE, vol. 5, no. 8, Article ID e12290, 2010.
[293]
S. Nishida, A. Yamaguchi, T. Tanizawa et al., “Increased bone formation by intermittent parathyroid hormone administration is due to the stimulation of proliferation and differentiation of osteoprogenitor cells in bone marrow,” Bone, vol. 15, no. 6, pp. 717–723, 1994.
[294]
A. B. Hodsman, D. C. Bauer, D. W. Dempster et al., “Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use,” Endocrine Reviews, vol. 26, no. 5, pp. 688–703, 2005.
[295]
E. C. Weir, C. W. G. M. Lowik, I. Paliwal, and K. L. Insogna, “Colony stimulating factor-1 plays a role in osteoclast formation and function in bone resorption induced by parathyroid hormone and parathyroid hormone-related protein,” Journal of Bone and Mineral Research, vol. 11, no. 10, pp. 1474–1481, 1996.
[296]
Y. L. Ma, R. L. Cain, D. L. Halladay et al., “Catabolic effects of continuous human PTH (1-38) in vivo is associated with sustained stimulation of RANKL and inhibition of osteoprotegerin and gene-associated bone formation,” Endocrinology, vol. 142, no. 9, pp. 4047–4054, 2001.
[297]
B. G. Hory, M. C. Roussanne, S. Rostand, A. Bourdeau, T. B. Drüeke, and J. Gogusev, “Absence of response to human parathyroid hormone in athymic mice grafted with human parathyroid adenoma, hyperplasia or parathyroid cells maintained in culture,” Journal of Endocrinological Investigation, vol. 23, no. 5, pp. 273–279, 2000.
[298]
T. J. Rosol, C. C. Capen, and R. L. Horst, “Effects of infusion of human parathyroid hormone-related protein-(1-40) in nude mice: histomorphometric and biochemical investigations,” Journal of Bone and Mineral Research, vol. 3, no. 6, pp. 699–706, 1988.
[299]
H. E. Alten and P. Groscurth, “The postnatal development of the ovary in the “nude” mouse,” Anatomy and Embryology, vol. 148, no. 1, pp. 35–46, 1975.
[300]
H. Nagasawa and R. Yanai, “Mammary growth and function and pituitary prolactin secretion in female nude mice,” Acta Endocrinologica, vol. 86, no. 4, pp. 794–802, 1977.
[301]
Y. Gao, X. Wu, M. Terauchi et al., “T cells potentiate PTH-induced cortical bone loss through CD40L signaling,” Cell Metabolism, vol. 8, no. 2, pp. 132–145, 2008.
[302]
B. Bedi, J. Y. Li, F. Grassi, H. Tawfeek, M. N. Weitzmann, and R. Pacifici, “Inhibition of antigen presentation and T cell costimulation blocks PTH-induced bone loss,” Annals of the New York Academy of Sciences, vol. 1192, pp. 215–221, 2010.
[303]
R. M. Neer, C. D. Arnaud, J. R. Zanchetta et al., “Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis,” The New England Journal of Medicine, vol. 344, no. 19, pp. 1434–1441, 2001.
[304]
I. U. Schmidt, H. Dobnig, and R. T. Turner, “Intermittent parathyroid hormone treatment increases osteoblast number, steady state messenger ribonucleic acid levels for osteocalcin, and bone formation in tibial metaphysis of hypophysectomized female rats,” Endocrinology, vol. 136, no. 11, pp. 5127–5134, 1995.
[305]
H. Dobnig and R. T. Turner, “Evidence that intermittent treatment with parathyroid hormone increases bone formation in adult rats by activation of bone lining cells,” Endocrinology, vol. 136, no. 8, pp. 3632–3638, 1995.
[306]
G. J. Pettway, J. A. Meganck, A. J. Koh, E. T. Keller, S. A. Goldstein, and L. K. McCauley, “Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation,” Bone, vol. 42, no. 4, pp. 806–818, 2008.
[307]
R. L. Jilka, “Molecular and cellular mechanisms of the anabolic effect of intermittent PTH,” Bone, vol. 40, no. 6, pp. 1434–1446, 2007.
[308]
R. L. Jilka, R. S. Weinstein, T. Bellido, P. Roberson, A. M. Parfitt, and S. C. Manolagas, “Increased bone formation byprevention of osteoblast apoptosis with parathyroid hormone,” Journal of Clinical Investigation, vol. 104, no. 4, pp. 439–446, 1999.
[309]
T. Bellido, A. A. Ali, L. I. Plotkin et al., “Proteasomal degradation of Runx2 shortens parathyroid hormone-induced anti-apoptotic signaling in osteoblasts: a putative explanation for why intermittent administration is needed for bone anabolism,” Journal of Biological Chemistry, vol. 278, no. 50, pp. 50259–50272, 2003.
[310]
P. V. N. Bodine and B. S. Komm, “Wnt signaling and osteoblastogenesis,” Reviews in Endocrine & Metabolic Disorders, vol. 7, no. 1-2, pp. 33–39, 2006.
[311]
T. Bellido, A. A. Ali, I. Gubrij et al., “Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis,” Endocrinology, vol. 146, no. 11, pp. 4577–4583, 2005.
[312]
G. Hardiman, S. Albright, J. I. Tsunoda, T. McClanahan, and F. Lee, “The mouse Wnt-10B gene isolated from helper T cells is widely expressed and a possible oncogene in BR6 mouse mammary tumorigenesis,” Gene, vol. 172, no. 2, pp. 199–205, 1996.
[313]
Y. Ouji, M. Yoshikawa, A. Shiroi, and S. Ishizaka, “Wnt-10b secreted from lymphocytes promotes differentiation of skin epithelial cells,” Biochemical and Biophysical Research Communications, vol. 342, no. 4, pp. 1063–1069, 2006.
[314]
M. Terauchi, J. Y. Li, B. Bedi et al., “T lymphocytes amplify the anabolic activity of parathyroid hormone through Wnt10b signaling,” Cell Metabolism, vol. 10, no. 3, pp. 229–240, 2009.
[315]
B. Bedi, J. Y. Li, H. Tawfeek et al., “Silencing of parathyroid hormone (PTH) receptor 1 in T cells blunts the bone anabolic activity of PTH,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 12, pp. E725–E733, 2012.
[316]
J. J. Goronzy and C. M. Weyand, “T-cell senescence and contraction of T-cell repertoire diversity—catalysts of autoimmunity and chronic inflammation,” Arthritis Research and Therapy, vol. 5, no. 5, pp. 225–234, 2003.
[317]
A. N. Vallejo, M. Schirmer, C. M. Weyand, and J. J. Goronzy, “Clonality and longevity of CD4+CD28(null) T cells are associated with defects in apoptotic pathways,” Journal of Immunology, vol. 165, no. 11, pp. 6301–6307, 2000.
[318]
M. H. Weisman, “What are the risks of biologic therapy in rheumatoid arthritis? An update on safety,” Journal of Rheumatology, vol. 29, no. 65, pp. 33–38, 2002.
