Skip to main content

Advertisement

SpringerLink
Log in

Impaired bone remodeling in children with osteogenesis imperfecta treated and untreated with bisphosphonates: the role of DKK1, RANKL, and TNF-α

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

In this study, we investigated the bone cell activity in patients with osteogenesis imperfecta (OI) treated and untreated with neridronate. We demonstrated the key role of Dickkopf-1 (DKK1), receptor activator of nuclear factor-κB ligand (RANKL), and tumor necrosis factor alpha (TNF-α) in regulating bone cell of untreated and treated OI subjects. These cytokines could represent new pharmacological targets for OI.

Introduction

Bisphosphonates are widely used in the treatment of children with osteogenesis imperfecta (OI) with the objective of reducing the risk of fractures. Although bisphosphonates increase bone mineral density in OI subjects, the effects on fracture incidence are conflicting. The aim of this study was to investigate the mechanisms underlying bone cell activity in subjects with mild untreated forms of OI and in a group of subjects with severe OI treated with cycles of intravenous neridronate.

Methods

Sclerostin, DKK1, TNF-α, RANKL, osteoprotegerin (OPG), and bone turnover markers were quantified in serum of 18 OI patients (12 females, mean age 8.86 ± 3.90), 8 of which were receiving cyclic intravenous neridronate, and 21 sex- and age-matched controls. The effects on osteoblastogenesis and OPG expression of media conditioned by the serum of OI patients and anti-DKK1 neutralizing antibody were evaluated. Osteoclastogenesis was assessed in cultures from patients and controls.

Results

DKK1 and RANKL levels were significantly increased both in untreated and in treated OI subjects with respect to controls. The serum from patients with high DKK1 levels inhibited both osteoblast differentiation and OPG expression in vitro. High RANKL and low OPG messenger RNA (mRNA) levels were found in lymphomonocytes from patients. High amounts of TNF-α were expressed by monocytes, and an elevated percentage of circulating CD11b-CD51/CD61+ osteoclast precursors was observed in patients.

Conclusions

Our study demonstrated the key role of DKK1, RANKL, and TNF-α in regulating bone cell activity of subjects with OI untreated and treated with bisphosphonates. These cytokines could represent new pharmacological targets for OI patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Marini JC (2001) Osteogenesis imperfecta. In: Behrman RE, Kliegman RM, Jensen HB (eds) Nelson textbook of pediatrics, 17th edn. Saunders, Philadelphia, pp 2336–2338

    Google Scholar 

  2. Forlino A, Cabral WA, Barnes AM, Marini JC (2011) New perspectives on osteogenesis imperfecta. Nat Rev Endocrinol 7:540–557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cheung MS, Glorieux FH (2008) Osteogenesis imperfecta: update on presentation and management. Rev Endocr Metab Disord 9:153–160

    Article  PubMed  Google Scholar 

  4. Rohrbach M, Giunta C (2012) Recessive osteogenesis imperfecta: clinical, radiological, and molecular findings. Am J Med Genet C: Semin Med Genet 160C:175–189

    Article  Google Scholar 

  5. Rauch F, Travers R, Parfitt AM, Glorieux FH (2000) Static and dynamic bone histomorphometry in children with osteogenesis imperfecta. Bone 26:581–589

    Article  CAS  PubMed  Google Scholar 

  6. Baron R, Gertner JM, Lang R, Vignery A (1983) Increased bone turnover with decreased bone formation by osteoblasts in children with osteogenesis imperfecta tarda. Pediatr Res 17:204–207

    Article  CAS  PubMed  Google Scholar 

  7. Eghbali-Fatourechi G (2014) Bisphosphonate therapy in pediatric patients. J Diabetes Metab Disord 13:109

    Article  PubMed  PubMed Central  Google Scholar 

  8. Dwan K, Phillipi CA, Steiner RD, Basel D (2014) Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database Syst Rev 7:CD005088. doi:10.1002/14651858.CD005088.pub3

    Google Scholar 

  9. Land C, Rauch F, Glorieux FH (2006) Cyclical intravenous pamidronate treatment affects metaphyseal modeling in growing patients with osteogenesis imperfecta. J Bone Miner Res 21:374–379

