Current Osteoporosis Reports

, Volume 10, Issue 1, pp 93–100

Potential Role for Therapies Targeting DKK1, LRP5, and Serotonin in the Treatment of Osteoporosis

Future Therapeutics (P Miller, Section Editor)

Abstract

Osteoporosis is a common disorder in which diminished bone mass leads to progressive microarchitectural skeletal deterioration and increased fracture risk. Our understanding of both normal and pathologic bone biology continues to evolve, and with it our grasp of the highly coordinated relationships between primary bone cells (osteoblasts, osteoclasts, and osteocytes) and the complex molecular signals bone cells use to integrate signals derived from other organ systems, including the immune, hematopoietic, gastrointestinal, and central nervous systems. It is now clear that the Wnt signaling pathway is central to regulation of both skeletal modeling and remodeling. Herein, we discuss components of the Wnt signaling pathway (DKK1, an endogenous soluble inhibitor of Wnt signaling) and LRP5 (a plasma membrane-localized Wnt co-receptor) as potential future targets for osteoporosis therapy. Finally, we discuss the current controversial role for serotonin in skeletal metabolism, and the potential role of future therapies targeting serotonin for osteoporosis treatment.

Keywords

Dickhopf1 (DKK1) Serotonin Low-density lipoprotein receptor-related protein 5 (LRP5) Osteoporosis 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Rachner TD, Khosla S, Hofbauer LC: Osteoporosis: now and the future 2011, 377:1276–1287.Google Scholar
  2. 2.
    Westendorf JJ, Kahler RA, Schroeder TM. Wnt signaling in osteoblasts and bone diseases. Gene. 2004;341:19–39.PubMedCrossRefGoogle Scholar
  3. 3.
    Baron R, Rawadi G. Targeting the Wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology. 2007;148:2635–43.PubMedCrossRefGoogle Scholar
  4. 4.
    •• Goltzman D: LRP5, serotonin, and bone: complexity, contradictions, and conundrums. J Bone Miner Res 2011, 26:1997–2001. This succinct commentary clearly delineates the current controversies regarding the roles of LRP5 and serotonin in bone mass regulation. PubMedCrossRefGoogle Scholar
  5. 5.
    Glinka A, Wu W, Delius H, et al. Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature. 1998;391:357–62.PubMedCrossRefGoogle Scholar
  6. 6.
    Ohnaka K, Taniguchi H, Kawate H, et al. Glucocorticoid enhances the expression of dickkopf-1 in human osteoblasts: novel mechanism of glucocorticoid–induced osteoporosis. Biochem Biophys Res Commun. 2004;318:259–64.PubMedCrossRefGoogle Scholar
  7. 7.
    Butler JS, Queally JM, Devitt BM, et al. Silencing DKK1 expression rescues dexamethasone-induced suppression of primary human osteoblast differentiation. BMC Musculoskelet Disord. 2010;11:210.PubMedCrossRefGoogle Scholar
  8. 8.
    Li J, Sarosi I, Cattley RC, et al. Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone. 2006;39:754–66.PubMedCrossRefGoogle Scholar
  9. 9.
    Morvan F, Boulukos K, Clement-Lacroix P, et al. Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J Bone Miner Res. 2006;21:934–45.PubMedCrossRefGoogle Scholar
  10. 10.
    Reppe S, Refvem H, Gautvik VT, et al. Eight genes are highly associated with BMD variation in postmenopausal Caucasian women. Bone. 2010;46:604–12.PubMedCrossRefGoogle Scholar
  11. 11.
    • Butler JS, Murray DW, Hurson CJ, et al.: The role of Dkk1 in bone mass regulation: correlating serum Dkk1 expression with bone mineral density. J Orthop Res 2011, 29:414–418. Although not demonstrating causality, this study shows that serum DKK1 levels are higher in subjects with osteoporosis, and inversely associated with BMD at the hip and spine. PubMedCrossRefGoogle Scholar
  12. 12.
