Skip to main content

Current Analysis of Skeletal Phenotypes in Down Syndrome

Abstract

Purpose

Down syndrome (DS) is caused by trisomy 21 (Ts21) and results in skeletal deficits including shortened stature, low bone mineral density, and a predisposition to early onset osteoporosis. Ts21 causes significant alterations in skeletal development, morphology of the appendicular skeleton, bone homeostasis, age-related bone loss, and bone strength. However, the genetic or cellular origins of DS skeletal phenotypes remain unclear.

Recent Findings

New studies reveal a sexual dimorphism in characteristics and onset of skeletal deficits that differ between DS and typically developing individuals. Age-related bone loss occurs earlier in the DS as compared to general population.

Summary

Perturbations of DS skeletal quality arise from alterations in cellular and molecular pathways affected by the overexpression of trisomic genes. Sex-specific alterations occur in critical developmental pathways that disrupt bone accrual, remodeling, and homeostasis and are compounded by aging, resulting in increased risks for osteopenia, osteoporosis, and fracture in individuals with DS.

This is a preview of subscription content, access via your institution.

References

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

  1. de Graaf G, Buckley F, Skotko BG. Estimation of the number of people with Down syndrome in the United States. Genet Med. 2017;19(4):439–47. https://doi.org/10.1038/gim.2016.127.

    Article  PubMed  Google Scholar 

  2. de Moraes ME, Tanaka JL, de Moraes LC, Filho EM, de Melo Castilho JC. Skeletal age of individuals with Down Syndrome. Spec Care Dentist. 2008;28(3):101–6. https://doi.org/10.1111/j.1754-4505.2008.00020.x.

    Article  PubMed  Google Scholar 

  3. Keeling JW, Hansen BF, Kjaer I. Pattern of malformations in the axial skeleton in human trisomy 21 fetuses. Am J Med Genet. 1997;68(4):466–71. https://doi.org/10.1002/(SICI)1096-8628(19970211)68:4<466::AID-AJMG19>3.0.CO;2-Q.

    CAS  Article  PubMed  Google Scholar 

  4. Barden HS. Growth and development of selected hard tissues in Down syndrome: a review. Hum Biol. 1983;55(3):539–76.

    CAS  PubMed  Google Scholar 

  5. Nyberg DA, Souter VL, El-Bastawissi A, Young S, Luthhardt F, Luthy DA. Isolated sonographic markers for detection of fetal Down syndrome in the second trimester of pregnancy. J Ultrasound Med. 2001;20(10):1053–63. https://doi.org/10.7863/jum.2001.20.10.1053.

    CAS  Article  PubMed  Google Scholar 

  6. Bromley B, Lieberman E, Shipp TD, Benacerraf BR. The genetic sonogram: a method of risk assessment for Down syndrome in the second trimester. J Ultrasound Med. 2002;21(10):1087–96 quiz 97-8.

    Article  Google Scholar 

  7. Rarick GL, Rapaport IF, Seefeldt V. Long bone growth in down’s syndrome. Am J Dis Child. 1966;112(6):566–71. https://doi.org/10.1001/archpedi.1966.02090150110012.

    CAS  Article  PubMed  Google Scholar 

  8. Guihard-Costa AM, Khung S, Delbecque K, Menez F, Delezoide AL. Biometry of face and brain in fetuses with trisomy 21. Pediatr Res. 2006;59(1):33–8.

    Article  Google Scholar 

  9. Baptista F, Varela A, Sardinha LB. Bone mineral mass in males and females with and without Down syndrome. Osteoporos Int. 2005;16(4):380–8.

    Article  Google Scholar 

  10. Angelopoulou N, Souftas V, Sakadamis A, Mandroukas K. Bone mineral density in adults with Down's syndrome. Eur Radiol. 1999;9(4):648–51.

