Advertisement

Osteoporosis International

, Volume 25, Issue 10, pp 2383–2388 | Cite as

Serum levels of sclerostin, Dickkopf-1, and secreted frizzled-related protein-4 are not changed in individuals with high bone mass causing mutations in LRP5

  • C. A. SimpsonEmail author
  • D. Foer
  • G. S. Lee
  • J. Bihuniak
  • B. Sun
  • R. Sullivan
  • J. Belsky
  • K. L. Insogna
Original Article

Abstract

Summary

We compared circulating levels of Wnt inhibitors among patients with high bone mass mutations in LRP5, unaffected kindred, and unrelated normal controls. Inhibitors were unchanged in affected and unaffected kindred. We saw no meaningful differences between controls and affected individuals. LRP5 signaling may not influence circulating levels of these inhibitors.

Introduction

It is thought that gain-of-function mutations in LRP5 result in high bone mass syndromes because these allelic variants confer resistance to the actions of endogenous inhibitors of Wnt signaling. We therefore attempted to determine if circulating levels of Wnt inhibitors are altered in patients with gain-of-function mutations in LRP5.

Methods

This is a cross-sectional study in a university research center. Serum was collected from consented volunteers known to have either the G171V or N198S gain-of-function mutations in LRP5, kindred members affected with either mutation, unrelated kindred, and unrelated normal age-matched controls. BMD was provided or measured on site.

Results

There were no significant differences found in the serum levels of sclerostin (SOST), Dickkopf-1 (Dkk-1), or secreted frizzled-related protein-4 (SFRP-4) in affected vs. unaffected individuals from different kindreds or when compared to age-matched unrelated normal individuals. Mean serum SOST values in affected and unaffected kindred members and unrelated normal controls were 52.7 ± 6.1, 36.5 ± 9.6, and 54.8 ± 5.4, respectively. For Dkk-1, the values were 25.9 ± 3.4, 25.7 ± 3.0, and 17.3 ± 2.3 and for SFRP-4, 38.1 ± 2.3, 39.8 ± 3.6, and 28.5 ± 1.7. Serum levels of RANKL and osteoprotegerin (OPG) were not different in the three groups.

Conclusions

Circulating levels of endogenous Wnt inhibitors do not change in patients with gain-of-function mutations in LRP5 including Dkk1, which is suppressed by Wnt signaling. It may be that circulating levels of Wnt inhibitors do not reflect changes in target tissues. It is also possible that other mechanisms besides or in addition to resistance in Wnt inhibitors explains the skeletal effects of these mutations.

Keywords

HBM mutations High bone mass LRP5 Wnt inhibitors 

Notes

Acknowledgments

This work was supported by the Yale Bone Center and in part by CTSA Grant Number UL1 RR024139 from the National Center for Research Resources (NCRR) and the National Center for Advancing Translational Science (NCATS), components of the National Institutes of Health (NIH), and NIH roadmap for Medical Research.

Conflicts of interest

None.

