Osteoimmunology


Authors: O. Růžičková
Authors‘ workplace: Revmatologický ústav Praha
Published in: Čes. Revmatol., 20, 2012, No. 4, p. 181-197.
Category: Overview Reports

Overview

The skeleton forms the supporting structure of the muscular system, protects internal organs, is a site of hematopoiesis and participates in maintaining homeostasis of the human body. Bone tissue serves as storage of calcium and phosphorus that is able to participate in maintaining homeostasis if necessary. The skeleton is living tissue, which undergoes changes during the entire life. Remodeling, consisting of bone resorption and formation, thus facilitates adaptation of the skeleton to actual needs of the organism and repairs the microtrauma. Loss of bone mass accompanies several diseases such as chronic infectious diseases, rheumatoid arthritis, leukemia, postmenopausal osteoporosis, bone metastases etc. Bone remodeling, which includes bone resorption mediated by osteoclasts followed by deposition of new bone produced by osteoblasts, occurs on the surface of all bones according to actual needs. Bone remodeling is a process, which takes place in basic multicellular units at particular sites of the bone surface only. It is a continuous process, comprising bone resorption and formation, which enables regeneration of the bone while preserving its structure. Differentiation and activation of osteoblasts and osteoclasts is regulated by transcription factors, cytokines and growth factors, which are produced either locally by osseous cells or by systemic factors. RANKL/RANK interaction has a crucial role in the differentiation and survival of osteoclasts. OPG and RANKL have a key role in linking the function of osteoblasts and osteoclasts. Thus they have become a target of potential pharmacologic treatment of bone resorption. Upon binding of RANKL to RANK, a signal cascade regulating the differentiation and activation of osteoclasts is activated. RANKL-RANK stimulation is essential for the induction of osteoclastogenesis. Other signaling pathways may only modulate this dominant signaling cascade in a positive or negative way. OPG cannot affect the inflammatory activity of the disease. However, it can prevent the development of erosions and joint destruction. The effect of OPG is associated with the regulation of bone turnover. Bone remodeling and bone loss are controlled by the RANKL-RANK-OPG axis. RANKL is also produced by T cells as a response to antigenic stimulus. These T cells can also participate in the development and activation of osteoclasts. Thus, immune cells take part in bone metabolism both in health and the presence of inflammatory or autoimmune diseases such as rheumatoid arthritis. The development of denosumab, a human monoclonal antibody against RANKL, is a new, highly effective approach in the prevention of fragile osteoporotic fractures, skeletal complications of tumorous diseases and bone erosions in rheumatoid arthritis. Blockade of RANKL/RANK signaling does not lead to an immune dysfunction. Inhibition of RANKL does not affect the inflammatory reactions mediated by T cells in rheumatoid arthritis.

Key words:
osteoporosis, rheumatoid arthritis, bone remodeling, RANK, RANKL, OPG, denosumab


Sources

1. Kanis JA, Burles N, Cooper C, et al. European Guyance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 2008 Apr; 19(4):399-428.

2. Boyle WJ, Simonet WS, Lacey DL: Osteoclast differentiation and activation. Nature 2003; 423:337-341.

3. Hofbauer LC, Schoppet M: Clinical implications of the osteoprotegerin/RANKL/RANK systém for bone and vascular diseases. JAMA 2004;292:490-495.

4. Hsu H, Lacey DL, Dunstan CR, et al. Tumor necrosis factor receptor family member RANK mediates osteoclasts differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA 1999;96:3540-3545.

5. Reid P., Holen I. Pathophysiological role sof osteoprotegerin (OPG)European Journal of Cell Biology. 2009; 88: 1-17.

6. Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: a novel secreted protein invelved in the regulativ of bone density. Cell 1997; 89: 309-319.

7. Tsuda E.,GOTO M., Mochizuki S., et al. Isolation of novel cytosine from human fibroblasts that specifically inhibic osteoclastogenesis. Biochem. Biophys. Res.Commun. 1997; 234: 137-143.

8. Viereck V., Grundker C., Blaschke S., et al. Raloxifene concurrently stimulans osteoprotegerin and inhibic interleukin 6 production by human trabecular osteoblasts. J Clin Endorinol Metab 2003; 88: 4206- 4213.

9. Viereck V., Emons G., Lauck V., et al. Bisphosphonates pamidronate and zoledronic acid stimulate osteoprotegerin production by primary human osteoblasts. Biochem Biophys Res Commun 2002; 291: 680-686.

