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Failures of Endochondral Ossification in the Mucopolysaccharidoses

  • Rare Bone Disease (CB Langman and E Shore, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders characterized by abnormal accumulation of glycosaminoglycans (GAGs) in cells and tissues. MPS patients frequently exhibit failures of endochondral ossification during postnatal growth leading to skeletal deformity and short stature. In this review, we outline the current understanding of the cellular and molecular mechanisms underlying failures of endochondral ossification in MPS and discuss associated treatment challenges and opportunities.

Recent Findings

Studies in MPS patients and animal models have demonstrated that skeletal cells and tissues exhibit significantly elevated GAG storage from early in postnatal life and that this is associated with impaired cartilage-to-bone conversion in primary and secondary ossification centers, and growth plate dysfunction. Recent studies have begun to elucidate the underlying cellular and molecular mechanisms, including impaired chondrocyte proliferation and hypertrophy, diminished growth factor signaling, disrupted cell cycle progression, impaired autophagy, and increased cell stress and apoptosis. Current treatments such as hematopoietic stem cell transplantation and enzyme replacement therapy fail to normalize endochondral ossification in MPS. Emerging treatments including gene therapy and small molecule–based approaches hold significant promise in this regard.

Summary

Failures of endochondral ossification contribute to skeletal deformity and short stature in MPS patients, increasing mortality and reducing quality of life. Early intervention is crucial for effective treatment, and there is a critical need for new approaches that normalize endochondral ossification by directly targeting affected cells and signaling pathways.

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References

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

  1. Muenzer J. Overview of the mucopolysaccharidoses. Rheumatology (Oxford). 2011;50(Suppl 5):v4–12.

    CAS  Google Scholar 

  2. Zelei T, Csetneki K, Vokó Z, Siffel C. Epidemiology of Sanfilippo syndrome: results of a systematic literature review. Orphanet J Rare Dis. 2018;13:53–3.

  3. Andrade F, Aldámiz-Echevarría L, Llarena M, Couce ML. Sanfilippo syndrome: overall review. Pediatr Int : official journal of the Japan Pediatric Society. 2015;57:331–8.

    Google Scholar 

  4. Kowalewski B, Lamanna WC, Lawrence R, et al. Arylsulfatase G inactivation causes loss of heparan sulfate 3-O-sulfatase activity and mucopolysaccharidosis in mice. Proc Natl Acad Sci U S A. 2012;109:10310–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Neufeld E, Muenzer J. The mucopolysaccharidoses. In: Sciver C, Beaudet A, Sly W, Valle D, editors. The metabolic and molecular bases of inherited disease. New York: McGraw hill; 2001. p. 3421–52.

    Google Scholar 

  6. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. The extracellular matrix of animal connective tissues. New York: Molecular biology of the cell, Garland Science; 2008. p. 1178–94.

    Google Scholar 

  7. Long F, Ornitz DM. Development of the endochondral skeleton. Cold Spring Harb Perspect Biol. 2013;5:a008334.

    PubMed  PubMed Central  Google Scholar 

  8. Mackie EJ, Tatarczuch L, Mirams M. The skeleton: a multi-functional complex organ: the growth plate chondrocyte and endochondral ossification. J Endocrinol. 2011;211:109–21.

    CAS  PubMed  Google Scholar 

  9. MacLean HE, Kim JI, Glimcher MJ, Wang J, Kronenberg HM, Glimcher LH. Absence of transcription factor c-maf causes abnormal terminal differentiation of hypertrophic chondrocytes during endochondral bone development. Dev Biol. 2003;262:51–63.

    CAS  PubMed  Google Scholar 

  10. Tsang KY, Chan D, Cheah KS. Fate of growth plate hypertrophic chondrocytes: death or lineage extension? Develop Growth Differ. 2015;57:179–92.

    CAS  Google Scholar 

  11. Mackie EJ, Ahmed YA, Tatarczuch L, Chen KS, Mirams M. Endochondral ossification: how cartilage is converted into bone in the developing skeleton. Int J Biochem Cell Biol. 2008;40:46–62.

