Calcified Tissue International

, Volume 102, Issue 6, pp 635–643 | Cite as

Analysis of Circulating Mediators of Bone Remodeling in Prader–Willi Syndrome

  • G. Brunetti
  • G. Grugni
  • L. Piacente
  • M. Delvecchio
  • A. Ventura
  • P. Giordano
  • M. Grano
  • G. D’Amato
  • D. Laforgia
  • A. Crinò
  • M. F. Faienza
Original Research
  • 86 Downloads

Abstract

We tested the hypothesis that the levels of bone remodeling mediators may be altered in Prader–Willi syndrome (PWS). We assessed RANKL, OPG, sclerostin, DKK-1 serum levels, and bone metabolism markers in 12 PWS children (7.8 ± 4.3 years), 14 PWS adults (29.5 ± 7.2 years), and 31 healthy controls matched for sex and age. Instrumental parameters of bone mineral density (BMD) were also evaluated. Lumbar spine BMD Z-scores were reduced in PWS children (P < 0.01), reaching osteopenic levels in PWS adults. PWS patients showed lower 25(OH)-vitamin D serum levels than controls (P < 0.001). Osteocalcin was increased in PWS children but reduced in adults respect to controls (P < 0.005 and P < 0.01, respectively). RANKL levels were higher in both pediatric and PWS adults than controls (P < 0.004), while OPG levels were significantly reduced (P < 0.004 and P < 0.006, respectively). Sclerostin levels were increased in children (P < 0.04) but reduced in adults compared to controls (P < 0.01). DKK-1 levels did not show significant difference between patients and controls. In PWS patients, RANKL, OPG, and sclerostin significantly correlated with metabolic and bone instrumental parameters. Consistently, with adjustment for age, multiple linear regression analysis showed that BMD and osteocalcin were the most important predictors for RANKL, OPG, and sclerostin in children, and GH and sex steroid replacement treatment in PWS adults. We demonstrated the involvement of RANKL, OPG, and sclerostin in the altered bone turnover of PWS subjects suggesting these molecules as markers of bone disease and new potential pharmacological targets to improve bone health in PWS.

Keywords

Prader–Willi syndrome RANKL OPG Sclerostin DKK-1 

Notes

Compliance with Ethical Standards

Conflict of interest

G. Brunetti, G. Grugni, L. Piacente, M. Delvecchio, A. Ventura, P. Giordano, M. Grano, G. D’Amato, D. Laforgia, A. Crinò, and M. F. Faienza declare that they have no conflict of interest to disclose.

Human and Animal Rights

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed Consent

Written informed consent was obtained from all the legal guardians, and from the patients when applicable, prior to inclusion. All procedures were approved by local institutional review boards.

