Selective targeting of RANK signaling pathways as new therapeutic strategies for osteoporosis

Expert Opinion on Therapeutic Targets

Volumn 14, Issue 9, 2010, Pages 923-934

  Jules, Joel ^a   Ashley, Jason W ^a   Feng, Xu ^a  

^a University of Alabama at Birmingham   (United States)

Author keywords

Antiresorptive drug; OPG; Osteoclast; Osteoporosis; RANK; RANKL; Therapeutic target

Indexed keywords

BISPHOSPHONIC ACID DERIVATIVE; CALCITONIN; DENOSUMAB; ESTROGEN; OSTEOCLAST DIFFERENTIATION FACTOR; OSTEOPROTEGERIN; RECEPTOR ACTIVATOR OF NUCLEAR FACTOR KAPPA B; SELECTIVE ESTROGEN RECEPTOR MODULATOR;

CELL DIFFERENTIATION; CELL SURVIVAL; CLINICAL TRIAL; DRUG ACTIVITY; DRUG TARGETING; HUMAN; NONHUMAN; OSTEOCLAST; OSTEOCLAST ACTIVITY; OSTEOPOROSIS; PROTEIN MOTIF; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; DRUG DELIVERY SYSTEMS; DRUG DESIGN; HUMANS; OSTEOPOROSIS; OSTEOPROTEGERIN; RANK LIGAND; SIGNAL TRANSDUCTION;

EID: 77955438141     PISSN: 14728222     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728222.2010.511179     Document Type: Review

References (103)