10. Hofbauer LC., Gori F., Riggs BL., et al. Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential parafine mechanisms of glucocorticoids-induced osteoporosis. Endocrinology 1999; 140: 4382-4389.

11. Takayanagi H., Iizuka H., Juji T., et al. Involment of receptor activator of nuclear factor kappa B ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum. 2000; 43:259-269.

12. Schett G., Middleton S., Bolon B., et al. Additive bone protective effect of anabolic treatment hen used in conjuction with RANKL and tumor necrosis factor inhibition in two rat arthritis models. Arthritis Rheum. 2005; 52: 1604 – 1611.

13. Whyte MP. Pagets disease of bone and genetic disorders of RANKL/OPG/RANK/NF- kappaB signaling. Ann NY Acad Sci. 2006; 1068: 143-164.

14. Mezquita-Raya P., de la Higuera M., Garcia DF., et al. The contribution of serum osteoprotegerin to bene mass and vertebral fractures in postmenopausal women. Osteoporosis Int 2005; 16: 1368-1374.

15. Dobnig H., Hofbauer LC., Viereck V., et al. Changes in the RANK ligand/osteoprotegerin systém are correlated to ganges in bone mineral density in bisphosphonate-traeted osteoporotic pacients. Osteoporosis Int 2006;17: 693-703.

16. Messalli EM., Mainini G., Scaffa C., et al. Raloxifene therapy interacts with serum osteoprotegerin in postmenopausal women. Maturitas 2007;56: 38-44.

17. Martini G., Gennari L., Merlotti D., et al. Serum OPG and RANKL levels efore and after intravenous bisphosphonate treatment in Pagets disease of bone. Bone 2007; 40: 457-463.

18. Feuerherm AJ., Borset M.,Seidel C., et al.Elevated levels of osteoprotegerin ( OPG) and hepatocyte growth factor (HGF) in rheumatoid arthritis. Scand J Rheumatol. 2001; 30:229-234.

19. Geusens PP., Landewe RB., Garnero P., et al. The ratio of circulating osteoprotegerin to RANKL in early rheumatoid arthritis predicts later joint destruction. Arthritis Rheum. 2006;54: 1772-1777.

20. Leibbrandt A., Penninger JM. RANK/RANKL:Regulators of Immune Responses and Bone Physiology. Ann.N.Y. Acad.Sci.2008;1143:123-150.

21. Anderson, D.M. et al. 1997. A homologue of the TNF receptor and its ligand enhance T-cell growthand dendritic-cell function. Nature 390: 175–179.

22. Wong, B.R. et al. 1997. 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.

23. Lacey, D.L. et al. 1998. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93: 165–176.

24. Yasuda, H. et al. 1998. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc. Natl. Acad. Sci. USA 95: 3597–3602.

25. Wong, B.R. et al. 1997. 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.

26. Kartsogiannis, V. et al. 1999. Localization of RANKL (receptor activator of NF kappa B ligand) mRNA and protein in skeletal and extraskeletal tissues. Bone 25: 525–534.

27. Fata, J.E. et al. 2000. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103: 41–50.

28. Loser, K. et al. 2006. Epidermal RANKL controls regulatoryT-cell numbers via activation of dendritic cells. Nat. Med. 12: 1372–1379.

29. Schlondorff, J., L. Lum & C.P. Blobel. 2001. Biochemical and pharmacological criteria define two shedding activities for TRANCE/OPGL that are distinct from the tumor necrosis factor alpha convertase. J. Biol. Chem. 276: 14665–14674.

30. Chesneau, V. et al. 2003. Catalytic properties of ADAM19. J. Biol. Chem. 278: 22331–22340.

31. Lynch, C.C. et al. 2005. MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Can. Cell 7: 485–496.

32. Fata, J.E. et al. 2000. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103: 41–50.

33. Nakagawa, N. et al. 1998. RANK is the essential signaling receptor for osteoclast differentiation factor in

34. Williamson, E., J.M. Bilsborough & J.L. Viney. 2002. Regulation of mucosal dendritic cell fiction by receptor activator of NF-kappa B (RANK)/RANK ligand interactions: impact on tolerance induction. J. Immunol. 169: 3606–3612.

35. Gonzalez-Suarez, E. et al. 2007. RANK overexpression in transgenic mice with mouse mammary tumor virus promoter-controlled RANK increases proliferation and impairs alveolar differentiation in the mammary epithelia and disrupts lumen formativ in cultured epithelial acini. Mol. Cell Biol. 27: 1442–1454.

