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An update on the role of RANKL–RANK/osteoprotegerin and WNT-ß-catenin signaling pathways in pediatric diseases

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Abstract

Background

Bone remodeling is a lifelong process due to the balanced activity of osteoclasts (OCs), the bone-reabsorbing cells, and osteoblasts (OBs), and the bone-forming cells. This equilibrium is regulated by numerous cytokines, but it has been largely demonstrated that the RANK/RANKL/osteoprotegerin and Wnt/β-catenin pathways play a key role in the control of osteoclastogenesis and osteoblastogenesis, respectively. The pro-osteoblastogenic activity of the Wnt/β-catenin can be inhibited by sclerostin and Dickkopf-1 (DKK-1). RANKL, sclerostin and DKKs-1 are often up-regulated in bone diseases, and they are the target of new monoclonal antibodies.

Data sources

The authors performed a systematic literature search in PubMed and EMBASE to June 2018, reviewed and selected articles, based on pre-determined selection criteria.

Results

We re-evaluated the role of RANKL, osteoprotegerin, sclerostin and DKK-1 in altered bone remodeling associated with some inherited and acquired pediatric diseases, such as type 1 diabetes mellitus (T1DM), alkaptonuria (AKU), hemophilia A, osteogenesis imperfecta (OI), 21-hydroxylase deficiency (21OH-D) and Prader–Willi syndrome (PWS). To do so, we considered recent clinical studies done on pediatric patients in which the roles of RANKL-RANK/osteoprotegerin and WNT-ß-catenin signaling pathways have been investigated, and for which innovative therapies for the treatment of osteopenia/osteoporosis are being developed.

Conclusions

The case studies taken into account for this review demonstrated that quite frequently both bone reabsorbing and bone deposition are impaired in pediatric diseases. Furthermore, for some of them, bone damage began in childhood but only manifested with age. The use of denosumab could represent a valid alternative therapeutic approach to improve bone health in children, although further studies need to be carried out.

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References

  1. Lu J, Shin Y, Yen MS, Sun SS. Peak bone mass and patterns of change in total bone mineral density and bone mineral contents from childhood into young adulthood. J Clin Densitom. 2016;19:180–91.

    Article  PubMed  Google Scholar 

  2. Massey HM, Flanagan AM. Human osteoclasts derive from CD14-positive monocytes. Br J Haematol. 1999;106:167–70.

    Article  PubMed  CAS  Google Scholar 

  3. Boyle WJ, Scott Simonet W, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423:337–42.

    Article  PubMed  CAS  Google Scholar 

  4. Theill LE, Boyle WJ, Penninger JM. RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu Rev Immunol. 2002;20:795–823.

    Article  PubMed  CAS  Google Scholar 

  5. Krishnan V, Bryant HU, Mac Dougald OA. Regulation of bone mass by Wnt signaling. J Clin Invest. 2006;116:1202–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Reya T, Clevers H. Wnt signalling in stem cell and cancer. Nature. 2005;434:843–50.

    Article  PubMed  CAS  Google Scholar 

  7. Kato M, Patel MS, Lavasseur R, Lobov I, Chang BH, Glass DA, 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;157:763–71.

    Article  Google Scholar 

  8. Bodine PV, Zhao W, Kharode Y, Bex FJ, Lambert AJ, Goad MB, et al. The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice. Mol Endocrinol. 2004;18:1222–37.

    Article  PubMed  CAS  Google Scholar 

  9. Morvan F, Boulukos K, Clément-Lacroix P, Roman Roman S, Suc- Royer I, Vayssière B, 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.

    Article  PubMed  CAS  Google Scholar 

  10. Delgado-Calle J, Sato AJ, Bellido T. Role and mechanism of action of sclerostin in bone. Bone. 2017;96:29–37.

    Article  PubMed  CAS  Google Scholar 

  11. Baron R, Kneissel M. Wnt signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med. 2013;19:1791–2.

    Article  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Dalbeth N, Pool B, Smith T, Callon KE, Lobo M, Taylor WJ, et al. Circulating mediators of bone remodeling in psoriatic arthritis: implications for disordered osteoclastogenesis and bone erosion. Arthritis Res Ther. 2010;12:R164.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Pan H, Wu N, Yang T, He W. Association between bone mineral density and type 1 diabetes mellitus: a meta analysis of cross sectional studies. Diabetes Metab Res Rev. 2014;30:531–42.

