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Regulatory pathways revealing new approaches to the development of anabolic drugs for osteoporosis

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Abstract

The understanding of cell interactions and genetic controls of bone cells has provided new approaches to drug development for osteoporosis. Current emphasis in the development of new anabolic therapies is directed at modifying the effects of Wnt signalling on osteoblast differentiation and bone formation. Local signalling that results in bone formation during remodelling takes place in several ways. Growth factors released from resorbed bone matrix can contribute to preosteoblast differentiation and bone formation. Osteoclasts in the bone multicellular units (BMUs) might also generate activity that contributes to bone formation. The preosteoblasts themselves, growing in the resorption space, can communicate through cell contact and paracrine signalling mechanisms to differentiate. Osteocytes can sense the need for bone repair by detecting damage and pressure changes, and signalling to surface cells to respond appropriately. These recent insights into cell communication, together with discoveries from human and mouse genetics, have opened new pathways to drug development for osteoporosis. With the anabolic effect of parathyroid hormone on the skeleton having been established, human genetics revealed the major role of Wnt signalling in bone formation, and this has become the target of activity. Current approaches include activation at any of several points in the Wnt pathway, and neutralization of sclerostin, the protein product of the SOST gene that is produced in osteocytes as a powerful inhibitor of bone formation.

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References

  1. Delmas PD (2002) Treatment of postmenopausal osteoporosis. Lancet 359:2018–2026

    PubMed  CAS  Google Scholar 

  2. Parfitt AM (1996) Skeletal heterogeneity and the purposes of bone remodelling: implications for the understanding of osteoporosis. In: Marcus R, Feldman D, Kelsey J (eds) Osteoporosis. Academic, San Diego, pp 315–339

    Google Scholar 

  3. Seeman E, Delmas PD (2006) Bone quality—the material and structural basis of bone strength and fragility. N Engl J Med 354:2250–2261

    PubMed  CAS  Google Scholar 

  4. Van der Linden JC, Homminga J, Verhaar JA, Weinans H (2001) Mechanical consequences of bone loss in cancellous bone. J Bone Miner Res 16:457–465

    PubMed  Google Scholar 

  5. Hauge EM, Qvesel D, Eriksen EF, Mosekilde L, Melsen F (2001) Cancellous bone remodeling occurs in specialized compartments lined by cells expressing osteoblastic markers. J Bone Miner Res 16:1575–1582

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  7. Eghbali-Fatourechi GZ, Lamsam J, Fraser D, Nagel D, Riggs BL, Khosla S (2005) Circulating osteoblast-lineage cells in humans. N Engl J Med 352:1959–1966

    PubMed  CAS  Google Scholar 

  8. Modder UI, Khosla S (2008) Skeletal stem/osteoprogenitor cells: current concepts, alternate hypotheses, and relationship to the bone remodeling compartment. J Cell Biochem 103(2):393–400

    PubMed  CAS  Google Scholar 

  9. Neer RM, Arnaud CD, Zanchetta JR et al (2001) Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:1434–1441

    PubMed  CAS  Google Scholar 

  10. Lips P, Courpron P, Meunier PJ (1978) Mean wall thickness of trabecular bone packets in the human iliac crest: changes with age. Calcif Tissue Res 26:13–17

    PubMed  CAS  Google Scholar 

  11. Vedi S, Compston JE, Webb A, Tighe JR (1982) Histomorphometric analysis of bone biopsies from the iliac crest of normal British subjects. Metab Bone Dis Relat Res 4:231–236

    PubMed  CAS  Google Scholar 

  12. Bikle DD, Sakata T, Leary C et al (2002) Insulin-like growth factor I is required for the anabolic actions of parathyroid hormone on mouse bone. J Bone Miner Res 17:1570–1578

    PubMed  CAS  Google Scholar 

  13. Miyakoshi N, Kasukawa Y, Linkhart TA, Baylink DJ, Mohan S (2001) Evidence that anabolic effects of PTH on bone require IGF-I in growing mice. Endocrinology 142:4349–4356