    Article  CAS  PubMed  Google Scholar 

  10. Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19:1791–1792

    Article  Google Scholar 

  11. Mao B, Wu W, Davidson G, Marhold J, Li M, Mechler BM, Delius H, Hoppe D, Stannek P, Walter C, Glinka A, Niehrs C (2002) Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. Nature 417:664–667

    Article  CAS  PubMed  Google Scholar 

  12. 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 280:19883–19887

    Article  CAS  PubMed  Google Scholar 

  13. Morvan F, Boulukos K, Clément-Lacroix P, Roman Roman S, Suc-Royer I, Vayssière B, Ammann P, Martin P, Pinho S, Pognonec P, Mollat P, Niehrs C, Baron R, Rawadi G (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

    Article  CAS  PubMed  Google Scholar 

  14. Qiang YW, Chen Y, Stephens O, Brown N, Chen B, Epstein J, Barlogie B, Shaughnessy JD Jr (2008) Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma. Blood 112:196–207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dalbeth N, Pool B, Smith T, Callon KE, Lobo M, Taylor WJ, Jones PB, Cornish J, McQueen FM (2010) Circulating mediators of bone remodeling in psoriatic arthritis: implications for disordered osteoclastogenesis and bone erosion. Arthritis Res Ther 12:R164

    Article  PubMed  PubMed Central  Google Scholar 

  16. Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D, Korb A, Smolen J, Hoffmann M, Scheinecker C, van der Heide D, Landewe R, Lacey D, Richards WG, Schett G (2007) Dickkopf-1 is a master regulator of joint remodeling. Nat Med 13:156–163

    Article  CAS  PubMed  Google Scholar 

  17. Sillence DO, Senn A, Danks DM (1979) Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 15:101–116

    Article  Google Scholar 

  18. Gatti D, Antoniazzi F, Prizzi R, Braga V, Rossini M, Tatò L, Viapiana O, Adami S (2005) Intravenous neridronate in children with osteogenesis imperfecta: a randomized controlled study. J Bone Miner Res 20:758–763

    Article  CAS  PubMed  Google Scholar 

  19. Ogden CL, Kuczmarski RJ, Flegal KM, Mei Z, Guo S, Wei R, Grummer-Strawn LM, Curtin LR, Roche AF, Johnson CL (2002) Centers for disease control and prevention 2000 growth charts for the united states: improvements to the 1977 national center for health statistics version. Pediatrics 109:45–60

    Article  PubMed  Google Scholar 

  20. Vignali DA (2000) Multiplexed particle-based flow cytometric assays. J Immunol Methods 243:243–255

    Article  CAS  PubMed  Google Scholar 

  21. Mori G, Ballini A, Carbone C, Oranger A, Brunetti G, Di Benedetto A, Rapone B, Cantore S, Di Comite M, Colucci S, Grano M, Grassi FR (2012) Osteogenic differentiation of dental follicle stem cells. Int J Med Sci 9:480–487

    Article  PubMed  PubMed Central  Google Scholar 

  22. Brunetti G, Faienza MF, Piacente L, Ventura A, Oranger A, Carbone C, Benedetto AD, Colaianni G, Gigante M, Mori G, Gesualdo L, Colucci S, Cavallo L, Grano M (2013) High dickkopf-1 levels in sera and leukocytes from children with 21-hydroxylase deficiency on chronic glucocorticoid treatment. Am J Physiol Endocrinol Metab 304:E546–554

    Article  CAS  PubMed  Google Scholar 

  23. Jang WG, Kim EJ, Kim DK, Ryoo HM, Lee KB, Kim SH, Choi HS, Koh JT (2012) BMP2 protein regulates osteocalcin expression via Runx2-mediated Atf6 gene transcription. J Biol Chem 287:905–915

    Article  CAS  PubMed  Google Scholar 

  24. Gatti D, Viapiana O, Adami S, Idolazzi L, Fracassi E, Rossini M (2012) Bisphosphonate treatment of postmenopausal osteoporosis is associated with a dose dependent increase in serum sclerostin. Bone 50:739–742