    CAS  PubMed  Google Scholar 

  12. Maes C, Kronenberg HM. Chapter 60 - Bone development and remodeling A2. In: Larry JJ, Groot LJD, Kretser DMD, Giudice LC, Grossman AB, Melmed S, Potts JT, Weir GC, editors. Endocrinology: adult and pediatric. 7th ed. Philadelphia: W.B. Saunders; 2016. p. 1038–1062.e1038.

    Google Scholar 

  13. Trueta J, Amato VP. The vascular contribution to osteogenesis. III. Changes in the growth cartilage caused by experimentally induced ischaemia. J Bone Joint Surg (Br). 1960;42-B:571–87.

    CAS  Google Scholar 

  14. Trueta J, Trias A. The vascular contribution to osteogenesis. IV. The effect of pressure upon the epiphysial cartilage of the rabbit. J Bone Joint Surg (Br). 1961;43-b:800–13.

    CAS  Google Scholar 

  15. Maeda Y, Nakamura E, Nguyen MT, Suva LJ, Swain FL, Razzaque MS, et al. Indian hedgehog produced by postnatal chondrocytes is essential for maintaining a growth plate and trabecular bone. Proc Natl Acad Sci U S A. 2007;104:6382–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Maes C. Signaling pathways effecting crosstalk between cartilage and adjacent tissues: seminars in cell and developmental biology: the biology and pathology of cartilage. Semin Cell Dev Biol. 2017;62:16–33.

    CAS  PubMed  Google Scholar 

  17. Rozdzynska-Swiatkowska A, Jurecka A, Cieslik J, Tylki-Szymanska A. Growth patterns in children with mucopolysaccharidosis I and II. World J Pediatr : WJP. 2015;11:226–31.

    PubMed  Google Scholar 

  18. Silveri CP, Kaplan FS, Fallon MD, Bayever E, August CS. Hurler syndrome with special reference to histologic abnormalities of the growth plate. Clin Orthop Relat Res. 1991:305–11.

  19. Peck SH, Casal ML, Malhotra NR, Ficicioglu C, Smith LJ. Pathogenesis and treatment of spine disease in the mucopolysaccharidoses. Mol Genet Metab. 2016;118:232–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Lin HY, Shih SC, Chuang CK, Chen MR, Niu DM, Lin SP. Assessment of bone mineral density by dual energy x-ray absorptiometry in patients with mucopolysaccharidoses. Orphanet J Rare Dis. 2013;8:71.

    PubMed  PubMed Central  Google Scholar 

  21. Polgreen LE, Miller BS. Growth patterns and the use of growth hormone in the mucopolysaccharidoses. J Pediatr Rehabil Med. 2010;3:25–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Parini R, Jones SA, Harmatz PR, Giugliani R, Mendelsohn NJ. The natural history of growth in patients with Hunter syndrome: data from the Hunter Outcome Survey (HOS). Mol Genet Metab. 2016;117:438–46.

    CAS  PubMed  Google Scholar 

  23. Różdżyńska-Świątkowska A, Jurecka A, Żuber Z, Tylki-Szymańska A. Can macrosomia or large for gestational age be predictive of mucopolysaccharidosis type I, II and VI? Pediatr Neonatol. 2016;57:181–7.

    PubMed  Google Scholar 

  24. Rozdzynska A, Tylki-Szymanska A, Jurecka A, Cieslik J. Growth pattern and growth prediction of body height in children with mucopolysaccharidosis type II. Acta Paediatrica (Oslo, Norway : 1992). 2011;100:456–60.

    Google Scholar 

  25. Young ID, Harper PS. Mild form of Hunter’s syndrome: clinical delineation based on 31 cases. Arch Dis Child. 1982;57:828–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Patel P, Suzuki Y, Maeda M, Yasuda E, Shimada T, Orii KE, et al. Growth charts for patients with Hunter syndrome. Mol Gen Metab Rep. 2014;1:5–18.

    Google Scholar 

  27. Fung EB, Johnson JA, Madden J, Kim T, Harmatz P. Bone density assessment in patients with mucopolysaccharidosis: a preliminary report from patients with MPS II and VI. J Pediatr Rehabil Med. 2010;3:13–23.