36. Simonet, W.S. et al. 1997. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89: 309–319.

37. Theill, L.E., W.J. Boyle & J.M. Penninger. 2002. RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu. Rev. Immunol. 20: 795–823.

38. Kong, Y.Y. et al. 1999. OPGL is a key regulator of osteo­clastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397: 315–323.

39. Li, J. et al. 2000. RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and kalcium metabolism. Proc. Natl. Acad. Sci. USA 97: 1566– 1571.

40. Bucay, N. et al. 1998. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes. Dev. 12: 1260–1268.

41. Mizuno, A. et al. 1998. Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/ osteoprotegerin. Biochem. Biophys. Res. Commun. 247: 610–615.

42. Hughes, A.E. et al. 2000. Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat. Genet. 24: 45–48.

43. Whyte, M.P. et al. 2000. Expansile skeletal hyperphosphatasia: a new familial metabolic bone disease. J. Bone. Miner. Res. 15: 2330–2344.

44. Whyte, M.P. & A.E. Hughes. 2002. Expansile skeletal hyperphosphatasia is caused by a 15-base pair tandem duplication in TNFRSF11A encoding RANK and is allelic to familial expansile osteolysis. J. Bone. Miner. Res. 17: 26–29.

45. Cundy, T. et al. 2002. A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype. Hum. Mol. Genet. 11: 2119–2127.

46. Chong, B. et al. 2003. Idiopathic hyperphosphatasia and TNFRSF11B mutations: relationships between phenotype and genotype. J. Bone. Miner. Res. 18:2095–2104.

47. Darnay, B.G. et al. 1998. Characterization of the intracellular domain of receptor activator of NFkappaB (RANK). Interaction with tumor necrosis factor receptor-associated factors and activation of NF-kappab and c-Jun N-terminal kinase. J. Biol. Chem. 273: 20551–20555.

48. Wong, B.R. et al. 1998. The TRAF family of signal transducers mediates NF-kappaB activation by the TRANCE receptor. J. Biol. Chem. 273: 28355–28359.

49. Wong, B.R., R. Josien & Y. Choi. 1999. TRANCE is a TNF family member that regulates dendritic cell and osteoclast function. J. Leukoc. Biol. 65: 715–724.

50. Galibert, L. et al. 1998. The involvement ofmultiple tumor necrosis factor receptor (TNFR)-associated factors in the signaling mechanisms of receptor activator of NF-kappaB, a member of the TNFR superfamily. J. Biol. Chem. 273: 34120–34127.

51. Lee, Z.H. et al. 2000. Activation of c-Jun N-terminal kinase and activator protein 1 by receptor activator of nuclear factor kappa B. Mol. Pharmacol. 58: 1536–1545.

52. Ruocco, M.G. et al. 2005. I{kappa}B kinase (IKK){beta}, but not IKK{alpha}, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss. J. Exp. Med. 201: 1677–1687.

53. David, J.P. et al. 2002. JNK1 modulates osteoclastogenesis through both c-Jun phosphorylationdependent and -independent mechanisms. J. Cell Sci. 115: 4317–4325.

54. Wagner, E.F. 2002. Functions of AP1 (Fos/Jun) in bone development. Ann. Rheum. Dis. 61(Suppl 2): ii40–ii42.

55. Yamamoto, A. et al. 2002. Possible involvement of IkappaB kinase 2 and MKK7 in osteoclastogenesis induced by receptor activator of nuclear factor kappaB ligand. J. Bone. Miner. Res. 17: 612–621.

56. Kenner, L. et al. 2004. Mice lacking JunB are osteopenic due to cell-autonomous osteoblast and osteoclast defects. J. Cell Biol. 164: 613–623.

57. Takayanagi, H. et al. 2002. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev. Cell. 3: 889–901.

58. Takayanagi, H. 2007. Osteoimmunology: Sharp mechanisms and crosstalk between the immune and bone systems. Nat. Rev. Immunol. 7: 292–304.

59. Mao, D. et al. 2006. PLCgamma2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2. J. Clin. Invest. 116: 2869–2879.

60. Takayanagi, H. et al. 2000. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature 408: 600–605.

61. Takayanagi, H. et al. 2002. RANKLmaintains bone homeostasis through c-Fos-dependent induction of interferon-beta. Nature 416: 744–749.

62. Abu-Amer, Y. 2001. IL-4 abrogates osteoclastogenesis through STAT6-dependent inhibition of NFkappaB. J. Clin. Invest. 107: 1375–1385.