    CAS  Article  Google Scholar 

  11. Esbensen AJ. Health conditions associated with aging and end of life of adults with Down syndrome. Int Rev Res Ment Retard. 2010;39(C):107–26. https://doi.org/10.1016/S0074-7750(10)39004-5.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Hawli Y, Nasrallah M, El-Hajj Fuleihan G. Endocrine and musculoskeletal abnormalities in patients with Down syndrome. Nat Rev Endocrinol. 2009;5(6):327–34.

    CAS  Article  Google Scholar 

  13. Center J, Beange H, McElduff A. People with mental retardation have an increased prevalence of osteoporosis: a population study. Am J Ment Retard. 1998;103(1):19–28. https://doi.org/10.1352/0895-8017(1998)103<0019:PWMRHA>2.0.CO;2.

    CAS  Article  PubMed  Google Scholar 

  14. Garcia-Hoyos M, Riancho JA, Valero C. Bone health in Down syndrome. Med Clin (Barc). 2017;149(2):78–82. https://doi.org/10.1016/j.medcli.2017.04.020.

    Article  Google Scholar 

  15. Gonzalez-Aguero A, Vicente-Rodriguez G, Gomez-Cabello A, Casajus JA. Cortical and trabecular bone at the radius and tibia in male and female adolescents with Down syndrome: a peripheral quantitative computed tomography (pQCT) study. Osteoporos Int. 2013;24(3):1035–44. https://doi.org/10.1007/s00198-012-2041-7.

    CAS  Article  PubMed  Google Scholar 

  16. • LaCombe JM, Roper RJ. Skeletal dynamics of Down syndrome: a developing perspective. Bone. 2020;133:115215. https://doi.org/10.1016/j.bone.2019.115215Bone abnormalities in DS result from changes in bone formation and homeostasis early in development. Adolescents with DS have a high rate of fractures.

    Article  PubMed  Google Scholar 

  17. Matute-Llorente A, Gonzalez-Aguero A, Gomez-Cabello A, Vicente-Rodriguez G, Casajus JA. Decreased levels of physical activity in adolescents with Down syndrome are related with low bone mineral density: a cross-sectional study. BMC Endocr Disord. 2013;13:22. https://doi.org/10.1186/1472-6823-13-22.

    Article  PubMed  PubMed Central  Google Scholar 

  18. •• Tang JYM, Luo H, Wong GHY, Lau MMY, Joe GM, Tse MA, et al. Bone mineral density from early to middle adulthood in persons with Down syndrome. J Intellect Disabil Res. 2019;63(8):936–46. https://doi.org/10.1111/jir.12608Individuals with DS exhibited age-related bone loss compared to those without DS, with men with DS exhibiting gradual bone loss since early adulthood, increasing their risk for onset of osteoporosis compared to females with DS. BMD in adults with DS with continued age-related loss in men and rapid loss in women with DS.

    CAS  Article  PubMed  Google Scholar 

  19. Baird PA, Sadovnick AD. Life tables for Down syndrome. Hum Genet. 1989;82(3):291–2.

    CAS  Article  Google Scholar 

  20. Bittles AH, Glasson EJ. Clinical, social, and ethical implications of changing life expectancy in Down syndrome. Dev Med Child Neurol. 2004;46(4):282–6.

    CAS  Article  Google Scholar 

  21. Weijerman ME, de Winter JP. Clinical practice. The care of children with Down syndrome. Eur J Pediatr. 2010;169(12):1445–52. https://doi.org/10.1007/s00431-010-1253-0.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Whooten R, Schmitt J, Schwartz A. Endocrine manifestations of Down syndrome. Curr Opin Endocrinol Diabetes Obes. 2018;25(1):61–6. https://doi.org/10.1097/MED.0000000000000382.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. •• Burke EA, Carroll R, O'Dwyer MO, Walsh JB, McCallion P, McCarron M. Osteoporosis and people with Down syndrome: a preliminary descriptive examination of the intellectual disability supplement to the irish longitudinal study on ageing wave 1 results. Health. 2018;10:1233–49 Individuals with are considered a high risk group for the development of osteopenia and osteoporosis compared to the general population and low screening rates might lead to undiagnosed skeletal disease.