    PubMed  PubMed Central  Google Scholar 

  28. Muschol NM, Pape D, Kossow K, Ullrich K, Arash-Kaps L, Hennermann JB, et al. Growth charts for patients with Sanfilippo syndrome (mucopolysaccharidosis type III). Orphanet J Rare Dis. 2019;14:93.

    PubMed  PubMed Central  Google Scholar 

  29. Ruijter GJ, Goudriaan DA, Boer AM, Van den Bosch J, Van der Ploeg AT, Elvers LH, et al. Newborn screening for hunter disease: a small-scale feasibility study. JIMD reports. 2014;14:23–7.

    CAS  PubMed  Google Scholar 

  30. Montaño AM, Tomatsu S, Brusius A, Smith M, Orii T. Growth charts for patients affected with Morquio A disease. Am J Med Genet A. 2008;146A:1286–95.

    PubMed  Google Scholar 

  31. McClure J, Smith PS, Sorby-Adams G, Hopwood J. The histological and ultrastructural features of the epiphyseal plate in Morquio type a syndrome (mucopolysaccharidosis type IVA). Pathology. 1986;18:217–21.

    CAS  PubMed  Google Scholar 

  32. Kubaski F, Kecskemethy HH, Harcke HT, Tomatsu S. Bone mineral density in mucopolysaccharidosis IVB. Mol Genet Metab Rep. 2016;8:80–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Heron D, Baumann C, Benichou JJ, Harpey JP, Le Merrer M. Early diagnosis of Maroteaux-Lamy syndrome in two patients with accelerated growth and advanced bone maturation. Eur J Pediatr. 2004;163:323–6.

    PubMed  Google Scholar 

  34. •• Montano AM, Lock-Hock N, Steiner RD, et al. Clinical course of sly syndrome (mucopolysaccharidosis type VII). J Med Genet. 2016;53:403–18. This study provides a comprehensive analysis of data on the natural history of MPS VII patients collected worldwide, allowing comparative understanding of the progression of the disease and the effects of treatments.

  35. Sly WS, Quinton BA, McAlister WH, Rimoin DL. Beta glucuronidase deficiency: report of clinical, radiologic, and biochemical features of a new mucopolysaccharidosis. J Pediatr. 1973;82:249–57.

    CAS  PubMed  Google Scholar 

  36. de Kremer RD, Givogri I, Argarana CE, Hliba E, Conci R, Boldini CD, et al. Mucopolysaccharidosis type VII (beta-glucuronidase deficiency): a chronic variant with an oligosymptomatic severe skeletal dysplasia. Am J Med Genet. 1992;44:145–52.

    PubMed  Google Scholar 

  37. Imundo L, Leduc CA, Guha S, Brown M, Perino G, Gushulak L, et al. A complete deficiency of hyaluronoglucosaminidase 1 (HYAL1) presenting as familial juvenile idiopathic arthritis. J Inherit Metab Dis. 2011;34:1013–22.

    PubMed  Google Scholar 

  38. Natowicz MR, Short MP, Wang Y, Dickersin GR, Gebhardt MC, Rosenthal DI, et al. Clinical and biochemical manifestations of hyaluronidase deficiency. N Engl J Med. 1996;335:1029–33.

    CAS  PubMed  Google Scholar 

  39. Quartel A, Hendriksz CJ, Parini R, Graham S, Lin P, Harmatz P. Growth charts for individuals with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). JIMD reports. 2015;18:1–11.

    PubMed  Google Scholar 

  40. Gardner CJ, Robinson N, Meadows T, Wynn R, Will A, Mercer J, et al. Growth, final height and endocrine sequelae in a UK population of patients with Hurler syndrome (MPS1H). J Inherit Metab Dis. 2011;34:489–97.

    PubMed  Google Scholar 

  41. Polgreen LE, Tolar J, Plog M, Himes JH, Orchard PJ, Whitley CB, et al. Growth and endocrine function in patients with Hurler syndrome after hematopoietic stem cell transplantation. Bone Marrow Transplant. 2008;41:1005–11.

    CAS  PubMed  Google Scholar 

  42. Anderson CE, Crane JT, Harper HA, Hunter TW. Morquio’s disease and dysplasia epiphysalis multiplex. A study of epiphyseal cartilage in seven cases. J Bone Joint Surg Am. 1962;44-a:295–306.