63. Koseki, T. et al. 2002. Role of TGF-beta family in osteoclastogenesis induced by RANKL. Cell Signal. 14: 31–36.

64. Dougall, W.C. et al. 1999. RANK is essential for osteoclast and lymph node development. Genes. Dev. 13: 2412–2424.

65. Kong, Y.Y. et al. 1999. OPGL is a key regulátor of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397: 315–323.

66. Li, J. et al. 2000. RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc. Natl. Acad. Sci. USA 97: 1566– 1571.

67. Koni, P.A. et al. 1997. Distinct roles in lymphoid organogenesis for lymphotoxins alpha and beta revealed in lymphotoxin beta-deficient mice. Immunity 6: 491–500.

68. Alimzhanov, M.B. et al. 1997. Abnormal development of secondary lymphoid tissues in lymphotoxin beta-deficient mice. Proc. Natl. Acad. Sci. USA 94: 9302–9307.

69. Sobacchi, C. et al. 2007. Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat. Genet. 39: 960–962.

70. Fu, Y.X. & D.D. Chaplin. 1999. Development and maturation of secondary lymphoid tissues. Annu. Rev. Immunol. 17: 399–433.

71. Mebius, R.E. 2003. Organogenesis of lymphoid tissues. Nat. Rev. Immunol. 3: 292–303.

72. Kim, D. et al. 2000. Regulation of peripheral lymph node genesis by the tumor necrosis factor family member TRANCE. J. Exp. Med. 192: 1467–1478.

73. Lacey, D.L. et al. 1998. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93: 165–176.

74. Yasuda, H. et al. 1998. Osteoclast differentiation factor is a ligand for osteoprotegerin/ osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc. Natl. Acad. Sci. USA 95:3597–3602.

75. Josien, R. et al. 2000. TRANCE, a tumor necrosis factor family member, enhances the longevity and adjuvant properties of dendritic cells in vivo. J. Exp. Med. 191: 495–502.

76. Bachmann, M.F. et al. 1999. TRANCE, a tumor necrosis factor family member critical for CD40 ligand-independent T helper cell activation. J. Exp. Med. 189: 1025–1031.

77. Fata, J.E. et al. 2000. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103: 41–50.

78. Hofbauer, L.C. et al. 1999. Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. Endocrinology 140:4367–4370.

79. Starr, T.K., S.C. Jameson & K.A. Hogquist. 2003.Positive and negative selection of T cells. Annu. Rev. Immunol. 21: 139–176.

80. Kyewski, B. & L. Klein. 2006. A central role for central tolerance. Annu. Rev. Immunol. 24: 571–606.

81. Sakaguchi, S. 2005. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat. Immunol.6: 345–352.

82. Steinman, R.M., D. Hawiger &M.C. Nussenzweig. 2003.Tolerogenic dendritic cells. Annu. Rev. Immunol. 21: 685–711.

83. Loser, K. et al. 2006. Epidermal RANKL controls regulatoryT-cell numbers via activation of dendritic cells. Nat. Med. 12: 1372–1379.

84. Kong, Y.Y. et al. 1999. Activated T cells regulace bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402: 304–309.

85. Feldmann, M., F.M. Brennan & R.N. Maini. 1996. Rheumatoid arthritis. Cell 85: 307–310.

86. Panayi,G.S., J.S. Lanchbury&G.H. Kingsley. 1992.The importance of the T cell in initiating and maintaining the chronic synovitis of rheumatoid arthritis. Arthritis. Rheum. 35: 729–735.

87. Campagnuolo, G., B. Bolon & U. Feige. 2002. Kinetics of bone protection by recombinant osteoprotegerin therapy in Lewis rats with adjuvant arthritis. Arthritis. Rheum. 46: 1926–1936.

88. Bolon, B., G. Campagnuolo & U. Feige. 2002. Duration of bone protection by a single osteoprotegerin injection in rats with adjuvant-induced arthritis. Cell Mol. Life Sci. 59: 1569–1576.

89. Keffer, J. et al. 1991. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 10: 4025–4031.

90. Mori, H. et al. 2002. RANK ligand, RANK, and OPG expression in type II collagen-induced arthritis mouse. Histochem. Cell Biol. 117: 283–292.

91. Redlich, K. et al. 2002. Tumor necrosis factor alphamediated joint destruction is inhibited by targeting osteoclasts with osteoprotegerin. Arthritis. Rheum. 46:785–792.

92. Romas, E. et al. 2002. Osteoprotegerin reduces osteoclast numbers and prevents bone erosion in collagen-induced arthritis. Am. J. Pathol. 161: 1419–1427.