    PubMed  CAS  Google Scholar 

  14. Zhang M, Xuan S, Bouxsein MLet al (2002) Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signalling in bone matrix mineralization. J Biol Chem 277:44005–44012

    PubMed  CAS  Google Scholar 

  15. Wang Y, Nishida S, Boudignon BM et al (2007) IGF-I receptor is required for the anabolic actions of parathyroid hormone on bone. J Bone Miner Res 22:1329–1337

    PubMed  CAS  Google Scholar 

  16. Ebeling PR, Jones JD, O’Fallon WM, Janes CH, Riggs BL (1993) Short-term effects of recombinant human insulin-like growth factor I on bone turnover in normal women. J Clin Endocrinol Metab 77:1384–1387

    PubMed  CAS  Google Scholar 

  17. Jilka RL, Weinstein RS, Bellido T, Roberson P, Parfitt AM, Manolagas SC (1999) Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J Clin Invest 104:439–446

    PubMed  CAS  Google Scholar 

  18. Jilka RL, Weinstein RS, Parfitt AM, Manolagas SC (2007) Quantifying osteoblast and osteocyte apoptosis: challenges and rewards. J Bone Miner Res 22:1492–1501

    PubMed  Google Scholar 

  19. Miao D, He B, Jiang Y et al (2005) Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1–34. J Clin Invest 115:2402–2411

    PubMed  CAS  Google Scholar 

  20. Zhao G, Monier-Faugere MC, Langub MC et al (2000) Targeted overexpression of insulin-like growth factor I to osteoblasts of transgenic mice: increased trabecular bone volume without increased osteoblast proliferation. Endocrinology 141:2674–2682

    PubMed  CAS  Google Scholar 

  21. Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC (1998) Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest 102:274–282

    PubMed  CAS  Google Scholar 

  22. Karsenty G (2001) Minireview: transcriptional control of osteoblast differentiation. Endocrinology 142:2731–2733

    PubMed  CAS  Google Scholar 

  23. Ducy P, Starbuck M, Priemel M et al (1999) A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development. Genes Dev 13:1025–1036

    PubMed  CAS  Google Scholar 

  24. Krishnan V, Moore TL, Ma YL et al (2003) Parathyroid hormone bone anabolic action requires Cbfa1/Runx2-dependent signalling. Mol Endocrinol 17:423–435

    PubMed  CAS  Google Scholar 

  25. Geoffroy V, Kneissel M, Fournier B, Boyde A, Matthias P (2002) High bone resorption in adult aging transgenic mice overexpressing cbfa1/runx2 in cells of the osteoblastic lineage. Mol Cell Biol 22:6222–6233

    PubMed  CAS  Google Scholar 

  26. Nakashima K, Zhou X, Kunkel G et al (2002) The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108:17–29

    PubMed  CAS  Google Scholar 

  27. Compston JE (2007) Skeletal actions of intermittent parathyroid hormone: effects on bone remodelling and structure. Bone 40:1447–1452

    PubMed  CAS  Google Scholar 

  28. Jilka RL (2007) Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone 40:1434–1446

    PubMed  CAS  Google Scholar 

  29. Frolik CA, Black EC, Cain RL et al (2003) Anabolic and catabolic bone effects of human parathyroid hormone (1–34) are predicted by duration of hormone exposure. Bone 33:372–379

    PubMed  CAS  Google Scholar 

  30. Dobnig H, Turner RT (1995) Evidence that intermittent treatment with parathyroid hormone increases bone formation in adult rats by activation of bone lining cells. Endocrinology 136:3632–3638

    PubMed  CAS  Google Scholar 

  31. Bellido T, Ali AA, Plotkin LI et al (2003) Proteasomal degradation of Runx2 shortens parathyroid hormone-induced anti-apoptotic signalling in osteoblasts. A putative explanation for why intermittent administration is needed for bone anabolism. J Biol Chem 278:50259–50272