    Article  PubMed  Google Scholar 

  15. Bechtold S, Dirlenbach I, Raile K, Noelle V, Bonfing W, Schwarz HP. Early manifestation of type 1 diabetes in children is a risk factor for changed bone geometry: data using peripheral quantitative computed tomography. Pediatrics. 2006;118:627–34.

    Article  Google Scholar 

  16. Weber DR, Haynes K, Leonard MB, Willi SM, Denburg MR. Type 1 diabetes is associated with an increased risk of fracture across the life span: a population-based cohort study using The Health Improvement Network (THIN). Diabetes Care. 2015;38:1913–20.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Liao CC, Lin CS, Shih CC, Yeh CC, Chang YC, Lee YW, et al. Increased risk of fracture and post fracture adverse events in patients with diabetes: two nationwide population-based retrospective cohort studies. Diabetes Care. 2014;37:2246–52.

    Article  PubMed  Google Scholar 

  18. Fowlkes JL, Bunn RC, Thrailkill KM. Contributions of the insulin/insulin-like growth factor-1 axis to diabetic osteopathy. J Diabetes Metab. 2011;1:S1–003.

    PubMed  PubMed Central  Google Scholar 

  19. Fowlkes JL, Nyman JS, Bunn RC, Jo C, Wahl EC, Liu L, et al. Osteo-promoting effects of insulin-like growth factor I (IGF-1) in a mouse model of type 1 diabetes. Bone. 2013;57:36–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Botolin S, McCabe LR. Chronic hyperglycemia modulates osteoblast gene expression through osmotic and non-osmotic pathways. J Cell Biochem. 2006;99:411–24.

    Article  PubMed  CAS  Google Scholar 

  21. Neumann T, Lodes S, Kästner B, Franke S, Kiehntopf M, Lehmann T, et al. High serum pentosidine but not esRAGE is associated with prevalent fracture type 1 diabetes independent of bone mineral density and glycaemic control. Osteoporos Int. 2014;25:1527–33.

    Article  PubMed  CAS  Google Scholar 

  22. Tsentidis C, Gourgiotis D, Kossiva L, Doulgeraki A, Marmarinos A, Galli-Tsinopoulou A, et al. Higher levels of s-RANK-L and osteoprotegerin in children and adolescents with type 1 diabetes mellitus may indicate increased osteoclast signaling and predisposition to lower bone mass: a multivariate cross-sectional analysis. Osteoporos Int. 2016;27:1631–43.

    Article  PubMed  CAS  Google Scholar 

  23. Faienza MF, Ventura A, Delvecchio M, Fusillo A, Piacente L, Aceto G, et al. High sclerostin and Dickkopf-1 (DKK-1) serum levels in children and adolescents with type 1 diabetes mellitus. J Clin Endocrinol Metab. 2017;102:1174–81.

    PubMed  Google Scholar 

  24. Tsentidis C, Gourgiotis D, Kossiva L, Marmarinos A, Doulgeraki A, Karavanaki K. Increased levels of Dickkopf-1 (DKK-1) are indicative of Wnt/β catenin downregulation and lower osteoblast signaling in children and adolescents with type 1 diabetes mellitus, contributing to lower bone mineral density. Osteoporosis Intern. 2017;28:945–53.

    Article  CAS  Google Scholar 

  25. Faienza MF, Brunetti G, Sanesi L, Colaianni G, Celi M, Piacente L, et al. High irisin levels are associated with better glycemic control and bone health in children with type 1 diabetes. Diabetes Res Clin Pract. 2018;141:10–7.

    Article  PubMed  CAS  Google Scholar 

  26. Natalicchio A, Marrano N, Biondi G, Spagnuolo R, Labarbuta R, Porreca I, et al. The myokine irisin is released in response to saturated fatty acids and promotes pancreatic β-cell survival and insulin secretion. Diabetes. 2017;66:2849–56.