References

  1. 1.
    Butler MG, Manzardo AM, Forster JL (2016) Prader-Willi syndrome: clinical genetics and diagnostic aspects with treatment approaches. Curr Pediatr Rev 12:136–166CrossRefPubMedGoogle Scholar
  2. 2.
    Lionti T, Reid SM, White SM, Rowell MM (2015) A population-based profile of 160 Australians with Prader-Willi syndrome: trends in diagnosis, birth prevalence and birth characteristics. Am J Med Genet A 167A:371–378CrossRefPubMedGoogle Scholar
  3. 3.
    Cassidy SB, Schwartz S, Miller JL, Driscoll DJ (2012) Prader-Willi syndrome. Genet Med 14:10–26CrossRefPubMedGoogle Scholar
  4. 4.
    Faienza MF, Ventura A, Lauciello R et al (2012) Analysis of endothelial protein C receptor gene and metabolic profile in Prader-Willi syndrome and obese subjects. Obesity 20:1866–1870CrossRefPubMedGoogle Scholar
  5. 5.
    Angulo MA, Butler MG, Cataletto ME (2015) Prader-Willi syndrome: a review of clinical, genetic, and endocrine findings. J Endocrinol Invest 38:1249–1263CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Burnett LC, LeDuc CA, Sulsona CR et al (2016) Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome. J Clin Invest.  https://doi.org/10.1172/JCI88648 Google Scholar
  7. 7.
    Vestergaard P, Kristensen K, Bruun JM, Østergaard JR, Heickendorff L, Mosekilde L, Richelsen B (2004) Reduced bone mineral density and increased bone turnover in Prader-Willi syndrome compared with controls matched for sex and body mass index: a cross-sectional study. J Pediatr 144:614–619CrossRefPubMedGoogle Scholar
  8. 8.
    Longhi S, Grugni G, Gatti D et al (2015) Adults with Prader-Willi syndrome have weaker bones: effect of treatment with GH and sex steroids. Calcif Tissue Int 96:160–166CrossRefPubMedGoogle Scholar
  9. 9.
    Butler MG, Haber L, Mernaugh R, Carlson MG, Price R, Feurer ID (2001) Decreased bone mineral density in Prader-Willi syndrome: comparison with obese subjects. Am J Med Genet 103:216–222CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Kroonen LT, Herman M, Pizzutillo PD, Macewen GD (2006) Prader-Willi syndrome: clinical concerns for the orthopaedic surgeon. J Pediatr Orthop 26:673–679CrossRefPubMedGoogle Scholar
  11. 11.
    Sinnema M, Maaskant MA, van Schrojenstein Lantman-de Valk HM, van Nieuwpoort IC, Drent ML, Curfs LM, Schrander-Stumpel CT (2011) Physical health problems in adults with Prader-Willi syndrome. Am J Med Genet A 155A:2112–2124CrossRefPubMedGoogle Scholar
  12. 12.
    Carrel AL, Myers SE, Whitman BY, Allen DB (2002) Benefits of long-term GH therapy in Prader-Willi syndrome: a 4-year study. J Clin Endocrinol Metab 87:1581–1585CrossRefPubMedGoogle Scholar
  13. 13.
    Carrel AL, Myers SE, Whitman BY, Eickhoff J, Allen DB (2010) Long-term growth hormone therapy changes the natural history of body composition and motor function in children with Prader-Willi syndrome. J Clin Endocrinol Metab 95:1131–1136CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    de Lind van Wijngaarden RF, Festen DA, Otten BJ et al (2009) Bone mineral density and effects of growth hormone treatment in prepubertal children with Prader-Willi syndrome: a randomized controlled trial. J Clin Endocrinol Metab 94:3763–3771CrossRefGoogle Scholar
  15. 15.
    Jørgensen AP, Ueland T, Sode-Carlsen R et al (2013) Two years of growth hormone treatment in adults with Prader-Willi syndrome do not improve the low BMD. J Clin Endocrinol Metab 98:E753–E760CrossRefPubMedGoogle Scholar
  16. 16.
    Grugni G (2013) Prader-Willi syndrome: GH therapy and bone. Nat Rev Endocrinol 9:320–321CrossRefPubMedGoogle Scholar
  17. 17.
    Khor EC, Fanshawe B, Qi Y et al (2016) Prader-Willi critical region, a non-translated, imprinted central regulator of bone mass: possible role in skeletal abnormalities in Prader-Willi syndrome. PLoS ONE 11:e0148155CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19:1791–1792CrossRefGoogle Scholar
  19. 19.
    Qiang YW, Chen Y, Stephens O et al (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 112:196–207CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Lewiecki EM (2014) Role of sclerostin in bone and cartilage and its potential as a therapeutic target in bone diseases. Ther Adv Musculoskelet Dis 6:48–57CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Holm VA, Cassidy SB, Butler MG, Hanchett JM, Greenswag LR, Whitman BY, Greenberg F (1993) Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics 91:398–402PubMedGoogle Scholar
  22. 22.
    Corneli G, Di Somma C, Baldelli R et al (2005) The cut-off limits of the GH response to GH-releasing hormone-arginine test related to body mass index. Eur J Endocrinol 153:257–264CrossRefPubMedGoogle Scholar
  23. 23.
    Cole TJ, Bellizzi MC, Flegal KM, Dietz WH (2000) Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ 320:1240–1243CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kuczmarski RJ, Ogden CL, Grummer-Strawn LM et al (2000) CDC growth charts: United States. Adv Data 8:1–27Google Scholar
  25. 25.
    Tanner JM, Whitehouse RH (1976) Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch Dis Child 51:170–179CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419CrossRefPubMedGoogle Scholar
  27. 27.
    Vignali DA (2000) Multiplexed particle-based flow cytometric assays. J Immunol Methods 243:243–255CrossRefPubMedGoogle Scholar