1. NIH Consensus Development Panel. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001;285:785-795
2. Marcus R, Bouxsein M. The nature of osteoporosis. In: Marcus R, Feldman D, Nelson DA, et al., editors, Osteoporosis. 3rd edition. Academic Press, San Diego; 2008. p. 27-36
3. Riggs BL, Wahner HW, Seeman E, et al. Changes in bone mineral density of the proximal femur and spine with aging. Differences between the postmenopausal and senile osteoporosis syndromes. J Clin Invest 1982;70:716-723 (Pubitemid 12038087)
4. Riggs BL, Khosla S, Melton LJ. The type I/type II model for involutional osteoporosis. In: Marcus R, Feldman D, Kelsey J, editors, Osteoporosis. 2nd edition. Academic Press, San Diego; 2001. p. 49-58
5. Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet 2003;4:638-649 (Pubitemid 36917505)
6. Teitelbaum SL. Osteoclasts: what do they do and how do they do it? Am J Pathol 2007;170:427-435
7. Raisz LG. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest 2005;115:3318-3325
8. Teitelbaum SL. Osteoclasts; culprits in inflammatory osteolysis. Arthritis Res Ther 2006;8:1-8
9. Goldring SR. Pathogenesis of bone and cartilage destruction in rheumatoid arthritis. Rheumatology 2003;42(Suppl 2):ii11-16 (Pubitemid 37220895)
10. Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002;2:584-593
11. Stefanick ML. Estrogens and progestins: background and history, trends in use, and guidelines and regimens approved by the US Food and Drug Administration. Am J Med 2005;118(Suppl 12B):64-73
12. Prince R, Muchmore DB, Siris ES. Estrogen analogues: selective estrogen receptor modulators and phytoestrogens. In: Marcus R, Feldman D, Nelson DA, et al., editors, Osteoporosis. 3rd edition. Academic Press, San Diego; 2008. p. 1705-1723
13. Miller P. Bisphosphonates: pharmacology and use in the treatment of osteoporosis. In: Marcus R, Feldman D, Nelson DA, et al., editors, Osteoporosis. 3rd edition. Academic Press, San Diego; 2008. p. 1725-1742
14. Gruber HE, Ivey JL, Baylink DJ, et al. Long-term calcitonin therapy in postmenopausal osteoporosis. Metabolism 1984;33:295-303
15. Miller PD, Derman RJ. What is the best balance of benefits and risks among anti-resorptive therapies for postmenopausal osteoporosis? Osteoporos Int 2010: published online 23 March 2010, doi: 10.1007/s00198-010-1208-3
16. Stepan JJ, Alenfeld F, Boivin G, et al. Mechanisms of action of antiresorptive therapies of postmenopausal osteoporosis. Endocr Regul 2003;37:225-238 (Pubitemid 38175992)
17. Lufkin EG, Sarkar S, Kulkarni PM, et al. Antiresorptive treatment of postmenopausal osteoporosis: review of randomized clinical studies and rationale for the Evista alendronate comparison (EVA) trial. Curr Med Res Opin 2004;20:351-357 (Pubitemid 38339175)
18. Marcus R, Wong M, Heath H III, et al. Antiresorptive treatment of postmenopausal osteoporosis: comparison of study designs and outcomes in large clinical trials with fracture as an endpoint. Endocr Rev 2002;23:16-37 (Pubitemid 34185305)
19. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423:337-342
20. Wittrant Y, Theoleyre S, Chipoy C, et al. RANKL/RANK/OPG: new therapeutic targets in bone tumours and associated osteolysis. Biochim Biophys Acta 2004;1704:49-57 (Pubitemid 39195349)
21. 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 (Pubitemid 43290920)
22. McClung MR. Inhibition of RANKL as a treatment for osteoporosis: preclinical and early clinical studies. Curr Osteoporos Rep 2006;4:28-33
23. Lewiecki EM. Current and emerging pharmacologic therapies for the management of postmenopausal osteoporosis. J Womens Health (Larchmt) 2009;18:1615-1626
24. Miller PD. Denosumab: anti-RANKL antibody. Curr Osteoporos Rep 2009;7:18-22
25. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756-765
26. Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998;93:165-176 (Pubitemid 28180851)
27. Yasuda H, Shima N, Nakagawa N, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/ osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 1998;95:3597-3602 (Pubitemid 28173173)
28. Anderson DM, Maraskovsky E, Billingsley WL, et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 1997;390:175-179 (Pubitemid 27507987)