    CAS  PubMed  Google Scholar 

  43. Smith LJ, Baldo G, Wu S, Liu Y, Whyte MP, Giugliani R, et al. Pathogenesis of lumbar spine disease in mucopolysaccharidosis VII. Mol Genet Metab. 2012;107:153–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Polgreen LE, Thomas W, Fung E, Viskochil D, Stevenson DA, Steinberger J, et al. Low bone mineral content and challenges in interpretation of dual-energy X-ray absorptiometry in children with mucopolysaccharidosis types I, II, and VI. J Clin Densitometry : the official journal of the International Society for Clinical Densitometry. 2014;17:200–6.

    Google Scholar 

  45. Herati RS, Knox VW, O’Donnell P, D’Angelo M, Haskins ME, Ponder KP. Radiographic evaluation of bones and joints in mucopolysaccharidosis I and VII dogs after neonatal gene therapy. Mol Genet Metab. 2008;95:142–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Nuttall JD, Brumfield LK, Fazzalari NL, Hopwood JJ, Byers S. Histomorphometric analysis of the tibial growth plate in a feline model of mucopolysaccharidosis type VI. Calcif Tissue Int. 1999;65:47–52.

    CAS  PubMed  Google Scholar 

  47. Evers M, Saftig P, Schmidt P, Hafner A, McLoghlin DB, Schmahl W, et al. Targeted disruption of the arylsulfatase B gene results in mice resembling the phenotype of mucopolysaccharidosis VI. Proc Natl Acad Sci U S A. 1996;93:8214–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Birkenmeier EH, Davisson MT, Beamer WG, Ganschow RE, Vogler CA, Gwynn B, et al. Murine mucopolysaccharidosis type VII. Characterization of a mouse with beta-glucuronidase deficiency. J Clin Invest. 1989;83:1258–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Jiang Z, Derrick-Roberts ALK, Jackson MR, Rossouw C, Pyragius CE, Xian C, et al. Delayed development of ossification centers in the tibia of prenatal and early postnatal MPS VII mice. Mol Genet Metab. 2018;124:135–42.

    CAS  PubMed  Google Scholar 

  50. Metcalf JA, Zhang Y, Hilton MJ, Long F, Ponder KP. Mechanism of shortened bones in mucopolysaccharidosis VII. Mol Genet Metab. 2009;97:202–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. • Rowan DJ, Tomatsu S, Grubb JH, Montano AM, Sly WS. Assessment of bone dysplasia by micro-CT and glycosaminoglycan levels in mouse models for mucopolysaccharidosis type I, IIIA, IVA, and VII. J Inherit Metab Dis. 2013;36:235–46. This study characterized skeletal phenotypes in multiple mouse models of MPS and suggested the importance of keratan sulfate in bone disease.

  52. Schultheiss PC, Gardner SA, Owens JM, Wenger DA, Thrall MA. Mucopolysaccharidosis VII in a cat. Vet Pathol. 2000;37:502–5.

    CAS  PubMed  Google Scholar 

  53. Wang P, Sorenson J, Strickland S, Mingus C, Haskins ME, Giger U. Mucopolysaccharidosis VII in a cat caused by 2 adjacent missense mutations in the GUSB gene. J Vet Intern Med. 2015;29:1022–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Tessitore A, Faella A, O’Malley T, Cotugno G, Doria M, Kunieda T, et al. Biochemical, pathological, and skeletal improvement of mucopolysaccharidosis VI after gene transfer to liver but not to muscle. Mol Ther. 2008;16:30–7.

    CAS  PubMed  Google Scholar 

  55. Breider MA, Shull RM, Constantopoulos G. Long-term effects of bone marrow transplantation in dogs with mucopolysaccharidosis I. Am J Pathol. 1989;134:677–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Haskins ME, Aguirre GD, Jezyk PF, Desnick RJ, Patterson DF. The pathology of the feline model of mucopolysaccharidosis I. Am J Pathol. 1983;112:27–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Russell C, Hendson G, Jevon G, Matlock T, Yu J, Aklujkar M, et al. Murine MPS I: insights into the pathogenesis of Hurler syndrome. Clin Genet. 1998;53:349–61.