    Article  PubMed  CAS  Google Scholar 

  27. Colaianni G, Cuscito C, Mongelli T, Pignataro P, Buccoliero C, Liu P, et al. The myokine irisin increases cortical bone mass. Proc Natl Acad Sci USA. 2015;112:12157–62.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Colaianni G, Mongelli T, Cuscito C, Pignataro P, Lippo L, Spiro G, et al. Irisin prevents and restores bone loss and muscle atrophy in hind-limb suspended mice. Sci Rep. 2017;7:2811.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Tsentidis C, Gourgiotis D, Kossiva L, Marmarinos A, Doulgeraki A, Karavanaki K. Sclerostin distribution in children and adolescents with type 1 diabetes mellitus and correlation with bone metabolism and bone mineral density. Pediatr Diabetes. 2016;17:289–99.

    Article  PubMed  CAS  Google Scholar 

  30. Neumann T, Hofbauer LC, Rauner M, Lodes S, Kästner B, Franke S, et al. Clinical and endocrine correlates of circulating sclerostin levels in patients with type 1 diabetes mellitus. Clin Endocrinol. 2014;80:649–55.

    Article  CAS  Google Scholar 

  31. Felício KM, de Souza ACCB, Neto JFA, de Melo FTC, Carvalho CT, Arbage TP, et al. Glycemic variability and insulin needs in patients with type 1 diabetes mellitus supplemented with vitamin D: a pilot study using continuous glucose monitoring system. Curr Diabetes Rev. 2018;14:395–403.

    Article  PubMed  CAS  Google Scholar 

  32. Al Hafid N, Christodoulou J. Phenylketonuria: a review of current and future treatments. Transl Pediatr. 2015;4:304–17.

    PubMed  PubMed Central  Google Scholar 

  33. Millucci L, Spreafico A, Tinti L, Braconi D, Ghezzi L, Paccagnini E, et al. Alkaptonuria is a novel human secondary amyloidogenic disease. Biochim Biophys Acta. 2012;1822:1682–16891.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Millucci L, Braconi D, Bernardini G, Lupetti P, Rovensky J, Ranganath L, et al. Amyloidosis in alkaptonuria. J Inherit Metab Dis. 2015;38:797–805.

    Article  PubMed  CAS  Google Scholar 

  35. Aliberti G, Pulignano I, Schiappoli A, Minisola S, Romagnoli E. Proietta M bone metabolism in ochronotic patients. J Intern Med. 2003;254:296–300.

    Article  PubMed  CAS  Google Scholar 

  36. Brunetti G, Tummolo A, D’amato G, Gaeta A, Ortolani F, Piacente L, et al. Mechanisms of enhanced osteoclastogenesis in alkaptonuria. Am J Pathol. 2018;188:1059–68.

    Article  PubMed  CAS  Google Scholar 

  37. Brunetti G, Rizzi R, Oranger A, Gigante I, Mori G, Taurino G, et al. LIGHT/TNFSF14 increases osteoclastogenesis and decreases osteoblastogenesis in multiple myeloma-bone disease. Oncotarget. 2014;5:12950–67.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL. TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest. 2000;106:1481–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Brunetti G, Faienza MF, Colaianni G, Gigante I, Oranger A, Pignataro P, et al. Impairment of bone remodeling in LIGHT/TNFSF14-deficient mice. J Bone Miner Res. 2018;33:704–19.

    Article  PubMed  CAS  Google Scholar 

  40. Christoforidis A, Economou M, Papadopoulou E, Kazantzidou E, Farmaki E, Tzimouli V, et al. Comparative study of dual energy X-ray absorptiometry and quantitative ultrasonography with the use of biochemical markers of bone turnover in boys with haemophilia. Haemophilia. 2011;17:217–22.

    Article  CAS  Google Scholar 

  41. Katsarou O, Terpos E, Chatzismalis P, Provelengios S, Adraktas T, Hadjidakis D, et al. Increased bone resorption is implicated in the pathogenesis of bone loss in hemophiliacs: correlations with hemophilic arthropathy and HIV infection. Ann Haematol. 2010;89:67–74.