    Article  Google Scholar 

  24. Myrelid A, Gustafsson J, Ollars B, Anneren G. Growth charts for Down’s syndrome from birth to 18 years of age. Arch Dis Child. 2002;87(2):97–103. https://doi.org/10.1136/adc.87.2.97.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Zemel BS, Pipan M, Stallings VA, Hall W, Schadt K, Freedman DS, et al. Growth charts for children with down syndrome in the United States. Pediatrics. 2015;136(5):e1204–11. https://doi.org/10.1542/peds.2015-1652.

    Article  PubMed  Google Scholar 

  26. Burr DB, Allen MR. Basic and applied bone biology. Amsterdam: Elsevier/Academic Press; 2013.

    Google Scholar 

  27. Baxter-Jones AD, Faulkner RA, Forwood MR, Mirwald RL, Bailey DA. Bone mineral accrual from 8 to 30 years of age: an estimation of peak bone mass. J Bone Miner Res. 2011;26(8):1729–39. https://doi.org/10.1002/jbmr.412.

    Article  PubMed  Google Scholar 

  28. Gonzalez-Aguero A, Vicente-Rodriguez G, Moreno LA, Casajus JA. Bone mass in male and female children and adolescents with Down syndrome. Osteoporos Int. 2011;22(7):2151–7. https://doi.org/10.1007/s00198-010-1443-7.

    CAS  Article  PubMed  Google Scholar 

  29. Burke EA, McCallion P, Carroll R, Walsh JB, McCarron M. An exploration of the bone health of older adults with an intellectual disability in Ireland. J Intellect Disabil Res. 2017;61(2):99–114. https://doi.org/10.1111/jir.12273.

    CAS  Article  PubMed  Google Scholar 

  30. van Allen MI, Fung J, Jurenka SB. Health care concerns and guidelines for adults with Down syndrome. Am J Med Genet. 1999;89(2):100–10.

    Article  Google Scholar 

  31. Angelopoulou N, Matziari C, Tsimaras V, Sakadamis A, Souftas V, Mandroukas K. Bone mineral density and muscle strength in young men with mental retardation (with and without Down syndrome). Calcif Tissue Int. 2000;66(3):176–80.

    CAS  Article  Google Scholar 

  32. •• Costa R, De Miguel R, Garcia C, de Asua DR, Castaneda S, Moldenhauer F, et al. Bone mass assessment in a cohort of adults with Down syndrome: a cross-sectional study. Intellect Dev Disabil. 2017;55(5):315–24. https://doi.org/10.1352/1934-9556-55.5.315Areal BMD study of a large cohort of individuals with DS found high rate of osteopenia and osteoporosis in the femoral neck and lumbar spine. Young adults with DS have BMD that is similar to postmenopausal women, with males having lower levesl than females with DS.

    Article  PubMed  Google Scholar 

  33. McKelvey KD, Fowler TW, Akel NS, Kelsay JA, Gaddy D, Wenger GR, et al. Low bone turnover and low bone density in a cohort of adults with Down syndrome. Osteoporos Int. 2013;24(4):1333–8. https://doi.org/10.1007/s00198-012-2109-4.

    CAS  Article  PubMed  Google Scholar 

  34. Herault Y, Delabar JM, Fisher EMC, Tybulewicz VLJ, Yu E, Brault V. Rodent models in Down syndrome research: impact and future opportunities. Dis Model Mech. 2017;10(10):1165–86. https://doi.org/10.1242/dmm.029728.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Gupta M, Dhanasekaran AR, Gardiner KJ. Mouse models of Down syndrome: gene content and consequences. Mamm Genome. 2016;27(11-12):538–55. https://doi.org/10.1007/s00335-016-9661-8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Reeves RH, Irving NG, Moran TH, Wohn A, Kitt C, Sisodia SS, et al. A mouse model for Down syndrome exhibits learning and behaviour deficits. Nat Genet. 1995;11(2):177–84.