    CAS  PubMed  Google Scholar 

  58. Tomatsu S, Gutierrez M, Nishioka T, et al. Development of MPS IVA mouse (Galnstm(hC79S.mC76S)slu) tolerant to human N-acetylgalactosamine-6-sulfate sulfatase. Hum Mol Genet. 2005;14:3321–35.

    CAS  PubMed  Google Scholar 

  59. Tomatsu S, Alméciga-Díaz CJ, Barbosa H, et al. Therapies of mucopolysaccharidosis IVA (Morquio A syndrome). Expert Opin Orphan Drugs. 2013;1:805–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Abreu S, Hayden J, Berthold P, Shapiro IM, Decker S, Patterson D, et al. Growth plate pathology in feline mucopolysaccharidosis VI. Calcif Tissue Int. 1995;57:185–90.

    CAS  PubMed  Google Scholar 

  61. Simonaro CM, D’Angelo M, Haskins ME, Schuchman EH. Joint and bone disease in mucopolysaccharidoses VI and VII: identification of new therapeutic targets and biomarkers using animal models. Pediatr Res. 2005;57:701–7.

    CAS  PubMed  Google Scholar 

  62. Vogler C, Levy B, Galvin N, Lessard M, Soper B, Barker J. Early onset of lysosomal storage disease in a murine model of mucopolysaccharidosis type VII: undegraded substrate accumulates in many tissues in the fetus and very young MPS VII mouse. Pediatr Dev Pathol : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society. 2005;8:453–62.

    CAS  Google Scholar 

  63. Peck SH, O’Donnell PJM, Kang JL, Malhotra NR, Dodge GR, Pacifici M, et al. Delayed hypertrophic differentiation of epiphyseal chondrocytes contributes to failed secondary ossification in mucopolysaccharidosis VII dogs. Mol Genet Metab. 2015;116:195–203.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Haskins ME, Jezyk PF, Desnick RJ, McDonough SK, Patterson DF. Alpha-L-iduronidase deficiency in a cat: a model of mucopolysaccharidosis I. Pediatr Res. 1979;13:1294–7.

    CAS  PubMed  Google Scholar 

  65. Clarke LA, Russell CS, Pownall S, Warrington CL, Borowski A, Dimmick JE, et al. Murine mucopolysaccharidosis type I: targeted disruption of the murine alpha-L-iduronidase gene. Hum Mol Genet. 1997;6:503–11.

    CAS  PubMed  Google Scholar 

  66. Garcia AR, Pan J, Lamsa JC, Muenzer J. The characterization of a murine model of mucopolysaccharidosis II (Hunter syndrome). J Inherit Metab Dis. 2007;30:924–34.

    CAS  PubMed  Google Scholar 

  67. Liu Y, Xu L, Hennig AK, et al. Liver-directed neonatal gene therapy prevents cardiac, bone, ear, and eye disease in mucopolysaccharidosis I mice. Mol Ther : the journal of the American Society of Gene Therapy. 2005;11:35–47.

    CAS  Google Scholar 

  68. Frohbergh M, Ge Y, Meng F, Karabul N, Solyom A, Lai A, et al. Dose responsive effects of subcutaneous pentosan polysulfate injection in mucopolysaccharidosis type VI rats and comparison to oral treatment. PLoS One. 2014;9:e100882.

    PubMed  PubMed Central  Google Scholar 

  69. Chiaro JA, Baron MD, Del Alcazar CM, O’Donnell P, Shore EM, Elliott DM, et al. Postnatal progression of bone disease in the cervical spines of mucopolysaccharidosis I dogs. Bone. 2013;55:78–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Byers S, Nuttall JD, Crawley AC, Hopwood JJ, Smith K, Fazzalari NL. Effect of enzyme replacement therapy on bone formation in a feline model of mucopolysaccharidosis type VI. Bone. 1997;21:425–31.

    CAS  PubMed  Google Scholar 

  71. Ma X, Liu Y, Tittiger M, Hennig A, Kovacs A, Popelka S, et al. Improvements in mucopolysaccharidosis I mice after adult retroviral vector–mediated gene therapy with immunomodulation. Mol Ther. 2007;15:889–902.