References

  1. 1.
    Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP (2002) High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346:1513–1521PubMedCrossRefGoogle Scholar
  2. 2.
    Little RD, Carulli JP, Del Mastro RG et al (2002) A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet 70:11–19PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Van Wesenbeeck L, Cleiren E, Gram J et al (2003) Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet 72:763–771PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Bollerslev J, Henriksen K, Frost Nielsen M, Brixen K, Van Hul W (2013) Autosomal dominant osteopetrosis revisited: lessons from recent studies. Eur J Endocrinol 169:R39–R57PubMedCrossRefGoogle Scholar
  5. 5.
    Cui Y, Niziolek PJ, MacDonald BT et al (2011) Lrp5 functions in bone to regulate bone mass. Nat Med 17:684–691PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Gong Y, Slee RB, Fukai N et al (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107:513–523PubMedCrossRefGoogle Scholar
  7. 7.
    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 157:303–314PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Estrada K, Styrkarsdottir U, Evangelou E et al (2012) Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet 44:491–501PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Williams BO, Insogna KL (2009) Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone. J Bone Miner Res 24:171–178PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19:179–192PubMedCrossRefGoogle Scholar
  11. 11.
    Clevers H, Nusse R (2012) Wnt/beta-catenin signaling and disease. Cell 149:1192–1205PubMedCrossRefGoogle Scholar
  12. 12.
    Essers MA, de Vries-Smits LM, Barker N, Polderman PE, Burgering BM, Korswagen HC (2005) Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science 308:1181–1184PubMedCrossRefGoogle Scholar
  13. 13.
    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 10:537–543PubMedCrossRefGoogle Scholar
  14. 14.
    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 21:934–945PubMedCrossRefGoogle Scholar
  15. 15.
    Bodine PV, Stauffer B, Ponce-de-Leon H et al (2009) A small molecule inhibitor of the Wnt antagonist secreted frizzled-related protein-1 stimulates bone formation. Bone 44:1063–1068PubMedCrossRefGoogle Scholar
  16. 16.
    Moore WJ, Kern JC, Bhat R et al (2009) Modulation of Wnt signaling through inhibition of secreted frizzled-related protein I (sFRP-1) with N-substituted piperidinyl diphenylsulfonyl sulfonamides. J Med Chem 52:105–116PubMedCrossRefGoogle Scholar
  17. 17.
    Li J, Sarosi I, Cattley RC et al (2006) Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone 39:754–766PubMedCrossRefGoogle Scholar
  18. 18.
    Nakanishi R, Akiyama H, Kimura H, Otsuki B, Shimizu M, Tsuboyama T, Nakamura T (2008) Osteoblast-targeted expression of Sfrp4 in mice results in low bone mass. J Bone Miner Res 23:271–277PubMedCrossRefGoogle Scholar
  19. 19.
    Schulze J, Seitz S, Saito H et al (2010) Negative regulation of bone formation by the transmembrane Wnt antagonist Kremen-2. PLoS One 5:e10309PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Brommage R, Jeter-Jones S, Xiong W, Champ R, J L (2013) Mouse femoral neck architecture determined by microCT reflects skeletal architecture observed at other bone sites. J Bone Min Res Off J Am Soc Bone Miner Res 28 (Suppl 1)Google Scholar
  21. 21.
    Bhat BM, Allen KM, Liu W et al (2007) Structure-based mutation analysis shows the importance of LRP5 beta-propeller 1 in modulating Dkk1-mediated inhibition of Wnt signaling. Gene 391:103–112PubMedCrossRefGoogle Scholar
  22. 22.
    Ahn VE, Chu ML, Choi HJ, Tran D, Abo A, Weis WI (2011) Structural basis of Wnt signaling inhibition by Dickkopf binding to LRP5/6. Dev Cell 21:862–873PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, Lowik CW, Reeve J (2005) Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J 19:1842–1844PubMedGoogle Scholar
  24. 24.
    Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D (2005) Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 280:19883–19887PubMedCrossRefGoogle Scholar
  25. 25.
    Jones SE, Jomary C (2002) Secreted frizzled-related proteins: searching for relationships and patterns. Bioessays 24:811–820PubMedCrossRefGoogle Scholar
  26. 26.
    Chamorro MN, Schwartz DR, Vonica A, Brivanlou AH, Cho KR, Varmus HE (2005) FGF-20 and DKK1 are transcriptional targets of beta-catenin and FGF-20 is implicated in cancer and development. EMBO J 24:73–84PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Whyte MP, Reinus WH, Mumm S (2004) High-bone-mass disease and LRP5. N Engl J Med 350:2096–2099, author reply 2096-2099PubMedCrossRefGoogle Scholar
  28. 28.
    Kerstetter JE, Caseria DM, Mitnick ME, Ellison AF, Gay LF, Liskov TA, Carpenter TO, Insogna KL (1997) Increased circulating concentrations of parathyroid hormone in healthy, young women consuming a protein-restricted diet. Am J Clin Nutr 66:1188–1196PubMedGoogle Scholar
  29. 29.
    Walsh J, Gossiel F, Paggiosi M, R E (2013) Circulating sclerostin is negatively associated with cortical BMD, PINP, estradiol and IGF-1. J Bone Miner Res 28 (Suppl 1)Google Scholar
  30. 30.
    Modder UI, Hoey KA, Amin S, McCready LK, Achenbach SJ, Riggs BL, Melton LJ 3rd, Khosla S (2011) Relation of age, gender, and bone mass to circulating sclerostin levels in women and men. J Bone Miner Res 26:373–379PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Thorson S, Prasad T, Sheu Y, Danielson ME, Arasu A, Cummings SR, Cauley JA (2013) Sclerostin and bone strength in women in their 10th decade of life. J Bone Miner Res 28:2008–2016PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Babij P, Zhao W, Small C et al (2003) High bone mass in mice expressing a mutant LRP5 gene. J Bone Miner Res 18:960–974PubMedCrossRefGoogle Scholar
  33. 33.
    Frost M, Andersen T, Gossiel F, Hansen S, Bollerslev J, van Hul W, Eastell R, Kassem M, Brixen K (2011) 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 26:1721–1728PubMedCrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2014

Authors and Affiliations

  • C. A. Simpson
    • 1
    Email author
  • D. Foer
    • 1
  • G. S. Lee
    • 1
  • J. Bihuniak
    • 1
  • B. Sun
    • 1
  • R. Sullivan
    • 1
  • J. Belsky
    • 2
  • K. L. Insogna
    • 1
  1. 1.Department of Medicine, Section of EndocrinologyYale School of MedicineNew HavenUSA
  2. 2.Department of MedicineDanbury HospitalDanburyUSA

Personalised recommendations