    CAS  Article  Google Scholar 

  37. Blazek JD, Gaddy A, Meyer R, Roper RJ, Li J. Disruption of bone development and homeostasis by trisomy in Ts65Dn Down syndrome mice. Bone. 2011;48(2):275–80. https://doi.org/10.1016/j.bone.2010.09.028.

    CAS  Article  PubMed  Google Scholar 

  38. Blazek JD, Abeysekera I, Li J, Roper RJ. Rescue of the abnormal skeletal phenotype in Ts65Dn Down syndrome mice using genetic and therapeutic modulation of trisomic Dyrk1a. Hum Mol Genet. 2015;24(20):5687–96. https://doi.org/10.1093/hmg/ddv284.

    CAS  Article  PubMed  Google Scholar 

  39. Fowler TW, McKelvey KD, Akel NS, Vander Schilden J, Bacon AW, Bracey JW, et al. Low bone turnover and low BMD in Down syndrome: effect of intermittent PTH treatment. PLoS One. 2012;7(8):e42967. https://doi.org/10.1371/journal.pone.0042967.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Olson LE, Richtsmeier JT, Leszl J, Reeves RH. A chromosome 21 critical region does not cause specific Down syndrome phenotypes. Science. 2004;306(5696):687–90.

    CAS  Article  Google Scholar 

  41. Olson LE, Roper RJ, Sengstaken CL, Peterson EA, Aquino V, Galdzicki Z, et al. Trisomy for the Down syndrome 'critical region' is necessary but not sufficient for brain phenotypes of trisomic mice. Hum Mol Genet. 2007;16(7):774–82. https://doi.org/10.1093/hmg/ddm022.

    CAS  Article  PubMed  Google Scholar 

  42. Olson LE, Mohan S. Bone density phenotypes in mice aneuploid for the Down syndrome critical region. Am J Med Genet A. 2011;155(10):2436–45. https://doi.org/10.1002/ajmg.a.34203.

    Article  Google Scholar 

  43. •• Thomas JR, LaCombe J, Long R, Lana-Elola E, Watson-Scales S, Wallace JM, et al. Interaction of sexual dimorphism and gene dosage imbalance in skeletal deficits associated with Down syndrome. Bone. 2020;136:115367. https://doi.org/10.1016/j.bone.2020.115367Sexual dimorphism, age, gene dosage and skeletal sites are influenced by three copies of genes homologous to Hsa21 and result in sex-specific and age-related skeletal abnormalities.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. Lana-Elola E, Watson-Scales S, Slender A, Gibbins D, Martineau A, Douglas C, et al. Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel. eLife. 2016;5. https://doi.org/10.7554/eLife.11614.

  45. Guijarro M, Valero C, Paule B, Gonzalez-Macias J, Riancho JA. Bone mass in young adults with Down syndrome. J Intellect Disabil Res. 2008;52(Pt 3):182–9. https://doi.org/10.1111/j.1365-2788.2007.00992.x.

    CAS  Article  PubMed  Google Scholar 

  46. •• Carfi A, Liperoti R, Fusco D, Giovannini S, Brandi V, Vetrano DL, et al. Bone mineral density in adults with Down syndrome. Osteoporos Int. 2017;28(10):2929–34. https://doi.org/10.1007/s00198-017-4133-xAdults with DS have lower bone mineral density compared to the general population, and a sharp decline in bone mass with age, men with DS have lower BMAD compared to women with DS.

    CAS  Article  PubMed  Google Scholar 

  47. Garcia-Hoyos M, Garcia-Unzueta MT, de Luis D, Valero C, Riancho JA. Diverging results of areal and volumetric bone mineral density in Down syndrome. Osteoporos Int. 2017;28(3):965–72. https://doi.org/10.1007/s00198-016-3814-1.