    CAS  PubMed  Google Scholar 

  72. Derrick-Roberts AL, Panir K, Pyragius CE, Zarrinkalam KH, Atkins GJ, Byers S. Reversal of established bone pathology in MPS VII mice following lentiviral-mediated gene therapy. Mol Genet Metab. 2016;119:249–57.

    CAS  PubMed  Google Scholar 

  73. • Peck SH, Tobias JW, Shore EM, Malhotra NR, Haskins ME, Casal ML, et al. Molecular profiling of failed endochondral ossification in mucopolysaccharidosis VII. Bone. 2019;128:115042. This study provided comprehensive insights into the molecular mechanisms underlying delayed endochondral ossification in MPS VII and suggested several dysregulated signaling pathways, which may be potential theraputic targets.

  74. • Jiang Z, Derrick-Roberts ALK, Reichstein C, Byers S. Cell cycle progression is disrupted in murine MPS VII growth plate leading to reduced chondrocyte proliferation and transition to hypertrophy. Bone. 2020;132:115195. This study provides important insights to mechanisms of impaired chondrocyte and growth plate function in MPS VII using a mouse model.

  75. Smith LJ, Martin JT, Szczesny SE, Ponder KP, Haskins ME, Elliott DM. Altered lumbar spine structure, biochemistry, and biomechanical properties in a canine model of mucopolysaccharidosis type VII. J Orthop Res. 2010;28:616–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Cortes M, Baria AT, Schwartz NB. Sulfation of chondroitin sulfate proteoglycans is necessary for proper Indian hedgehog signaling in the developing growth plate. Development (Cambridge, England). 2009;136:1697–706.

    CAS  Google Scholar 

  77. da Costa Soares D, Reis RL, Pashkuleva I. Sulfation of glycosaminoglycans and its implications in human health and disorders. Annu Rev Biomed Eng. 2017;19:1–26.

    Google Scholar 

  78. Schlessinger J, Plotnikov AN, Ibrahimi OA, Eliseenkova AV, Yeh BK, Yayon A, et al. Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization. Mol Cell. 2000;6:743–50.

    CAS  PubMed  Google Scholar 

  79. Troeberg L, Lazenbatt C, Anower EKMF, Freeman C, Federov O, Habuchi H, et al. Sulfated glycosaminoglycans control the extracellular trafficking and the activity of the metalloprotease inhibitor TIMP-3. Chem Biol. 2014;21:1300–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. De Pasquale V, Pavone LM. Heparan sulfate proteoglycans: the sweet side of development turns sour in mucopolysaccharidoses. Biochim Biophys Acta (BBA) - Mol Basis Dis. 2019;1865:165539.

    Google Scholar 

  81. Bellesso S, Salvalaio M, Lualdi S, et al. FGF signaling deregulation is associated with early developmental skeletal defects in animal models for mucopolysaccharidosis type II (MPSII). Hum Mol Genet. 2018;27:2262–75.

    CAS  PubMed  Google Scholar 

  82. Settembre C, Fraldi A, Medina DL, Ballabio A. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol. 2013;14:283–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Ballabio A, Gieselmann V. Lysosomal disorders: from storage to cellular damage. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2009;1793:684–96.

    CAS  Google Scholar 

  84. de la Mata M, Cotán D, Villanueva-Paz M, de Lavera I, Álvarez-Córdoba M, Luzón-Hidalgo R, et al. Mitochondrial dysfunction in lysosomal storage disorders. Diseases. 2016;4:31.

    PubMed Central  Google Scholar 

  85. Rashid H-O, Yadav RK, Kim H-R, Chae H-J. ER stress: autophagy induction, inhibition and selection. Autophagy. 2015;11:1956–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Seranova E, Connolly KJ, Zatyka M, Rosenstock TR, Barrett T, Tuxworth RI, et al. Dysregulation of autophagy as a common mechanism in lysosomal storage diseases. Essays Biochem. 2017;61:733–49.

    PubMed  PubMed Central  Google Scholar 

  87. Pierzynowska K, Gaffke L, Podlacha M, Brokowska J, Węgrzyn G. Mucopolysaccharidosis and autophagy: controversies on the contribution of the process to the pathogenesis and possible therapeutic applications. NeuroMol Med. 2019.