    PubMed  CAS  Google Scholar 

  32. Bellido T, Ali AA, Gubrij I et al (2005) Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis. Endocrinology 146:4577–4583

    PubMed  CAS  Google Scholar 

  33. Shoback DM, Bilezikian JP, Turner SA, McCary LC, Guo MD, Peacock M (2003) The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism. J Clin Endocrinol Metab 88:5644–5649

    PubMed  CAS  Google Scholar 

  34. Nemeth EF, Delmar EG, Heaton WL et al (2001) Calcilytic compounds: potent and selective Ca2+ receptor antagonists that stimulate secretion of parathyroid hormone. J Pharmacol Exp Ther 299:323–331

    PubMed  CAS  Google Scholar 

  35. Gowen M, Stroup GB, Dodds RA et al (2000) Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats. J Clin Invest 105:1595–1604

    PubMed  CAS  Google Scholar 

  36. Kumar S, Liang X, Vasko JA et al (2007) Oral treatment with calcium receptor antagonist SB-423557 causes PTH release in multiple species and positive bone forming effects in the rat. J Bone Miner Res 22:S88

    Google Scholar 

  37. Ethgen D, Danoff, Schultz et al (2007) Antagonism of a calcium sensing receptor stimulates dose-related release of endogenous parathyroid hormone in normal volunteers: a proof of concept study. J Bone Miner Res 22:S128

    Google Scholar 

  38. Ethgen D, Phillips JC, Matheny C et al (2007) Dose-dependent increases in endogenous parathyroid hormone concentration after administration of a calcium-sensing receptor antagonist to normal volunteers for an oral bone forming agent. J Bone Miner Res 22:S38

    Google Scholar 

  39. Philbrick WM, Wysolmerski JJ, Galbraith S (1996) Defining the roles of parathyroid hormone-related protein in normal physiology. Physiol Rev 76:127–173

    PubMed  CAS  Google Scholar 

  40. Martin TJ, Moseley JM, Williams ED (1997) Parathyroid hormone-related protein: hormone and cytokine. J Endocrinol 154 [Suppl]:S23–S37

    PubMed  CAS  Google Scholar 

  41. Hock JM, Fonseca J, Gunness-Hey M, Kemp BE, Martin TJ (1989) Comparison of the anabolic effects of synthetic parathyroid hormone-related protein (PTHrP) 1–34 and PTH 1–34 on bone in rats. Endocrinology 125:2022–2027

    Article  PubMed  CAS  Google Scholar 

  42. Everhart-Caye M, Inzucchi SE, Guinness-Henry J, Mitnick MA, Stewart AF (1996) Parathyroid hormone (PTH)-related protein(1–36) is equipotent to PTH(1–34) in humans. J Clin Endocrinol Metab 81:199–208

    PubMed  CAS  Google Scholar 

  43. Horwitz MJ, Tedesco MB, Gundberg C, Garcia-Ocana A, Stewart AF (2003) Short-term, high-dose parathyroid hormone-related protein as a skeletal anabolic agent for the treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab 88:569–575

    PubMed  CAS  Google Scholar 

  44. Hodsman AB, Steer BM (1993) Early histomorphometric changes in response to parathyroid hormone therapy in osteoporosis: evidence for de novo bone formation on quiescent cancellous surfaces. Bone 14:523–527

    PubMed  CAS  Google Scholar 

  45. Kostenuik PJ, Ferrari S, Pierroz D et al (2007) Infrequent delivery of a long-acting PTH-Fc fusion protein has potent anabolic effects on cortical and cancellous bone. J Bone Miner Res 22:1534–1547

    PubMed  CAS  Google Scholar 

  46. Amizuka N, Warshawsky H, Henderson JE, Goltzman D, Karaplis AC (1994) Parathyroid hormone-related peptide-depleted mice show abnormal epiphyseal cartilage development and altered endochondral bone formation. J Cell Biol 126:1611–1623