    Article  CAS  PubMed  Google Scholar 

  25. Braga V, Gatti D, Rossini M, Colapietro F, Battaglia E, Viapiana O, Adami S (2004) Bone turnover markers in patients with osteogenesis imperfecta. Bone 34:1013–1016

    Article  CAS  PubMed  Google Scholar 

  26. Giordano P, Brunetti G, Lassandro G, Notarangelo LD, Luciani M, Mura RM, Lazzareschi I, Santagostino E, Piacente L, Ventura A, Cavallo L, Grano M, Faienza MF (2015) High serum sclerostin levels in children with haemophilia A. Br J Haematol. doi:10.1111/bjh.13481

    Google Scholar 

  27. Lee N, Smolarz AJ, Olson S, David O, Reiser J, Kutner R, Daw NC, Prockop DJ, Horwitz EM, Gregory CA (2007) A potential role for Dkk-1 in the pathogenesis of osteosarcoma predicts novel diagnostic and treatment strategies. Br J Cancer 97:1552–1559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Aicher A, Kollet O, Heeschen C, Liebner S, Urbich C, Ihling C, Orlandi A, Lapidot T, Zeiher AM, Dimmeler S (2008) The Wnt antagonist Dickkopf-1 mobilizes vasculogenic progenitor cells via activation of the bone marrow endosteal stem cell niche. Circ Res 103:796–803

    Article  CAS  PubMed  Google Scholar 

  29. Fujita K, Janz S (2007) Attenuation of WNT signaling by DKK-1 and −2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF. Mol Cancer 6:71

    Article  PubMed  PubMed Central  Google Scholar 

  30. Terpos E, Heath DJ, Rahemtulla A, Zervas K, Chantry A, Anagnostopoulos A, Pouli A, Katodritou E, Verrou E, Vervessou EC, Dimopoulos MA, Croucher PI (2006) Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-kappaB ligand concentrations and normalises indices of bone remodelling in patients with relapsed multiple myeloma. Br J Haematol 135:688–692

    Article  CAS  PubMed  Google Scholar 

  31. Rossini M, Viapiana O, Zanotti R, Tripi G, Perbellini O, Idolazzi L, Bonifacio M, Adami S, Gatti D (2015) Dickkopf-1 and sclerostin serum levels in patients with systemic mastocytosis. Calcif Tissue Int 96:410–416

    Article  CAS  PubMed  Google Scholar 

  32. Rossini M, Viapiana O, Adami S, Fracassi E, Idolazzi L, Dartizio C, Povino MR, Orsolini G, Gatti D (2015) In patients with rheumatoid arthritis, DKK1 serum levels are correlated with parathyroid hormone, bone erosions and BMD. Clin Exp Rheumatol 33:77–83

    PubMed  Google Scholar 

  33. Zeitlin L, Fassier F, Glorieux FH (2003) Modern approach to children with osteogenesis imperfecta. J Pediatr Orthop B 12:77–87

    PubMed  Google Scholar 

  34. Kalajzic I, Terzic J, Rumboldt Z, Mack K, Naprta A, Ledgard F, Gronowicz G, Clark SH, Rowe DW (2002) Osteoblastic response to the defective matrix in the osteogenesis imperfecta murine (oim) mouse. Endocrinology 143:1594–1601

    Article  CAS  PubMed  Google Scholar 

  35. Zhang H, Doty SB, Hughes C, Dempster D, Camacho NP (2007) Increased resorptive activity and accompanying morphological alterations in osteoclasts derived from the oim/oim mouse model of osteogenesis imperfecta. J Cell Biochem 102:1011–1020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Uveges TE, Collin-Osdoby P, Cabral WA, Ledgard F, Goldberg L, Bergwitz C, Forlino A, Osdoby P, Gronowicz GA, Marini JC (2008) Cellular mechanism of decreased bone in Brtl mouse model of OI: imbalance of decreased osteoblast function and increased osteoclasts and their precursors. J Bone Miner Res 23:1983–1994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li H, Jiang X, Delaney J, Franceschetti T, Bilic-Curcic I, Kalinovsky J, Lorenzo JA, Grcevic D, Rowe DW, Kalajzic I (2010) Immature osteoblast lineage cells increase osteoclastogenesis in osteogenesis imperfecta murine. Am J Pathol 176:2405–2413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. D’Eufemia P, Finocchiaro R, Celli M, Zambrano A, Tetti M, Villani C, Persiani P, Mari E, Zicari A (2008) High levels of serum prostaglandin E2 in children with osteogenesis imperfecta are reduced by neridronate treatment. Pediatr Res 63:203–206