  88. Settembre C, Fraldi A, Rubinsztein DC, Ballabio A. Lysosomal storage diseases as disorders of autophagy. Autophagy. 2008;4:113–4.

    PubMed  Google Scholar 

  89. Woloszynek JC, Kovacs A, Ohlemiller KK, Roberts M, Sands MS. Metabolic adaptations to interrupted glycosaminoglycan recycling. J Biol Chem. 2009;284:29684–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Tessitore A, Pirozzi M, Auricchio A. Abnormal autophagy, ubiquitination, inflammation and apoptosis are dependent upon lysosomal storage and are useful biomarkers of mucopolysaccharidosis VI. PathoGenetics. 2009;2:4.

    PubMed  PubMed Central  Google Scholar 

  91. Pshezhetsky AV. Lysosomal storage of heparan sulfate causes mitochondrial defects, altered autophagy, and neuronal death in the mouse model of mucopolysaccharidosis III type C. Autophagy. 2016;12:1059–60.

    CAS  PubMed  Google Scholar 

  92. Vitry S, Bruyere J, Hocquemiller M, Bigou S, Ausseil J, Colle MA, et al. Storage vesicles in neurons are related to Golgi complex alterations in mucopolysaccharidosis IIIB. Am J Pathol. 2010;177:2984–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Viana GM, do Nascimento CC, Paredes-Gamero EJ, D’Almeida V. Altered cellular homeostasis in murine MPS I fibroblasts: evidence of cell-specific physiopathology. JIMD Reports. 2017;36:109–16.

    PubMed  PubMed Central  Google Scholar 

  94. Simonaro CM, Ge Y, Eliyahu E, He X, Jepsen KJ, Schuchman EH. Involvement of the Toll-like receptor 4 pathway and use of TNF-alpha antagonists for treatment of the mucopolysaccharidoses. Proc Natl Acad Sci U S A. 2010;107:222–7.

    CAS  PubMed  Google Scholar 

  95. • Bartolomeo R, Cinque L, De Leonibus C, et al. mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy. J Clin Invest. 2017;127:3717–29. This study suggested the first time that mTORC1 and autophagy play roles in imparied chondrocyte function and bone growth in MPS VII models.

  96. Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, et al. Protection against fatal Sindbis virus encephalitis by Beclin, a novel Bcl-2-interacting protein. J Virol. 1998;72:8586.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Yin X, Cao L, Peng Y, Tan Y, Xie M, Kang R, et al. A critical role for UVRAG in apoptosis. Autophagy. 2011;7:1242–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Wirawan E, Vande Walle L, Kersse K, et al. Caspase-mediated cleavage of Beclin-1 inactivates Beclin-1-induced autophagy and enhances apoptosis by promoting the release of proapoptotic factors from mitochondria. Cell Death Dis. 2010;1:e18–8.

  99. Stevenson DA, Rudser K, Kunin-Batson A, Fung EB, Viskochil D, Shapiro E, et al. Biomarkers of bone remodeling in children with mucopolysaccharidosis types I, II, and VI. J Pediatr Rehabil Med. 2014;7:159–65.

    PubMed  PubMed Central  Google Scholar 

  100. Wilson S, Hashamiyan S, Clarke L, Saftig P, Mort J, Dejica VM, et al. Glycosaminoglycan-mediated loss of cathepsin K collagenolytic activity in MPS I contributes to osteoclast and growth plate abnormalities. Am J Pathol. 2009;175:2053–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Monroy MA, Ross FP, Teitelbaum SL, Sands MS. Abnormal osteoclast morphology and bone remodeling in a murine model of a lysosomal storage disease. Bone. 2002;30:352–9.

    CAS  PubMed  Google Scholar 

  102. Jiang Z, Lau YK, Wu M, Casal ML, Smith LJ. Ultrastructural analysis of different skeletal cell types in mucopolysaccharidosis dogs at the onset of postnatal growth. J Anat. https://doi.org/10.1111/joa.13305.

  103. Kuehn SC, Koehne T, Cornils K, et al. Impaired bone remodeling and its correction by combination therapy in a mouse model of mucopolysaccharidosis-I. Hum Mol Genet. 2015;24:7075–86.