    PubMed  CAS  Google Scholar 

  47. Kartsogiannis V, Moseley J, McKelvie B et al (1997) Temporal expression of PTHrP during endochondral bone formation in mouse and intramembranous bone formation in an in vivo rabbit model. Bone 21:385–392

    PubMed  CAS  Google Scholar 

  48. Suda N, Gillespie MT, Traianedes K et al (1996) Expression of parathyroid hormone-related protein in cells of osteoblast lineage. J Cell Physiol 166:94–104

    PubMed  CAS  Google Scholar 

  49. Amizuka N, Karaplis AC, Henderson JE (1996) Haploinsufficiency of parathyroid hormone-related peptide (PTHrP) results in abnormal postnatal bone development. Dev Biol 175:166–176

    PubMed  CAS  Google Scholar 

  50. Jiang Y, Zhao JJ, Mitlak BH, Wang O, Genant HK, Eriksen EF (2003) Recombinant human parathyroid hormone (1–34) [teriparatide] improves both cortical and cancellous bone structure. J Bone Miner Res 18:1932–1941

    PubMed  CAS  Google Scholar 

  51. Seeman E, Delmas PD (2001) Reconstructing the skeleton with intermittent parathyroid hormone. Trends Endocrinol Metab 12:281–283

    PubMed  CAS  Google Scholar 

  52. Martin TJ, Sims NA (2005) Osteoclast-derived activity in the coupling of bone formation to resorption. Trends Mol Med 11:76–81

    PubMed  CAS  Google Scholar 

  53. Karsdal MA, Martin TJ, Bollerslev J, Christiansen C, Henriksen K (2007) Are nonresorbing osteoclasts sources of bone anabolic activity? J Bone Miner Res 22:487–494

    PubMed  CAS  Google Scholar 

  54. Lindsay R, Cosman F, Zhou H et al (2006) A novel tetracycline labeling schedule for longitudinal evaluation of the short-term effects of anabolic therapy with a single iliac crest bone biopsy: early actions of teriparatide. J Bone Miner Res 21:366–373

    PubMed  CAS  Google Scholar 

  55. Dobnig H, Sipos A, Jiang Y et al (2005) Early changes in biochemical markers of bone formation correlate with improvements in bone structure during teriparatide therapy. J Clin Endocrinol Metab 90:3970–3977

    PubMed  CAS  Google Scholar 

  56. Koh AJ, Demiralp B, Neiva KG et al (2005) Cells of the osteoclast lineage as mediators of the anabolic actions of parathyroid hormone in bone. Endocrinology 146:4584–4596

    PubMed  CAS  Google Scholar 

  57. Delmas PD, Seeman E (2004) Changes in bone mineral density explain little of the reduction in vertebral or nonvertebral fracture risk with anti-resorptive therapy. Bone 34:599–604

    PubMed  CAS  Google Scholar 

  58. Sarkar S, Mitlak BH, Wong M, Stock JL, Black DM, Harper KD (2002) Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy. J Bone Miner Res 17:1–10

    PubMed  CAS  Google Scholar 

  59. Ettinger B, San Martin J, Crans G, Pavo I (2004) Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate. J Bone Miner Res 19:745–751

    PubMed  CAS  Google Scholar 

  60. Black DM, Greenspan SL, Ensrud KE et al (2003) The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 349:1207–1215

    PubMed  CAS  Google Scholar 

  61. Finkelstein JS, Hayes A, Hunzelman JL, Wyland JJ, Lee H, Neer RM (2003) The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med 349:1216–1226

    PubMed  CAS  Google Scholar 

  62. Cosman F, Nieves J, Zion M, Woelfert L, Luckey M, Lindsay R (2005) Daily and cyclic parathyroid hormone in women receiving alendronate. N Engl J Med 353:566–575

    PubMed  CAS  Google Scholar 

  63. Martin TJ (2004) Does bone resorption inhibition affect the anabolic response to parathyroid hormone? Trends Endocrinol Metab 15:49–50