93. Nakashima, T., T. Wada & J.M. Penninger. 2003. RANKL and RANK as novel therapeutic targets for arthritis. Curr. Opin. Rheumatol. 15: 280–287.

94. Takayanagi, H. et al. 2000. Involvement of receptor activator of nuclear factor kappaB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis. Rheum. 43: 259–269.

95. Oliveri, M.B. et al. 1991. Vertebral compression fractures at the onset of acute lymphoblastic leukemia in a child. Henry Ford. Hosp. Med. J. 39:45–48.

96. Stellon, A.J. et al. 1985. Bone loss in autoimmune chronic active hepatitis on maintenance corticosteroid therapy. Gastroenterology 89: 1078–1083.

97. Ebeling, P.R. et al. 1998. Bone mineral density and bone turnover in asthmatics treated with long-term inhaled or oral glucocorticoids. J. Bone. Miner. Res.13: 1283–1289.

98. Mahamed, D.A. et al. 2005. G(-) anaerobes-reactive CD4+ T-cells trigger RANKL-mediated enhanced alveolar bone loss in diabetic NOD mice. Diabetes 54: 1477–1486.

99. Sato, K. et al. 2006. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J. Exp. Med. 203:2673–2682.

100. Harrington, L.E. et al. 2005. Interleukin 17- producing CD4+ effector T cells develop via a lineage distinct fromtheThelper type 1 and 2 lineages. Nat. Immunol. 6: 1123 –1132.

101. Park, H. et al. 2005. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6: 1133–1141.

102. Dong, C. 2006. Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells. Nat. Rev. Immunol. 6: 329–333.

103. McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006; 354: 821-831.

104. Miller PD, Bolognese MA, Lewiecki EM, et al. Effect of Denosumab on bone density and turnover in postmenopausal women with low bone mass after long term continued, discontinued, and restarting of therapy: a randomized, blinded phase 2clinical trial. Bone 2008;43: 222-229.

105. Bone HG, Bolognese MA, Yuen CK, et al. Effect of Denosumab on bone mineral density and bone turnover in postmenopausal women. J Clin Endocrinol Metab 2008; 93:2149-2157.

106. Brown JP, Prince RL, Deal C, et al. Comparison of the effect of Denosumab and Alendronate on BMD and biochemici markers of bone turnover in postmenopausal women with low bone mass: a randomized blinded, phase 3 trial. J Bone Miner Res 2009; 24: 153-161.

107. Lewiecki EM, Miller PD, McClung MR, et al. AMG 162 Bone Loss Studsy Group. Two year treatment with Denosumab ( AMG 162) in randomised phase 2 study of postmenopausal women with low BMD. J Bone Miner Res 2007; 22: 1832- 1841.

108. Kendler DL, Roux C, Benhamou CL, et al. Effect of Denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy. J Bone Miner Res 2010;25: 72-81.

109. Reid IR, Miller PD, Brown JP, et al. Effect of Denosumab on bone histomorphometry: the FREEDOM and STAND studies. J Bone Miner Res 2010; 25: 2256-2265.

110. Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev. 2000;21: 115-137.

111. Barragan-Adjemian C, Nicolella D, Dusevich V, Dallas MR, Eick JD, Bonewald LF. Mechanism by which MLO-A5 late osteoblasts/early osteocytes mineralize in culture: similarities with mineralization of lamellar bone. Calcif Tissue Int. 2006;79:340-353.

112. Holmbeck K, Bianco P, Pidoux I, et al. The metalloproteinase MT1-MMP is required for normal development and maintenance of osteocyte processes in bone. J Cell Sci. 2005;118:147-156.

113. Wetterwald A, Hoffstetter W, Cecchini MG, et al. Characterization and cloning of the E11 antigen, a marker expressed by rat osteo- blasts and osteocytes. Bone. 1996; 18:125-132.

114. Schulze E, Witt M, Kasper M, Lowik CW, Funk RH. Immunohisto chemical investigations on the differentiation marker protein E11 in rat calvaria, calvaria cell culture and the osteoblastic cell line ROS 17/ 2.8. Histochem Cell Biol. 1999;111:61-69.

115. Zhang K, Barragan-Adjemian C, Ye L, et al. E11/gp38 selective expression in osteocytes: regulation by mechanical strain and role in dendrite elongation. Mol Cell Biol. 2006;26:4539-4552.