    Gatti D, Viapiana O, Idolazzi L, et al. The waning of teriparatide effect on bone formation markers in postmenopausal osteoporosis is associated with increasing serum levels of DKK1. J Clin Endocrinol Metab. 2011;96:1555–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Ng AC, Khosla S, Charatcharoenwitthaya N, et al.: Bone microstructural changes revealed by high-resolution peripheral quantitative computed tomography imaging and elevated DKK1 and MIP-1á levels in patients with MGUS. Blood. 2011;118:6529–34.Google Scholar
  14. 14.
    Tian E, Zhan F, Walker R, et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med. 2003;349:2483–94.PubMedCrossRefGoogle Scholar
  15. 15.
    Kaiser M, Mieth M, Liebisch P, et al. Serum concentrations of DKK-1 correlate with the extent of bone disease in patients with multiple myeloma. Eur J Haematol. 2008;80:490–4.PubMedCrossRefGoogle Scholar
  16. 16.
    Diarra D, Stolina M, Polzer K, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med. 2007;13:156–63.PubMedCrossRefGoogle Scholar
  17. 17.
    Yaccoby S, Ling W, Zhan F, et al. Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood. 2007;109:2106–11.PubMedCrossRefGoogle Scholar
  18. 18.
    Heath DJ, Chantry AD, Buckle CH, et al. Inhibiting Dickkopf-1 (Dkk1) removes suppression of bone formation and prevents the development of osteolytic bone disease in multiple myeloma. J Bone Miner Res. 2009;24:425–36.PubMedCrossRefGoogle Scholar
  19. 19.
    Fulciniti M, Tassone P, Hideshima T, et al. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood. 2009;114:371–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Glantschnig H, Hampton RA, Lu P, et al. Generation and selection of novel fully human monoclonal antibodies that neutralize Dickkopf-1 (DKK1) inhibitory function in vitro and increase bone mass in vivo. J Biol Chem. 2010;285:40135–47.PubMedCrossRefGoogle Scholar
  21. 21.
    • Glantschnig H, Scott K, Hampton R, et al.: A rate-limiting role for dickkopf-1 in bone formation and the remediation of bone loss in mouse and primate models of postmenopausal osteoporosis by an experimental therapeutic antibody. J Pharmacol Exp Ther 2011, 338:568–578. In this study, a fully humanized monoclonal antibody against DKK1 increased bone formation markers and BMD in adult oviarectomized monkeys. PubMedCrossRefGoogle Scholar
  22. 22.
    Hoeppner LH, Secreto FJ, Westendorf JJ. Wnt signaling as a therapeutic target for bone diseases. Expert Opin Ther Targets. 2009;13:485–96.PubMedCrossRefGoogle Scholar
  23. 23.
    Giles RH, van Es JH, Clevers H. Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta. 2003;1653:1–24.PubMedGoogle Scholar
  24. 24.
    Canalis E. Update in new anabolic therapies for osteoporosis. J Clin Endocrinol Metab. 2010;95:1496–504.PubMedCrossRefGoogle Scholar
  25. 25.
    Gong Y, Slee RB, Fukai N, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107:513–23.PubMedCrossRefGoogle Scholar
  26. 26.
    Boyden LM, Mao J, Belsky J, et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med. 2002;346:1513–21.PubMedCrossRefGoogle Scholar
  27. 27.
    Little RD, Carulli JP, Del Mastro RG, et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet. 2002;70:11–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Ai M, Heeger S, Bartels CF, Schelling DK. Clinical and molecular findings in osteoporosis-pseudoglioma syndrome. Cell. 2005;77:741–53.Google Scholar
  29. 29.
    Kato M, Patel MS, Levasseur R, et al. Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol. 2002;157:303–14.PubMedCrossRefGoogle Scholar
  30. 30.
    Babij P, Zhao W, Small C, et al. High bone mass in mice expressing a mutant LRP5 gene. J Bone Miner Res. 2003;18:960–74.PubMedCrossRefGoogle Scholar