29. Wong BR, Rho J, Arron J, et al. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J Biol Chem 1997;272:25190-25194 (Pubitemid 27415705)
30. Bucay N, Sarosi I, Dunstan CR, et al. osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998;12:1260-1268 (Pubitemid 28213402)
31. Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997;89:309-319
32. Wong BR, Josien R, Lee SY, et al. TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. J Exp Med 1997;186:2075-2080 (Pubitemid 28013694)
33. Josien R, Wong BR, Li HL, et al. TRANCE, a TNF family member, is differentially expressed on T cell subsets and induces cytokine production in dendritic cells. J Immunol 1999;162:2562-2568 (Pubitemid 29309274)
34. Josien R, Li HL, Ingulli E, et al. TRANCE, a tumor necrosis factor family member, enhances the longevity and adjuvant properties of dendritic cells in vivo. J Exp Med 2000;191:495-502
35. Kong YY, Yoshida H, Sarosi I, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999;397:315-323 (Pubitemid 29061638)
36. Bachmann MF, Wong BR, Josien R, et al. TRANCE, a tumor necrosis factor family member critical for CD40 ligand-independent T helper cell activation. J Exp Med 1999;189:1025-1031 (Pubitemid 29169819)
37. Dougall WC, Glaccum M, Charrier K, et al. RANK is essential for osteoclast and lymph node development. Genes Dev 1999;13:2412-2424 (Pubitemid 29453612)
38. Kim D, Mebius RE, MacMicking JD, et al. Regulation of peripheral lymph node genesis by the tumor necrosis factor family member TRANCE. J Exp Med 2000;192:1467-1478
39. Akiyama T, Shimo Y, Yanai H, et al. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 2008;29:423-437
40. Hikosaka Y, Nitta T, Ohigashi I, et al. The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity 2008;29:438-450
41. Fata JE, Kong YY, Li J, et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 2000;103:41-50
42. Hanada R, Leibbrandt A, Hanada T, et al. Central control of fever and female body temperature by RANKL/RANK. Nature 2009;462:505-509
43. Suda T, Takahashi N, Udagawa N, et al. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev 1999;20:345-357 (Pubitemid 30649812)
44. Ross FP, Teitelbaum SL. Osteoclast biology. In: Marcus R, Feldman D, Kelsey J, editors, Osteoporosis. 2nd edition. Academic Press, San Diego; 2001. p. 73-106
45. Li J, Sarosi I, Yan X-Q, et al. RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci USA 2000;97:1566-1571 (Pubitemid 30118482)
46. Burgess TL, Qian Y, Kaufman S, et al. The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts. J Cell Biol 1999;145:527-538 (Pubitemid 29215717)
47. Fuller K, Wong B, Fox S, et al. TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J Exp Med 1998;188:997-1001 (Pubitemid 28433427)
48. Lum L, Wong BR, Josien R, et al. Evidence for a role of a tumor necrosis factor-alpha (TNF-alpha)-converting enzyme-like protease in shedding of TRANCE, a TNF family member involved in osteoclastogenesis and dendritic cell survival. J Biol Chem 1999;274:13613-13618 (Pubitemid 129518580)
49. Wong BR, Besser D, Kim N, et al. TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Mol Cell 1999;4:1041-1049 (Pubitemid 30054909)
50. Eghbali-Fatourechi G, Khosla S, Sanyal A, et al. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest 2003;111:1221-1230 (Pubitemid 36519939)
51. Cao J, Venton L, Sakata T, et al. Expression of RANKL and OPG correlates with age-related bone loss in male C57BL/6 mice. J Bone Miner Res 2003;18:270-277 (Pubitemid 36125919)
52. Cao JJ, Wronski TJ, Iwaniec U, et al. Aging increases stromal/osteoblastic cell-induced osteoclastogenesis and alters the osteoclast precursor pool in the mouse. J Bone Miner Res 2005;20:1659-1668 (Pubitemid 41243554)
53. Hsu H, Lacey DL, Dunstan CR, et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA 1999;96:3540-3545 (Pubitemid 29168945)
54. Hoorweg K, Cupedo T. Development of human lymph nodes and Peyer's patches. Semin Immunol 2008;20:164-170
55. Anastasilakis AD, Toulis KA, Goulis DG, et al. Efficacy and safety of denosumab in postmenopausal women with osteopenia or osteoporosis: a systematic review and a meta-analysis. Horm Metab Res 2009;41:721-729