    Article  Google Scholar 

  42. Giordano P, Brunetti G, Lassandro G, Notarangelo LD, Luciani M, Mura RM, et al. High serum sclerostin levels in children with haemophilia A. Br J Haematol. 2016;172:293–5.  

    Article  PubMed  Google Scholar 

  43. Forlino A, Cabral WA, Barnes AM, Marini JC. New perspectives on osteogenesis imperfecta. Nat Rev Endocrinol. 2011;7:540–57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Uveges TE, Collin-Osdoby P, Cabral WA, Ledgard F, Goldberg L, Bergwitz C, et al. Cellular mechanism of decreased bpne in Brtl mouse model of OI: imbalance of osteoblast function and increased osteoclasts and their precursors. J Bone Miner Res. 2008;23:1983–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Brunetti G, Papadia F, Tummolo A, Fischetto R, Nicastro F, Piacente L, 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. 2016;304:546–54.

    Google Scholar 

  46. Camacho NP, Raggio CL, Doty SB, Root L, Zraick V, Ilg WA, et al. A controlled study of the effects of alendronate in a growing mouse model of osteogenesis imperfecta. Calcif Tissue Int. 2001;69:94–101.

    Article  PubMed  CAS  Google Scholar 

  47. Evans KD, Lau ST, Oberbauer AM, Martin RB. Alendronate affects long bone length and growth plate morphology in the oim mouse model for osteogenesis imperfecta. Bone. 2003;2:268–74.

    Article  CAS  Google Scholar 

  48. McCarthy EA, Raggio CL, Hossack MD, Miller EA, Jain S, Boskey AL, et al. Alendronate treatment for infants with osteogenesis imperfecta: demonstration of efficacy in a mouse model. Pediatr Res. 2002;52:660–70.

    Article  PubMed  CAS  Google Scholar 

  49. Delos D, Yang X, Ricciardi BF, Myers ER, Bostrom MP, Camacho NP. The effects of RANKL inhibition on fracture healing and bone strength in a mouse model of osteogenesis imperfecta. J Orthop Res. 2008;26:153–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Bargman R, Huang A, Boskey A, Raggio C, Pleshko N. RANKL inhibition improves bone properties in a mouse model of osteogenesis imperfecta. Connect Tissue Res. 2010;51:123–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Bargman R, Posham R, Boskey A, Carter E, DiCarlo E, Verdelis K, et al. High- and low-dose OPG-Fc cause osteopetrosis-like changes in infant mice. Pediatr Res. 2012;72:495–501.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Bargman R, Posham R, Boskey AL, DiCarlo E, Raggio C, Pleshko N. Comparable outcomes in fracture reduction and bone properties with RANKL inhibition and alendronate treatment in a mouse model of osteogenesis imperfecta. Osteoporos Int. 2012;23:1141–50.

    Article  PubMed  CAS  Google Scholar 

  53. Semler O, Netzer C, Hoyer-Kuhn H, Becker J, Eysel P, Schoenau E. First use of the RANKL antibody denosumab in osteogenesis imperfecta type VI. J Musculoskelet Neuronal Interact. 2012;12:183–8.

    PubMed  CAS  Google Scholar 

  54. Joint LWPES/ESPE CAH Group. Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. J Clin Endocrinol Metab. 2002;87:4048–53.

    Article  CAS  Google Scholar 

  55. Ventura A, Brunetti G, Colucci S, Oranger A, Ladisa F, Cavallo L, et al. Glucocorticoid-induced osteoporosis in children with 21-hydroxylase deficiency. Biomed Res Int. 2013;2013:250462.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Faienza MF, Brunetti G, Colucci S, Piacente L, Ciccarelli M, Giordani L, et al. Osteoclastogenesis in children with 21-hydroxylase deficiency on long-term glucocorticoid therapy: the role of receptor activator of nuclear factor κB ligand/osteoprotegerin imbalance. J Clin Endocrinol Metab. 2009;94:2269–76.