  31. 31.
    Ai M, Holmen SL, Van Hul W, et al. Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling. Mol Cell Biol. 2005;25:4946–55.PubMedCrossRefGoogle Scholar
  32. 32.
    •• Cui Y, Niziolek PJ, MacDonald BT, et al.: Lrp5 functions in bone to regulate bone mass. Nat Med 2011, 17:684–691. Using both genetic and pharmacologic approaches, this study elegantly refutes the role of extraskeletal LRP5 and duodenal-derived serotonin as integral regulators of bone mass. PubMedCrossRefGoogle Scholar
  33. 33.
    Glass 2nd DA, Bialek P, Ahn JD, et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell. 2005;8:751–64.PubMedCrossRefGoogle Scholar
  34. 34.
    Holmen SL, Zylstra CR, Mukherjee A, et al. Essential role of beta-catenin in postnatal bone acquisition. J Biol Chem. 2005;280:21162–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Kramer I, Halleux C, Keller H, et al. Osteocyte Wnt/beta-catenin signaling is required for normal bone homeostasis. Mol Cell Biol. 2010;30:3071–85.PubMedCrossRefGoogle Scholar
  36. 36.
    Kubota T, Michigami T, Sakaguchi N, et al. Lrp6 hypomorphic mutation affects bone mass through bone resorption in mice and impairs interaction with Mesd. J Bone Miner Res. 2008;23:1661–71.PubMedCrossRefGoogle Scholar
  37. 37.
    •• Yadav VK, Ryu JH, Suda N, et al.: Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 2008, 135:825–837. In this study, LRP5 within enterochromaffin cells of the duodenum is shown to regulate Tph1 activity to modulate circulating serotonin levels and thereby control osteoblast-mediated bone formation. PubMedCrossRefGoogle Scholar
  38. 38.
    Walther DJ, Peter JU, Bashammakh S, et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science. 2003;299:76.PubMedCrossRefGoogle Scholar
  39. 39.
    Ducy P, Karsenty G. The two faces of serotonin in bone biology. J Cell Biol. 2010;191:7–13.PubMedCrossRefGoogle Scholar
  40. 40.
    Frost M, Andersen TE, Yadav VK, et al. Patients with high-bone-mass phenotype owing to Lrp5-T253I mutation have low plasma levels of serotonin. J Bone Miner Res. 2010;25:673–5.PubMedCrossRefGoogle Scholar
  41. 41.
    Frost M, Andersen T, Gossiel F, et al. Levels of serotonin, sclerostin, bone turnover markers as well as bone density and microarchitecture in patients with high-bone-mass phenotype due to a mutation in Lrp5. J Bone Miner Res. 2011;26:1721–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Modder UI, Achenbach SJ, Amin S, et al. Relation of serum serotonin levels to bone density and structural parameters in women. J Bone Miner Res. 2010;25:415–22.PubMedCrossRefGoogle Scholar
  43. 43.
    Karsenty G, Yadav VK. Regulation of bone mass by serotonin: molecular biology and therapeutic implications. Annu Rev Med. 2011;62:323–31.PubMedCrossRefGoogle Scholar
  44. 44.
    Yadav VK, Oury F, Suda N, et al. A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell. 2009;138:976–89.PubMedCrossRefGoogle Scholar
  45. 45.
    Yadav VK, Balaji S, Suresh PS, et al. Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis. Nat Med. 2010;16:308–12.PubMedCrossRefGoogle Scholar
  46. 46.
    • Inose H, Zhou B, Yadav VK, et al.: Efficacy of serotonin inhibition in mouse models of bone loss. J Bone Miner Res 2011, 26: 2002–2011. This proof-of-concept study demonstrates that use of a small molecule Tph1 inhibitor to decrease duodenal serotonin synthesis can both prevent and treat oviarectomy-induced bone loss in rodents, and is synergistic when provided in conjunction with bisphosphonate therapy. PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Division of Endocrinology, Department of MedicineCollege of Medicine, Mayo ClinicRochesterUSA

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