    CAS  Article  PubMed  Google Scholar 

  48. • Garcia Hoyos M, Humbert L, Salmon Z, Riancho JA, Valero C. Analysis of volumetric BMD in people with Down syndrome using DXA-based 3D modeling. Arch Osteoporos. 2019;14(1):98. https://doi.org/10.1007/s11657-019-0645-7Femurs analyzed with DXA-based 3D modeling technique revealed individuals with DS had lower vBMD compared to those without DS and age related bone loss was more pronounced in individuals with DS.

    Article  PubMed  Google Scholar 

  49. Wu J. Bone mass and density in preadolescent boys with and without Down syndrome. Osteoporos Int. 2013;24(11):2847–54. https://doi.org/10.1007/s00198-013-2393-7.

    CAS  Article  PubMed  Google Scholar 

  50. •• Costa R, Gullon A, De Miguel R, de Asua DR, Bautista A, Garcia C, et al. Bone mineral density distribution curves in Spanish adults with Down syndrome. J Clin Densitom. 2018;21(4):493–500. https://doi.org/10.1016/j.jocd.2018.03.001Individuals with DS reach peak bone mass earlier and have lower bone mineral density compared to the general population and the male gender is at an increased risk for developing low bone mineral density.

    Article  PubMed  Google Scholar 

  51. Barnhart RC, Connolly B. Aging and Down syndrome: implications for physical therapy. Phys Ther. 2007;87(10):1399–406. https://doi.org/10.2522/ptj.20060334.

    Article  PubMed  Google Scholar 

  52. Grimwood JS, Kumar A, Bickerstaff DR, Suvarna SK. Histological assessment of vertebral bone in a Down's syndrome adult with osteoporosis. Histopathology. 2000;36(3):279–80.

    CAS  Article  Google Scholar 

  53. Kamalakar A, Harris JR, McKelvey KD, Suva LJ. Aneuploidy and skeletal health. Curr Osteoporos Rep. 2014;12(3):376–82. https://doi.org/10.1007/s11914-014-0221-4.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Blazek JD, Malik AM, Tischbein M, Arbones ML, Moore CS, Roper RJ. Abnormal mineralization of the Ts65Dn Down syndrome mouse appendicular skeleton begins during embryonic development in a Dyrk1a-independent manner. Mech Dev. 2015;136:133–42. https://doi.org/10.1016/j.mod.2014.12.004.

    CAS  Article  PubMed  Google Scholar 

  55. • Williams DK, Parham SG, Schryver E, Akel NS, Shelton RS, Webber J, et al. Sclerostin antibody treatment stimulates bone formation to normalize bone mass in male down syndrome mice. JBMR Plus. 2018;2(1):47–54. https://doi.org/10.1002/jbm4.10025Examines the relationship between bone mineral density and skeletal health in individuals with Down syndrome.

    CAS  Article  PubMed  Google Scholar 

  56. Gonzalez-Aguero A, Vicente-Rodriguez G, Gomez-Cabello A, Ara I, Moreno LA, Casajus JA. A 21-week bone deposition promoting exercise programme increases bone mass in young people with Down syndrome. Dev Med Child Neurol. 2012;54(6):552–6. https://doi.org/10.1111/j.1469-8749.2012.04262.x.

    Article  PubMed  Google Scholar 

  57. Matute-Llorente A, Gonzalez-Aguero A, Vicente-Rodriguez G, Sardinha LB, Baptista F, Casajus JA. Physical activity and bone mineral density at the femoral neck subregions in adolescents with Down syndrome. J Pediatr Endocrinol Metab. 2017;30(10):1075–82. https://doi.org/10.1515/jpem-2017-0024.