56. Toulis KA, Anastasilakis AD. Erratum to: increased risk of serious infections in women with osteopenia or osteoporosis treated with denosumab. Osteoporos Int 2010: published online 5 February 2010, doi: 10.1007/s00198-010- 1173-x
57. Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 2001;104:487-501 (Pubitemid 32201945)
58. Bodmer JL, Schneider P, Tschopp J. The molecular architecture of the TNF superfamily. Trends Biochem Sci 2002;27:19-26 (Pubitemid 34131621)
59. Darnay BG, Haridas V, Ni J, et al. Characterization of the intracellular domain of receptor activator of NF-kB (RANK). Interaction with tumor necrosis factor receptor-associated factors and activation of NF-kB and c-Jun N-terminal kinase. J Biol Chem 1998;273:20551-20555 (Pubitemid 28377625)
60. Wong BR, Josien R, Lee SY, et al. The TRAF family of signal transducers mediates NF-kB activation by the TRANCE receptor. J Biol Chem 1998;273:28355-28359 (Pubitemid 28496137)
61. Kim HH, Lee DE, Shin JN, et al. Receptor activator of NF-kB recruits multiple TRAF family adaptors and activates c-Jun N-terminal kinase. FEBS Lett 1999;443:297-302
62. Darnay BG, Ni J, Moore PA, et al. Activation of NF-kB by RANK requires tumor necrosis factor receptor-associated factor (TRAF) 6 and NF-kB-inducing kinase. Identification of a novel TRAF6 interaction motif. J Biol Chem 1999;274:7724-7731 (Pubitemid 129518159)
63. Galibert L, Tometsko ME, Anderson DM, et al. The involvement of multiple tumor necrosis factor receptor (TNFR)-associated factors in the signaling mechanisms of receptor activator of NF-kB, a member of the TNFR superfamily. J Biol Chem 1998;273:34120-34127 (Pubitemid 129758357)
64. Armstrong AP, Tometsko ME, Glaccum M, et al. A RANK/ TRAF6-dependent signal transduction pathway is essential for osteoclast cytoskeletal organization and resorptive function. J Biol Chem 2002;277:44347-54436 (Pubitemid 36157870)
65. Liu W, Xu D, Yang H, et al. Functional identification of three RANK cytoplasmic motifs mediating osteoclast differentiation and function. J Biol Chem 2004;279:54759-54769
66. Takayanagi H, Kim S, Matsuo K, et al. RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-beta. Nature 2002;416:744-749 (Pubitemid 34429151)
67. Feng X. Regulatory roles and molecular signaling of TNF family members in osteoclasts. Gene 2005;350:1-13 (Pubitemid 40503139)
68. Ye H, Arron JR, Lamothe B, et al. Distinct molecular mechanism for initiating TRAF6 signalling. Nature 2002;418:443-447 (Pubitemid 34826847)
69. Mizukami J, Takaesu G, Akatsuka H, et al. Receptor activator of NF-kB ligand (RANKL) activates TAK1 mitogen-activated protein kinase kinase kinase through a signaling complex containing RANK, TAB2, and TRAF6. Mol Cell Biol 2002;22:992-1000 (Pubitemid 34094837)
70. Ninomiya-Tsuji J, Kishimoto K, Hiyama A, et al. The kinase TAK1 can activate the NIK-I kB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature 1999;398:252-256 (Pubitemid 29142861)
71. Shirakabe K, Yamaguchi K, Shibuya H, et al. TAK1 mediates the ceramide signaling to stress-activated protein kinase/c-Jun N-terminal kinase. J Biol Chem 1997;272:8141-8144 (Pubitemid 27147762)
72. Lee SW, Han SI, Kim HH, et al. TAK1-dependent activation of AP-1 and c-Jun N-terminal kinase by receptor activator of NF-kB. J Biochem Mol Biol 2002;35:371-376 (Pubitemid 43150806)
73. Ge B, Gram H, Di Padova F, et al. MAPKK-independent activation of p38alpha mediated by TAB1-dependent autophosphorylation of p38alpha. Science 2002;295:1291-1294 (Pubitemid 34157620)
74. Takayanagi H, Kim S, Koga T, et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 2002;3:889-901 (Pubitemid 35460788)
75. Ishida N, Hayashi K, Hoshijima M, et al. Large scale gene expression analysis of osteoclastogenesis in vitro and elucidation of NFAT2 as a key regulator. J Biol Chem 2002;277:41147-41156 (Pubitemid 35215706)
76. Wu H, Arron JR. TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology. BioEssays 2003;25:1096-1105 (Pubitemid 37411769)
77. Walsh MC, Kim GK, Maurizio PL, et al. TRAF6 autoubiquitination- independent activation of the NFkB and MAPK pathways in response to IL-1 and RANKL. PLoS One 2008;3:e4064