    Article  PubMed  Google Scholar 

  39. Camacho NP, Raggio CL, Doty SB, Root L, Zraick V, Ilg WA, Toledano TR, Boskey AL (2001) A controlled study of the effects of alendronate in a growing mouse model of osteogenesis imperfecta. Calcif Tissue Int 69:94–101

    Article  CAS  PubMed  Google Scholar 

  40. Evans KD, Lau ST, Oberbauer AM, Martin RB (2003) Alendronate affects long bone length and growth plate morphology in the oim mouse model for Osteogenesis Imperfecta. Bone 32:268–274

    Article  PubMed  Google Scholar 

  41. McCarthy EA, Raggio CL, Hossack MD, Miller EA, Jain S, Boskey AL, Camacho NP (2002) Alendronate treatment for infants with osteogenesis imperfecta: demonstration of efficacy in a mouse model. Pediatr Res 52:660–670

    Article  CAS  PubMed  Google Scholar 

  42. Delos D, Yang X, Ricciardi BF, Myers ER, Bostrom MP, Camacho NP (2008) The effects of RANKL inhibition on fracture healing and bone strength in a mouse model of osteogenesis imperfecta. J Orthop Res 26:153–164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bargman R, Huang A, Boskey A, Raggio C, Pleshko N (2010) RANKL inhibition improves bone properties in a mouse model of osteogenesis imperfecta. Connect Tissue Res 51:123–131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bargman R, Posham R, Boskey A, Carter E, DiCarlo E, Verdelis K, Raggio C, Pleshko N (2012) High- and low-dose OPG-Fc cause osteopetrosis-like changes in infant mice. Pediatr Res 72:495–501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bargman R, Posham R, Boskey AL, DiCarlo E, Raggio C, Pleshko N (2012) Comparable outcomes in fracture reduction and bone properties with RANKL inhibition and alendronate treatment in a mouse model of osteogenesis imperfecta. Osteoporos Int 23:1141–1150

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Ministero dell’Istruzione Università e Ricerca (ex 60 % grant to Maria Grano).

Author information

Authors and Affiliations

  1. Department of Basic Medical Sciences, Neuroscience and Sense Organs, Section of Human Anatomy and Histology, University “A. Moro” of Bari, Piazza Giulio Cesare, 11, 70124, Bari, Italy

    G. Brunetti, A. Oranger, I. Gigante, S. Colucci & M. Grano

  2. Department of Metabolic Diseases, Clinical Genetics and Diabetology, Giovanni XXIII Children’s Hospital, Bari, Italy

    F. Papadia, A. Tummolo, R. Fischetto & F. Nicastro

  3. Department of Biomedical Sciences and Human Oncology, Pediatric Section, University “A. Moro” of Bari, Piazza G. Cesare, 11, 70124, Bari, Italy

    L. Piacente, A. Ventura, M. Ciccarelli, L. Cavallo, M. Delvecchio & M. F. Faienza

  4. Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy

    G. Mori

Authors
  1. G. Brunetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F. Papadia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Tummolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Fischetto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F. Nicastro
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L. Piacente
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Ventura
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. G. Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A. Oranger
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. I. Gigante
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. S. Colucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. M. Ciccarelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. M. Grano
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. L. Cavallo
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. M. Delvecchio
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. M. F. Faienza
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to G. Brunetti or M. F. Faienza.

Ethics declarations

The local ethics committee approved the study. The study was conducted in accordance to the criteria of the declaration of Helsinki

Conflict of interest

None.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brunetti, G., Papadia, F., Tummolo, A. et al. Impaired bone remodeling in children with osteogenesis imperfecta treated and untreated with bisphosphonates: the role of DKK1, RANKL, and TNF-α. Osteoporos Int 27, 2355–2365 (2016). https://doi.org/10.1007/s00198-016-3501-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-016-3501-2

KEYWORD

Search

Navigation