    Article  PubMed  CAS  Google Scholar 

  57. Abd El Dayem SM, Anwar GM, Salama H, Kamel AF, Emara N. Bone mineral density, bone turnover markers, lean mass, and fat mass in Egyptian children with congenital adrenal hyperplasia. Arch Med Sci. 2010;6:104–10.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Metwalley KA, El-Saied AR. Bone mineral status in Egyptian children with classical congenital adrenal hyperplasia. A single center study from Upper Egypt. Indian J Endocrinol Metab. 2014;18:700–4.

    PubMed  PubMed Central  Google Scholar 

  59. Brunetti G, Faienza MF, Piacente L, Ventura A, Oranger A, Carbone C, et al. High dickkopf-1 levels in sera and leukocytes from children with 21-hydroxylase deficiency on chronic glucocorticoid treatment. Am J Physiol Endocrinol Metab. 2013;304:546–54.

    Article  CAS  Google Scholar 

  60. Butler MG, Manzardo AM, Forster JL. Prader–Willi syndrome: clinical genetics and diagnostic aspects with treatment approaches. Curr Pediatr Rev. 2016;12:136–66.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader–Willi syndrome. Genet Med. 2012;14:10–26.

    Article  PubMed  CAS  Google Scholar 

  62. Vestergaard P, Kristensen K, Bruun JM, Østergaard JR, Heickendorff L, Mosekilde L, et al. 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. 2004;144:614–9.

    Article  PubMed  Google Scholar 

  63. Carrel AL, Myers SE, Whitman BY, Allen DB. Benefits of long-term GH therapy in Prader–Willi syndrome: a 4-year study. J Clin Endocrinol Metab. 2002;87:1581–15885.

    Article  PubMed  CAS  Google Scholar 

  64. Brunetti G, Grugni G, Piacente L, Delvecchio M, Ventura A, Giordano P, et al. Analysis of circulating mediators of bone remodelling in Prader–Willi syndrome. Calcific Tissue Int. 2018;102:635–43.

    Article  CAS  Google Scholar 

  65. Faienza MF, Chiarito M, D’amato G, Colaianni G, Colucci S, Grano M, et al. Monoclonal antibodies for treating osteoporosis. Expert Opin Biol Ther. 2018;18:149–57.

    Article  PubMed  CAS  Google Scholar 

  66. Hoyer-Kuhn H, Franklin J, Allo G, Kron M, Netzer C, Eysel P, et al. Safety and efficacy of denosumab in children with osteogenesis imperfect-a first prospective trial. J Musculoskelet Neuronal Interact. 2016;16:24–32.

    PubMed  PubMed Central  CAS  Google Scholar 

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Authors and Affiliations

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

    Giacomina Brunetti & Silvia Colucci

  2. Neonatal Intensive Care Unit, Di Venere Hospital, Bari, Italy

    Gabriele D’Amato

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

    Mariangela Chiarito & Maria Felicia Faienza

  4. Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies-IBIOM, CNR, 70126, Bari, Italy

    Apollonia Tullo

  5. Department of Emergency and Organ Transplantation, University “A. Moro” of Bari, Bari, Italy

    Graziana Colaianni & Maria Grano

Authors
  1. Giacomina Brunetti
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  2. Gabriele D’Amato
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  3. Mariangela Chiarito
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  4. Apollonia Tullo
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  5. Graziana Colaianni
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  6. Silvia Colucci
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  7. Maria Grano
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  8. Maria Felicia Faienza
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Contributions

GB and MF wrote the review; GD and MC revised the literature; AT, GC, SC and MG wrote the introduction and conclusion and critically revised the manuscript.

Corresponding author

Correspondence to Maria Felicia Faienza.

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No financial or nonfinancial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.

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Brunetti, G., D’Amato, G., Chiarito, M. et al. An update on the role of RANKL–RANK/osteoprotegerin and WNT-ß-catenin signaling pathways in pediatric diseases. World J Pediatr 15, 4–11 (2019). https://doi.org/10.1007/s12519-018-0198-7

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