    PubMed  CAS  Google Scholar 

  64. Black DM, Bilezikian JP, Ensrud KE et al (2005) One year of alendronate after one year of parathyroid hormone (1–84) for osteoporosis. N Engl J Med 353:555–565

    PubMed  CAS  Google Scholar 

  65. Wodarz A, Nusse R (1998) Mechanisms of Wnt signalling in development. Annu Rev Cell Dev Biol 14:59–88

    PubMed  CAS  Google Scholar 

  66. Uusitalo M, Heikkila M, Vainio S (1999) Molecular genetic studies of Wnt signalling in the mouse. Exp Cell Res 253:336–348

    PubMed  CAS  Google Scholar 

  67. Westendorf JJ, Kahler RA, Schroeder TM (2004) Wnt signalling in osteoblasts and bone diseases. Gene 341:19–39

    PubMed  CAS  Google Scholar 

  68. Clevers H (2006) Wnt/beta-catenin signalling in development and disease. Cell 127:469–480

    PubMed  CAS  Google Scholar 

  69. Yang-Snyder J, Miller JR, Brown JD, Lai CJ, Moon RT (1996) A frizzled homolog functions in a vertebrate Wnt signalling pathway. Curr Biol 6:1302–1306

    PubMed  CAS  Google Scholar 

  70. Slusarski DC, Corces VG, Moon RT (1997) Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling. Nature 390:410–413

    PubMed  CAS  Google Scholar 

  71. He X, Saint-Jeannet JP, Wang Y, Nathans J, Dawid I, Varmus H (1997) A member of the Frizzled protein family mediating axis induction by Wnt-5A. Science 275:1652–1654

    PubMed  CAS  Google Scholar 

  72. Hsieh JC, Rattner A, Smallwood PM, Nathans J (1999) Biochemical characterization of Wnt-frizzled interactions using a soluble, biologically active vertebrate Wnt protein. Proc Natl Acad Sci USA 96:3546–3551

    PubMed  CAS  Google Scholar 

  73. Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC (2000) An LDL-receptor-related protein mediates Wnt signalling in mice. Nature 407:535–538

    PubMed  CAS  Google Scholar 

  74. Mao B, Wu W, Li Y et al (2001) LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature 411:321–325

    PubMed  CAS  Google Scholar 

  75. Mao J, Wang J, Liu B et al (2001) Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signalling pathway. Mol Cell 7:801–809

    PubMed  CAS  Google Scholar 

  76. Gong Y, Slee RB, Fukai N et al (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107:513–523

    PubMed  CAS  Google Scholar 

  77. Boyden LM, Mao J, Belsky J et al (2002) High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346:1513–1521

    PubMed  CAS  Google Scholar 

  78. Mani A, Radhakrishnan J, Wang H et al (2007) LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 315:1278–1282

    PubMed  CAS  Google Scholar 

  79. Balemans W, Van Hul W (2007) The genetics of low-density lipoprotein receptor-related protein 5 in bone: a story of extremes. Endocrinology 148:2622–2629

    PubMed  CAS  Google Scholar 

  80. Li J, Sarosi I, Cattley RC et al (2006) Dkk1-mediated inhibition of Wnt signalling in bone results in osteopenia. Bone 39:754–766

    PubMed  CAS  Google Scholar 

  81. Kato M, Patel MS, Levasseur R et al (2002) Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol 157:303–314

    PubMed  CAS  Google Scholar 

  82. Babij P, Zhao W, Small C et al (2003) High bone mass in mice expressing a mutant LRP5 gene. J Bone Miner Res 18:960–974

    PubMed  CAS  Google Scholar 

  83. Rawadi G, Vayssiere B, Dunn F, Baron R, Roman-Roman S (2003) BMP-2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop. J Bone Miner Res 18:1842–1853

    PubMed  CAS  Google Scholar 

  84. Johnson ML, Harnish K, Nusse R, Van Hul W (2004) LRP5 and Wnt signalling: a union made for bone. J Bone Miner Res 19:1749–1757