116. Guo D, Zhao H, Mishina Y, Feng J, Harris S, Bonewald L. Mice with Targeted Deletion of E11/gp38 in Late Osteoblasts Have Reduced Canaliculi per Osteocyte Which May Be Responsible for The Enhanced Trabecular Bone Volume. FR0268. J Bone Min Res. 2009;S126.

117. Tanaka-Kamioka K, Kamioka H, Ris H, Lim SS. Osteocyte shape is dependent on actin filaments and osteocyte processes are unique actin-rich projections. J Bone Miner Res. 1998;13:1555-1568.

118. Kamioka H, Sugawara Y, HonjoT, YamashiroT.Takano-YamamotoT. Terminal differentiation of osteoblasts to osteocytes is accompanied by dramatic changes in the distribution of actin-binding proteins. J Bone Miner Res. 2004;19:471-478.

119. Verborgt O, Tatton NA, Majeska FU, Schaffler MB. Spatial distribution of Bax and Bcl-2 in osteocytes after bone fatigue: complementary roles in bone remodeling regulation? J Bone Miner Res. 2002;17: 907-914.

120. Kogianni G, Mann V, Noble BS. Apoptotic bodies convey activity capable of initiating osteoclastogenesls and localized bone destruction. J Bone Miner Res. 2008;23:915-927.

121. Weinstein RS, Nicholas RW, Manolagas SC. Apoptosis of osteocytes in glucocorticoid-induced osteonecrosis of the hip. J Clin Endocrinol Metab. 2000;85:2907-2912

122. Bonewald L. Osteocytes. In: Marcus DF R, Nelson D, Rosen C, eds. Osteoporosis, 3rd ed. vol. 1. Elsevier, 2007:169-190.

123. Kitase Y, Barragan L, Jiang JX, Johnson ML, Bonewald LF. Mechanical induction of PGE2 in osteocytes blocks glucocorticoid-induced apoptosis through both the |3-catenin and PKA pathways. J Bone Miner Res. 2010;25. DOI: 10.1002/jbmr.168

124. Poole KE, van Bezooijen RL, Loveridge N, et al. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. Faseb J. 2005;19:1842-1844.

125. van Bezooijen RL, Roelen BA, Visser A, et al. Sclerostin is an osteocyte-expressed negative egulator of bone formation, but not a classical BMP antagonist. J Exp Med. 2004;199:805-814

126. Li X, Zhang Y, Kang H, et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem. 2005;280: 19883-19887.

127. Robling AG, Niziolek PJ, Baldridge LA, et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem. 2008;283:5866-5875.

128. Drake MT, Srinivasan B, Modder Ul, et al. Effects of parathyroid hormone treatment on circulating sclerostin levels in postmeno- pausal women. J Clin Endocrinol Metab. 2010;95:5056-5062.

129. Lewiecki EM. Emerging drugs for postmenopausal osteoporosis. Expert Opin Emerg Drugs. 2009;14:129-144.

130. Padhi D, Jang G, Stouch B, Fang L, Posvar E. Single-dose, placebo- controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res. 2011;26:19-26

131. Zaman G, Jessop HL, Muzylak M, et al. Osteocytes use estrogen receptor alpha to respond to strain but their ERalpha content is regulated by estrogen. J Bone Miner Res. 2006;21:1297-1306.

132. Bonewald LF. Osteocytes as Dynamic, Multifunctional Cells. Ann N Y Acad Sci. 2007;1116:281-290.

133. Thompson DL, Sabbagh Y, Tenenhouse HS, et al. Ontogeny of Phex/PHEX protein expression in mouse embryo and subcellular localization in osteoblasts. J Bone Miner Res. 2002;17:311-320.

134. Nampei A, Hashimoto J, Hayashida K, et al. Matrix extracellular phosphoglycoprotein (MEPE) is highly expressed in osteocytes in human bone. J Bone Miner Metab. 2004;22:176-184.

135. Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD. Pathogenic role of Fgf23 in Hyp mice. Am J Physiol Endocrinol Metab. 2006;291:E38-49.

136. Qing H, Ardeshirpour L, Dusevich V, Wysolmerski J, Bonewald LF.Osteocyte Perilacunar Remodeling Is Regulated Hormonally, but Not by Mechanical Unloading. Journal of Bone & Mineral Research. 2009;supple 1:Mo0255.

137. Potter R, Miller M, Moravits D, et al. Raman spectroscopic characterization of bone tissue material properties around the osteocyte lacuna: effect of aging. J Bone Miner Res. 2009;suppl 1:Su0266.