    CAS  Article  PubMed  Google Scholar 

  58. Matute-Llorente A, Gonzalez-Aguero A, Gomez-Cabello A, Olmedillas H, Vicente-Rodriguez G, Casajus JA. Effect of whole body vibration training on bone mineral density and bone quality in adolescents with Down syndrome: a randomized controlled trial. Osteoporos Int. 2015;26(10):2449–59. https://doi.org/10.1007/s00198-015-3159-1.

    CAS  Article  PubMed  Google Scholar 

  59. Antonarakis SE, Skotko BG, Rafii MS, Strydom A, Pape SE, Bianchi DW, et al. Down syndrome. Nat Rev Dis Primers. 2020;6(1):9. https://doi.org/10.1038/s41572-019-0143-7.

    Article  PubMed  Google Scholar 

  60. Stamoulis G, Garieri M, Makrythanasis P, Letourneau A, Guipponi M, Panousis N, et al. Single cell transcriptome in aneuploidies reveals mechanisms of gene dosage imbalance. Nat Commun. 2019;10(1):4495. https://doi.org/10.1038/s41467-019-12273-8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. Wiseman FK, Alford KA, Tybulewicz VL, Fisher EM. Down syndrome--recent progress and future prospects. Hum Mol Genet. 2009;18(R1):R75–83.

    CAS  Article  Google Scholar 

  62. Arron JR, Winslow MM, Polleri A, Chang CP, Wu H, Gao X, et al. NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature. 2006;441(7093):595–600.

    CAS  Article  Google Scholar 

  63. Duchon A, Herault Y. DYRK1A, a dosage-sensitive gene involved in neurodevelopmental disorders, is a target for drug development in Down syndrome. Front Behav Neurosci. 2016;10:104. https://doi.org/10.3389/fnbeh.2016.00104.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. Altafaj X, Dierssen M, Baamonde C, Marti E, Visa J, Guimera J, et al. Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome. Hum Mol Genet. 2001;10(18):1915–23.

    CAS  Article  Google Scholar 

  65. Branchi I, Bichler Z, Minghetti L, Delabar JM, Malchiodi-Albedi F, Gonzalez MC, et al. Transgenic mouse in vivo library of human Down syndrome critical region 1: association between DYRK1A overexpression, brain development abnormalities, and cell cycle protein alteration. J Neuropathol Exp Neurol. 2004;63(5):429–40.

    CAS  Article  Google Scholar 

  66. Guedj F, Pereira PL, Najas S, Barallobre MJ, Chabert C, Souchet B, et al. DYRK1A: a master regulatory protein controlling brain growth. Neurobiol Dis. 2012;46(1):190–203. https://doi.org/10.1016/j.nbd.2012.01.007.

    CAS  Article  PubMed  Google Scholar 

  67. Park J, Song WJ, Chung KC. Function and regulation of Dyrk1A: towards understanding Down syndrome. Cell Mol Life Sci. 2009;66(20):3235–40. https://doi.org/10.1007/s00018-009-0123-2.

    CAS  Article  PubMed  Google Scholar 

  68. Lee Y, Ha J, Kim HJ, Kim YS, Chang EJ, Song WJ, et al. Negative feedback Inhibition of NFATc1 by DYRK1A regulates bone homeostasis. J Biol Chem. 2009;284(48):33343–51. https://doi.org/10.1074/jbc.M109.042234.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. Stringer M, Goodlett CR, Roper RJ. Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits. Mol Genet Genomic Med. 2017;5(5):451–65. https://doi.org/10.1002/mgg3.334.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. Abbassi R, Johns TG, Kassiou M, Munoz L. DYRK1A in neurodegeneration and cancer: Molecular basis and clinical implications. Pharmacol Ther. 2015;151:87–98. https://doi.org/10.1016/j.pharmthera.2015.03.004.