    PubMed  CAS  Google Scholar 

  85. Mbalaviele G, Sheikh S, Stains JP et al (2005) Beta-catenin and BMP-2 synergize to promote osteoblast differentiation and new bone formation. J Cell Biochem 94:403–418

    PubMed  CAS  Google Scholar 

  86. Tu X, Joeng KS, Nakayama KI et al (2007) Noncanonical Wnt signalling through G protein-linked PKCdelta activation promotes bone formation. Dev Cell 12:113–127

    PubMed  CAS  Google Scholar 

  87. Takada I, Mihara M, Suzawa M et al (2007) A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation. Nat Cell Biol 9:1273–1285

    PubMed  CAS  Google Scholar 

  88. Balemans W, Ebeling M, Patel N et al (2001) Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 10:537–543

    PubMed  CAS  Google Scholar 

  89. Balemans W, Patel N, Ebeling M et al (2002) Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet 39:91–97

    PubMed  CAS  Google Scholar 

  90. Loots GG, Kneissel M, Keller H et al (2005) Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease. Genome Res 15:928–935

    PubMed  CAS  Google Scholar 

  91. Gardner JC, van Bezooijen RL, Mervis B et al (2005) Bone mineral density in sclerosteosis; affected individuals and gene carriers. J Clin Endocrinol Metab 90:6392–6395

    PubMed  CAS  Google Scholar 

  92. Wergedal JE, Veskovic K, Hellan M et al (2003) Patients with Van Buchem disease, an osteosclerotic genetic disease, have elevated bone formation markers, higher bone density, and greater derived polar moment of inertia than normal. J Clin Endocrinol Metab 88:5778–5783

    PubMed  CAS  Google Scholar 

  93. Winkler DG, Sutherland MK, Geoghegan JC et al (2003) Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 22:6267–6276

    PubMed  CAS  Google Scholar 

  94. Van Bezooijen RL, Roelen BA, Visser A et al (2004) Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med 199:805–814

    PubMed  Google Scholar 

  95. Poole KE, van Bezooijen RL, Loveridge N et al (2005) Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J 19:1842–1844

    PubMed  CAS  Google Scholar 

  96. Keller H, Kneissel M (2005) SOST is a target gene for PTH in bone. Bone 37:148–158

    PubMed  CAS  Google Scholar 

  97. Robling AG, Bellido T, Turner CH (2006) Mechanical stimulation in vivo reduces osteocyte expression of sclerostin. J Musculoskelet Neuronal Interact 6:354

    PubMed  CAS  Google Scholar 

  98. Li X, Zhang Y, Kang H et al (2005) Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signalling. J Biol Chem 280:19883–19887

    PubMed  CAS  Google Scholar 

  99. Hay E, Faucheu C, Suc-Royer I et al (2005) Interaction between LRP5 and Frat1 mediates the activation of the Wnt canonical pathway. J Biol Chem 280:13616–13623

    PubMed  CAS  Google Scholar 

  100. Clement-Lacroix P, Ai M, Morvan F et al (2005) Lrp5-independent activation of Wnt signalling by lithium chloride increases bone formation and bone mass in mice. Proc Natl Acad Sci USA 102:17406–17411

    PubMed  CAS  Google Scholar 

  101. Kulkarni NH, Onyia JE, Zeng Q et al (2006) Orally bioavailable GSK-3alpha/beta dual inhibitor increases markers of cellular differentiation in vitro and bone mass in vivo. J Bone Miner Res 21:910–920

    PubMed  CAS  Google Scholar 

  102. Kulkarni NH, Wei T, Kumar A et al (2007) Changes in osteoblast, chondrocyte, and adipocyte lineages mediate the bone anabolic actions of PTH and small molecule GSK-3 inhibitor. J Cell Biochem 102(6):1504–1518

    PubMed  CAS  Google Scholar 

  103. Glass DA II, Bialek P, Ahn JD et al (2005) Canonical Wnt signalling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 8:751–764