138. Rubin C. Skeletal strain and the functional significance of bone architecture. Calcif Tissue Int. 1984;36:S11-S18.

139. Turner CH, Forwood MR, Otter MW. Mechanotransduction in bone: do bone cells act as sensors of fluid flow? Faseb J. 1994;8:875-878.

140. Robling AG, Hinant FM, Burr DB, Turner CH. Shorter, more frequent mechanical loading sessions enhance bone mass. Med Sci Sports Exerc. 2002;34:196-202.

141. Seeman E, Delmas PD. Bone quality—the material and structural basis of bone strength and fragility. N Engl J Med 2006;354:2250-61.

142. Roodman CD. Cell biology of the osteoclast. Exp Hematol 1999;27:1229-41.

143. Winkler DG, Sutherland MK, Geoghegan’ JC, Yu C, Hayes T, Skonier JE, et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 2003;22:6267-76.

144. van Bezooijen RL, Roelen BA, Visser A, Wee-Pals L, de Wilt E, Karperien M, et al, Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med 2004;199:805-14.

145. Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, LowikCW, et al. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEBJ 2005;19:1842-4.

146. Elefteriou F. Neuronal signaling and the regulation of bone remodeling. Cell Mol Life Sci 2005;62:2339-49.

147. Karsenty G. Convergence between bone and energy homeostases: leptin regulation of bone mass. Cell Metab 2006;4:341-8.

148. Mansell JP, Collins C, Bailey AJ. Bone, not cartilage, should be the major focus in osteoarthritis. Nat Clin Pract Rheumatol 2007;3:306-7.

149. Elefteriou F, Ahn JD, Talceda S, Starbuck M, Yang X, Liu X, et al. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 2005;434: 514-20.

150. Takayanagi H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol 2007;7:292-304.

151. Eriksen EF, Eghbali-Fatourechi GZ, Khosla S. Remodeling and vascular spaces in bone. J Bone Miner Res 2007; 22:1-6.

152. Kollet O, Dar A. Shivtiel S, Kalinkovich A, Lapid K, Sztainberg Y, et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat Med 2006;12:657-64.

153. Porter RL, Calvi I.M. Communications between bone cells and hematopoietic stem cells. Arch Biochem Biophys 2008;473:193-200.

154. Bonewald LF. Osteocytes: a proposed multifunctional bone cell. J Musculoskelel Neuronal Interact 2002;2:239-41.

155. Parfitt AM. Misconceptions V-activation of osteoclasts is the first step in the bone remodeling cycle. Bone 2006;39: 1170-2.

156. Maejima-lkeda A, Aoki M, Tsuritani K, Kamioka K, Hiura K, Miyoshi T, et al. Chick osteocyte-derived protein inhibits osteoclastic bone resorption. Biochem J 1997;322(Pt 1):245-50.

157. Heino TJ, Hentunen TA, Vaananen HK. Osteocytes inhibit osteoclastic bone resorption through transforming growth factor-beta: enhancement by estrogen. J Cell Biochem 2002;85:185-97.

158. Gu G, Hentunen TA, Nars M, Harkonen PL, Vaananen HK. Estrogen protects primary osteocytes against glucocorticoid-induced apoptosis. Apoptosis 2005;10:583-95.

159. Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, et al. OPGL is a key [64 regulator of osteoclastogenesis. lymphocyte development and lymph-node organogenesis. Nature 1999;397:315-23.

160. Lacey DL, Timms E, Tan HL, Kelley MJ. Dunstan CR, Burgess T, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation [65 and activation. Cell 1998;93:165-76.

161. Wiktor-Jedrzejczak W, Bartocci A, Ferrante Jr AW, Ahmed-Ansari A, Sell KW,

162. Wiktor-Jedrzejczak W, Urbanowska E, Aukerman SL, Pollard JW, Stanley ER, Ralph [67 P, et al. Correction by CSF-1 of defects in the osteopetrotic op/op mouse suggests local, developmental, and humoral requirements for this growth factor. Exp Hematol 1991;19:1049-54.

163. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997;89:309 -19.

164. Yasuda H, Shima N, Nakagawa N, Mochizuki SI, Yano K, Fujise N, et al. Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPC/OCIF inhibits osteoclastogenesis in vitro. Endocrinology 1998;139:1329-37.

165. Kiviranta R. Morko J, Alatalo SL, NicAmhlaoibh R, Risteli J, Laitala-LeinonenT, et al. Impaired bone resorption in cathepsin K-deficient mice is partially compensated for by enhanced osteoclastogenesis and increased expression of other proteases via an increased RANKL/OPG ratio. Bone 2005;36:159-72.