    CAS  Article  PubMed  Google Scholar 

  71. Hammerle B, Ulin E, Guimera J, Becker W, Guillemot F, Tejedor FJ. Transient expression of Mnb/Dyrk1a couples cell cycle exit and differentiation of neuronal precursors by inducing p27KIP1 expression and suppressing NOTCH signaling. Development. 2011;138(12):2543–54. https://doi.org/10.1242/dev.066167.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. He Y, Staser K, Rhodes SD, Liu Y, Wu X, Park SJ, et al. Erk1 positively regulates osteoclast differentiation and bone resorptive activity. PLoS One. 2011;6(9):e24780. https://doi.org/10.1371/journal.pone.0024780.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. Neal JW, Clipstone NA. Glycogen synthase kinase-3 inhibits the DNA binding activity of NFATc. J Biol Chem. 2001;276(5):3666–73. https://doi.org/10.1074/jbc.M004888200.

    CAS  Article  PubMed  Google Scholar 

  74. Sato K, Suematsu A, Nakashima T, Takemoto-Kimura S, Aoki K, Morishita Y, et al. Regulation of osteoclast differentiation and function by the CaMK-CREB pathway. Nat Med. 2006;12(12):1410–6. https://doi.org/10.1038/nm1515.

    CAS  Article  PubMed  Google Scholar 

  75. Soppa U, Schumacher J, Florencio Ortiz V, Pasqualon T, Tejedor FJ, Becker W. The Down syndrome-related protein kinase DYRK1A phosphorylates p27(Kip1) and Cyclin D1 and induces cell cycle exit and neuronal differentiation. Cell Cycle. 2014;13(13):2084–100. https://doi.org/10.4161/cc.29104.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. Souchet B, Guedj F, Penke-Verdier Z, Daubigney F, Duchon A, Herault Y, et al. Pharmacological correction of excitation/inhibition imbalance in Down syndrome mouse models. Front Behav Neurosci. 2015;9:267. https://doi.org/10.3389/fnbeh.2015.00267.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. Valenti D, de Bari L, de Rasmo D, Signorile A, Henrion-Caude A, Contestabile A, et al. The polyphenols resveratrol and epigallocatechin-3-gallate restore the severe impairment of mitochondria in hippocampal progenitor cells from a Down syndrome mouse model. Biochim Biophys Acta. 2016;1862(6):1093–104. https://doi.org/10.1016/j.bbadis.2016.03.003.

    CAS  Article  PubMed  Google Scholar 

  78. Deshmukh V, O'Green AL, Bossard C, Seo T, Lamangan L, Ibanez M, et al. Modulation of the Wnt pathway through inhibition of CLK2 and DYRK1A by lorecivivint as a novel, potentially disease-modifying approach for knee osteoarthritis treatment. Osteoarthr Cartil. 2019;27(9):1347–60. https://doi.org/10.1016/j.joca.2019.05.006.

    CAS  Article  Google Scholar 

  79. Granno S, Nixon-Abell J, Berwick DC, Tosh J, Heaton G, Almudimeegh S, et al. Downregulated Wnt/beta-catenin signalling in the Down syndrome hippocampus. Sci Rep. 2019;9(1):7322. https://doi.org/10.1038/s41598-019-43820-4.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. Zainabadi K, Liu CJ, Caldwell ALM, Guarente L. SIRT1 is a positive regulator of in vivo bone mass and a therapeutic target for osteoporosis. PLoS One. 2017;12(9):e0185236. https://doi.org/10.1371/journal.pone.0185236.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

Work on this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number R15HD090603. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Randall J. Roper.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Genetics

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Thomas, J.R., Roper, R.J. Current Analysis of Skeletal Phenotypes in Down Syndrome. Curr Osteoporos Rep 19, 338–346 (2021). https://doi.org/10.1007/s11914-021-00674-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11914-021-00674-y

Keywords

  • Down syndrome
  • Trisomy 21
  • Bone mineral density
  • Osteoporosis
  • Osteopenia