    PubMed  CAS  Google Scholar 

  104. Holmen SL, Zylstra CR, Mukherjee A et al (2005) Essential role of beta-catenin in postnatal bone acquisition. J Biol Chem 280:21162–21168

    PubMed  CAS  Google Scholar 

  105. Cohen P, Frame S (2001) The renaissance of GSK3. Nat Rev Mol Cell Biol 2:769–776

    PubMed  CAS  Google Scholar 

  106. Harwood AJ (2001) Regulation of GSK-3: a cellular multiprocessor. Cell 105:821–824

    PubMed  CAS  Google Scholar 

  107. Morvan F, Boulukos K, Clement-Lacroix P et al (2006) Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J Bone Miner Res 21:934–945

    PubMed  CAS  Google Scholar 

  108. Tian E, Zhan F, Walker R et al (2003) The role of the Wnt-signalling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 349:2483–2494

    PubMed  CAS  Google Scholar 

  109. Yaccoby S, Ling W, Zhan F et al (2007) Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood 109:2106–2111

    PubMed  CAS  Google Scholar 

  110. Ott SM (2005) Sclerostin and Wnt signaling—the pathway to bone strength. J Clin Endocrinol Metab 90:6741–6743

    PubMed  Google Scholar 

  111. Ominsky M, Stouch B, Doellgast G et al (2006) Administration of sclerostin monoclonal antibodies to female cynomolgus monkeys results in increased bone formation, bone mineral density and bone strength. J Bone Miner Res 21:S94

    Google Scholar 

  112. Padhi D, Stouch B, Jang G et al (2007) Anti-sclerostin antibody increases markers of bone formation in healthy postmenopausal women. J Bone Miner Res 22:S37

    Google Scholar 

  113. Silvestrini G, Ballanti P, Leopizzi M et al (2007) Effects of intermittent parathyroid hormone (PTH) administration on SOST mRNA and protein in rat bone. J Mol Histol 38:261–269

    PubMed  CAS  Google Scholar 

  114. Van Bezooijen RL, ten Dijke P, Papapoulos SE, Lowik CW (2005) SOST/sclerostin, an osteocyte-derived negative regulator of bone formation. Cytokine Growth Factor Rev 16:319–327

    PubMed  Google Scholar 

  115. Sutherland MK, Geoghegan JC, Yu C et al (2004) Sclerostin promotes the apoptosis of human osteoblastic cells: a novel regulation of bone formation. Bone 35:828–835

    PubMed  CAS  Google Scholar 

  116. Leupin O, Kramer I, Collette NM et al (2007) Control of the SOST bone enhancer by PTH via MEF2 transcription factors. J Bone Miner Res 22(12):1957–1967

    PubMed  CAS  Google Scholar 

  117. Brack AS, Conboy MJ, Roy S et al (2007) Increased Wnt signalling during aging alters muscle stem cell fate and increases fibrosis. Science 317:807–810

    PubMed  CAS  Google Scholar 

  118. Liu H, Fergusson MM, Castilho RM et al (2007) Augmented Wnt signalling in a mammalian model of accelerated aging. Science 317:803–806

    PubMed  CAS  Google Scholar 

  119. Holowacz T, Zeng L, Lassar AB (2006) Asymmetric localization of numb in the chick somite and the influence of myogenic signals. Dev Dyn 235:633–645

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. St Vincent’s Institute of Medical Research, Melbourne, Australia

    T. J. Martin, N. A. Sims & K. W. Ng

  2. University of Melbourne Department of Medicine, St Vincent’s Health, Melbourne, Australia

    T. J. Martin, N. A. Sims & K. W. Ng

  3. Department of Endocrinology, St Vincent’s Health, Melbourne, Australia

    K. W. Ng

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Martin, T.J., Sims, N.A. & Ng, K.W. Regulatory pathways revealing new approaches to the development of anabolic drugs for osteoporosis. Osteoporos Int 19, 1125–1138 (2008). https://doi.org/10.1007/s00198-008-0575-5

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