166. Li CY. Jepsen KJ, Majeska RJ, Zhang J, Ni R, Gelb BD, et al. Mice lacking cathepsin K maintain bone remodeling but develop bone fragility despite high bone mass. J Bone Miner Res 2006;21:865-75.

167. Fratzl-Zelman N, Valenta A, Roschger P, Nader A, Gelb BD, Fratzl P, et al. Decreased bone turnover and deterioration of bone structure in two cases of pycnodysos- tosis. J clin endocrinol metab 2004;89:1538-47.

168. Zhao C, Irie N, Takada Y, Shimoda K, Miyamoto T, Nishiwaki T, et al. Bidirectional ephrinb2-ephb4 signaling controls bone homeostasis. Cell metab 2006;4: 111-21.

169. Karsdal MA, Fjording MS, Foged NT, Delaisse JM, Lochter A. Transforming growth factor-beta-induced osteoblast elongation regulates osteoclastic bone resorption through a p38 mitogen-activated protein kinase- and matrix metalloproteinase- dependent pathway. J biol chem 2001;276:39350-8.

170. Allan EH, Hausier KD, Wei T, Gooi JH, Quinn Jm, Crimeen-Lrwin B, et al. Ephrinb2 regulation by pth and pthrp revealed by molecular profiling in differentiating osteoblasts. J Bone Miner Res 2008;23:1170-81.

171. Alatalo Sl, Ivaska KK, Waguespack SG, Econs MJ, Vaananen HK, Halleen JM. (126 osteoclast-derived serum tartrate-resistant acid phosphatase 5b in albers- schonberg disease (type ii autosomal dominant osteopetrosis). Clin chem (127 2004;50:883-90.

172. Tran VP, Vignery A. Baron R. Cellular kinetics of the bone remodeling sequence in the rat. Anat rec 1982;202: 445-51.

173. Mundy GR, Bonewald LF. Role of TGF beta in bone remodeling. Ann NY Acad Sci 1990;593:91-7.

174. Baylink DJ, Finkelman RD, Mohan S. Growth factors to stimulate bone formation. J Bone Miner Res 1993;8(Suppl 2):S565-72.

175. Hayden JM, Mohan S, Baylink DJ. The insulin-like growth factor system and the coupling of formation to resorption. Bone 1995; 17:93S-8S. [

176. Lazowski DA, Fraher LJ, Hodsman A, Steer B, Modrowski D, Han VK. Regional variation of insulin-like growth factor-1 gene expression in mature rat bone and cartilage. Bone 1994;15:563-76.

177. Robinson JA, Riggs BL. Spelsberg TC, Oursler MJ. Osteoclasts and transforming growth factor-beta: estrogen-mediated isoform-specific regulation of production. Endocrinology 1996;137:615-21.

178. Taylor AF, Saunders MM, Shingle DL, Cimbala JM, Zhou Z, Donahue HJ. Mechanically stimulated osteocytes regulate osteoblastic activity via gap junctions. Am J Physiol, Cell Physiol 2007;292:C545-52.

179. Baron R, Rawadi G. Targeting the Wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology 2007;148:2635-43.

180. Bonewald LF. Osteocyte messages from a bony tomb. Cell Metab 2007;5:410-1 BellidoT, Ali AA, Gubrij I, Plotkin LI, Fu Q O’Brien CA, et al. Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis. Endocrinology 2005;146:4577-83.

181. Li X, Ominsky MS, Warmington KS. Morony S, Gong J. Cao J, et al. Sclerostin antibody treatment increases bone formation, bone mass and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res 2008 [Electronic publication ahead of print).

182. Yaccoby S, Ling W, Zhan F, Walker R, Barlogie B, Shaughnessy Jr JD. Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood 2007;109:2106-11.

183. Morony S, Capparelli C, Lee R, Shimamoto C, Boone T, Lacey DL, et al. A chimeric form of osteoprotegerin inhibits hypercalcemia and bone resorption induced by IL-1 beta, TNF-alpha, PTH, PTHrP, and 1, 25(OH)2D3. J Bone Miner Res 1999;14:1478-85.

184. Lee SK, Lorenzo JA. Parathyroid hormone stimulates TRANCE and inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone marrow cultures: correlation with osteoclast-like cell formation. Endocrinology

Labels
Dermatology & STDs Paediatric rheumatology Rheumatology
Login
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account