78. Azuma Y, Kaji K, Katogi R, et al. Tumor necrosis factor-alpha induces differentiation of and bone resorption by osteoclasts. J Biol Chem 2000;275:4858-4864 (Pubitemid 30108878)
79. Xu D, Wang S, Liu W, et al. A novel RANK cytoplasmic motif plays an essential role in osteoclastogenesis by committing macrophages to the osteoclast lineage. J Biol Chem 2006;281:4678-4690
80. Kim H, Choi HK, Shin JH, et al. Selective inhibition of RANK blocks osteoclast maturation and function and prevents bone loss in mice. J Clin Invest 2009;119:813-825
81. Wang Y, Lebowitz D, Sun C, et al. Identifying the relative contributions of Rac1 and Rac2 to osteoclastogenesis. J Bone Miner Res 2008;23:260-270 (Pubitemid 351160040)
82. Feng X. RANK signaling pathways as potent and specific therapeutic targets for bone erosion in rheumatoid arthritis. Future Rheumatol 2006;1:567-578
83. Chen T, Feng X. Cell-based assay strategy for identification of motif-specific RANK signaling pathway inhibitors. Assay Drug Dev Technol 2006;4:473-482 (Pubitemid 44793594)
84. Liu W, Wang S, Wei S, et al. Receptor activator of NF-kB (RANK) cytoplasmic motif, 369PFQEP373, plays a predominant role in osteoclast survival in part by activating Akt/PKB and its downstream effector AFX/ FOXO4. J Biol Chem 2005;280:43064-43072 (Pubitemid 43049272)
85. Pacifici R. Cytokines, estrogen, and postmenopausal osteoporosis-the second decade. Endocrinol 1998;139:2659-2661
86. Jilka RL. Cytokines, bone remodeling, and estrogen deficiency-a 1998 update. Bone 1998;23:75-81
87. Lam J, Takeshita S, Barker JE, et al. TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest 2000;106:1481-1488 (Pubitemid 32038586)
88. Kim JH, Jin HM, Kim K, et al. The mechanism of osteoclast differentiation induced by IL-1. J Immunol 2009;183:1862-1870
89. Jules J, Shi Z, Feng X. Three RANK cytoplasmic motifs, IVVY535"538, PVQEET559"564, and PVQEQG604-609, play a critical role in TNF/IL-1-mediated osteoclastogenesis. J Bone Miner Res 2008;23(Suppl):S34
90. Kobayashi T, Walsh PT, Walsh MC, et al. TRAF6 is a critical factor for dendritic cell maturation and development. Immunity 2003;19:353-363 (Pubitemid 37153412)
91. Sun L, Deng L, Ea CK, et al. The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol Cell 2004;14:289-301 (Pubitemid 38591401)
92. Qin J, Konno H, Ohshima D, et al. Developmental stage-dependent collaboration between the TNF receptor-associated factor 6 and lymphotoxin pathways for B cell follicle organization in secondary lymphoid organs. J Immunol 2007;179:6799-6807
93. Kobayashi T, Kim TS, Jacob A, et al. TRAF6 is required for generation of the B-1a B cell compartment as well as T cell-dependent and -independent humoral immune responses. PLoS One 2009;4:e4736
94. Shui C, Riggs BL, Khosla S. The immunosuppressant rapamycin, alone or with transforming growth factor-beta, enhances osteoclast differentiation of RAW264.7 monocyte-macrophage cells in the presence of RANK-ligand. Calcif Tissue Int 2002;71:437-446 (Pubitemid 36929607)
95. Battaglino R, Kim D, Fu B, et al. c-Myc is required for osteoclast differentiation. J Bone Miner Res 2002;17:763-773 (Pubitemid 34441892)
96. Feng X. RANKing intracelluar cellular signaling in osteoclasts. IUBMB Life 2005;57:389-395 (Pubitemid 41073120)
97. Jules J, Shi Z, Liu W, et al. The RANKL cytoplasmic motif, IVVY535-538, plays an essential role in TNF-alpha- and LI-1-induced osteoclastogenesis. J Bone Miner Res 2007;22(Suppl):S96
98. Taguchi Y, Gohda J, Koga T, et al. A unique domain in RANK is required for Gab2 and PLCgamma2 binding to establish osteoclastogenic signals. Genes Cells 2009;14:1331-1345
99. Burge R, Dawson-Hughes B, Solomon DH, et al. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res 2007;22:465-475 (Pubitemid 46797130)
100. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998;280:2077-2082
101. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996;348:1535-1541
102. Chesnut CH III, Silverman S, Andriano K, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. Am J Med 2000;109:267-276
103. Heaney RP, Zizic TM, Fogelman I, et al. Risedronate reduces the risk of first vertebral fracture in osteoporotic women. Osteoporos Int 2002;13:501-505 (Pubitemid 34742210)