  28. 28.
    Salle BL, Braillon P, Glorieux FH, Brunet J, Cavero E, Meunier PJ (1992) Lumbar bone mineral content measured by dual energy X-ray absorptiometry in newborns and infants. Acta Paediatr 81:953–958CrossRefPubMedGoogle Scholar
  29. 29.
    Southard RN, Morris JD, Mahan JD, Hayes JR, Torch MA, Sommer A, Zipf WB (1991) Bone mass in healthy children: measurement with quantitative DXA. Radiology 179:735–738CrossRefPubMedGoogle Scholar
  30. 30.
    Glastre C, Braillon P, David L, Cochat P, Meunier PJ, Delmas PD (1990) Measurement of bone mineral content of the lumbar spine by dual energy X-ray absorptiometry in normal children: correlations with growth parameters. J Clin Endocrinol Metab 70:1330–1333CrossRefPubMedGoogle Scholar
  31. 31.
    Faienza MF, Brunetti G, Colucci S et al (2009) Osteoclastogenesis in children with 21-hydroxylase deficiency on long-term glucocorticoid therapy: the role of receptor activator of nuclear factor-kappaB ligand/osteoprotegerin imbalance. J Clin Endocrinol Metab 94:2269–2276CrossRefPubMedGoogle Scholar
  32. 32.
    Faienza MF, Brunetti G, Ventura A et al (2015) Mechanisms of enhanced osteoclastogenesis in girls and young women with Turner’s Syndrome. Bone 81:228–236CrossRefPubMedGoogle Scholar
  33. 33.
    Brunetti G, Papadia F, Tummolo A et al (2016) Impaired bone remodeling in children with osteogenesis imperfecta treated and untreated with bisphosphonates: the role of DKK1, RANKL, and TNF-α. Osteoporos Int 27:2355–2365CrossRefPubMedGoogle Scholar
  34. 34.
    Faienza MF, Ventura A, Delvecchio M et al (2017) High sclerostin and Dickkopf-1 (DKK-1) serum levels in children and adolescents with type 1 diabetes mellitus. J Clin Endocrinol Metab 102:1174–1181PubMedGoogle Scholar
  35. 35.
    Giordano P, Brunetti G, Lassandro G et al (2016) High serum sclerostin levels in children with haemophilia A. Br J Haematol 172:293–295CrossRefPubMedGoogle Scholar
  36. 36.
    Delgado-Calle J, Bellido T (2015) Osteocytes and skeletal pathophysiology. Curr Mol Biol Rep 1(4):157–167CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Mogul HR, Lee PD, Whitman BY et al (2008) Growth hormone treatment of adults with Prader-Willi syndrome and growth hormone deficiency improves lean body mass, fractional body fat, and serum triiodothyronine without glucose impairment: results from the United States multicenter trial. J Clin Endocrinol Metab 93:1238–1245CrossRefPubMedGoogle Scholar
  38. 38.
    Sode-Carlsen R, Farholt S, Rabben KF et al (2012) Growth hormone treatment in adults with Prader-Willi syndrome: the Scandinavian study. Endocrine 41:191–199CrossRefPubMedGoogle Scholar
  39. 39.
    Sanchez-Ortiga R, Klibanski A, Tritos NA (2012) Effects of recombinant human growth hormone therapy in adults with Prader-Willi syndrome: a meta-analysis. Clin Endocrinol 77:86–93CrossRefGoogle Scholar
  40. 40.
    Tritos NA, Klibanski A (2016) Effects of growth hormone on bone. Prog Mol Biol Transl Sci 138:193–211CrossRefPubMedGoogle Scholar
  41. 41.
    Bakker NE, Kuppens RJ, Siemensma EP et al (2015) Bone mineral density in children and adolescents with Prader-Willi syndrome: longitudinal study during puberty and 9 years of growth hormone treatment. J Clin Endocrinol Metab 100:1609–1618CrossRefPubMedGoogle Scholar
  42. 42.
    Nakamura Y, Murakami N, Iida T, Asano S, Ozeki S, Nagai T (2014) Growth hormone treatment for osteoporosis in patients with scoliosis of Prader-Willi syndrome. J Orthop Sci 19:877–882CrossRefPubMedGoogle Scholar
  43. 43.
    Canalis E (2018) Management of endocrine disease: novel anabolic treatments for osteoporosis. Eur J Endocrinol 178(2):R33–R44CrossRefPubMedGoogle Scholar
  44. 44.
    Doyon A, Fischer DC, Bayazit AK et al (2015) Markers of bone metabolism are affected by renal function and growth hormone therapy in children with chronic kidney disease. PLoS ONE 10:e0113482CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Ueland T (2005) GH/IGF-I and bone resorption in vivo and in vitro. Eur J Endocrinol 152:327–332CrossRefPubMedGoogle Scholar
  46. 46.
    Faienza MF, Chiarito M, D’amato G, Colaianni G, Colucci S, Grano M, Brunetti G. Monoclonal antibodies for treating osteoporosis. Expert Opin Biol Ther 2017:1–9.  https://doi.org/10.1080/14712598.2018.1401607

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • G. Brunetti
    • 1
  • G. Grugni
    • 2
  • L. Piacente
    • 3
  • M. Delvecchio
    • 3
  • A. Ventura
    • 3
  • P. Giordano
    • 3
  • M. Grano
    • 4
  • G. D’Amato
    • 5
  • D. Laforgia
    • 3
  • A. Crinò
    • 6
  • M. F. Faienza
    • 3
  1. 1.Department of Basic Medical Sciences, Neuroscience and Sense Organs, Section of Human Anatomy and HistologyUniversity of Bari ‘A. Moro’BariItaly
  2. 2.Division of AuxologyIstituto Auxologico Italiano, Research InstituteVerbaniaItaly
  3. 3.Department of Biomedical Sciences and Human Oncology, Section of PediatricsUniversity of Bari ‘A. Moro’BariItaly
  4. 4.Department of Emergency and Organ TransplantationUniversity of Bari ‘A. Moro’BariItaly
  5. 5.Neonatal Intensive Care UnitDi Venere HospitalBariItaly
  6. 6.Autoimmune Endocrine Diseases UnitBambino Gesù Hospital, Research InstitutePalidoro (Rome)Italy

Personalised recommendations