    CAS  PubMed  Google Scholar 

  104. Hobbs JR, Hugh-Jones K, Barrett AJ, et al. Reversal of clinical features of Hurler’s disease and biochemical improvement after treatment by bone-marrow transplantation. Lancet. 1981;2:709–12.

    CAS  PubMed  Google Scholar 

  105. Schulze-Frenking G, Jones SA, Roberts J, Beck M, Wraith JE. Effects of enzyme replacement therapy on growth in patients with mucopolysaccharidosis type II. J Inherit Metab Dis. 2011;34:203–8.

    CAS  PubMed  Google Scholar 

  106. Aldenhoven M, Wynn RF, Orchard PJ, et al. Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: an international multicenter study. Blood. 2015;125:2164–72.

    CAS  PubMed  Google Scholar 

  107. Guffon N, Bertrand Y, Forest I, Fouilhoux A, Froissart R. Bone marrow transplantation in children with Hunter syndrome: outcome after 7 to 17 years. J Pediatr. 2009;154:733–7.

    PubMed  Google Scholar 

  108. Escolar M, Lakshminayanaran S, Szabolcs P, Poe M, Prasad V, Parikh S, et al. Neurobehavioral outcome in children with MPS III (Sanfilippo syndrome) after unrelated donor umbilical cord blood transplantation (UCBT). Biology Blood Marrow Transplant. 2006;12:125.

    Google Scholar 

  109. Tomatsu S, Yasuda E, Patel P, et al. Morquio A syndrome: diagnosis and current and future therapies. Pediatr Endocrinol Rev : PER. 2014;12(Suppl 1):141–51.

    PubMed  Google Scholar 

  110. Turbeville S, Nicely H, Rizzo JD, Pedersen TL, Orchard PJ, Horwitz ME, et al. Clinical outcomes following hematopoietic stem cell transplantation for the treatment of mucopolysaccharidosis VI. Mol Genet Metab. 2011;102:111–5.

    CAS  PubMed  Google Scholar 

  111. Auclair D, Hein LK, Hopwood JJ, Byers S. Intra-articular enzyme administration for joint disease in feline mucopolysaccharidosis VI: enzyme dose and interval. Pediatr Res. 2006;59:538–43.

    CAS  PubMed  Google Scholar 

  112. Garcia AR, DaCosta JM, Pan J, Muenzer J, Lamsa JC. Preclinical dose ranging studies for enzyme replacement therapy with idursulfase in a knock-out mouse model of MPS II. Mol Genet Metab. 2007;91:183–90.

    CAS  PubMed  Google Scholar 

  113. Herati RS, Ma X, Tittiger M, Ohlemiller KK, Kovacs A, Ponder KP. Improved retroviral vector design results in sustained expression after adult gene therapy in mucopolysaccharidosis I mice. J Gene Med. 2008;10:972–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Rowan DJ, Tomatsu S, Grubb JH, Haupt B, Montano AM, Oikawa H, et al. Long circulating enzyme replacement therapy rescues bone pathology in mucopolysaccharidosis VII murine model. Mol Genet Metab. 2012;107:161–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Sands MS, Barker JE, Vogler C, Levy B, Gwynn B, Galvin N, et al. Treatment of murine mucopolysaccharidosis type VII by syngeneic bone marrow transplantation in neonates. Lab Investig. 1993;68:676–86.

    CAS  PubMed  Google Scholar 

  116. Aldenhoven M, Boelens JJ, de Koning TJ. The clinical outcome of Hurler syndrome after stem cell transplantation. Biol Blood Marrow Transplant : journal of the American Society for Blood and Marrow Transplantation. 2008;14:485–98.

    CAS  Google Scholar 

  117. Herskhovitz E, Young E, Rainer J, Hall CM, Lidchi V, Chong K, et al. Bone marrow transplantation for Maroteaux-Lamy syndrome (MPS VI): long-term follow-up. J Inherit Metab Dis. 1999;22:50–62.

    CAS  PubMed  Google Scholar 

  118. Field RE, Buchanan JA, Copplemans MG, Aichroth PM. Bone-marrow transplantation in Hurler’s syndrome. Effect on skeletal development. J Bone Joint Surg (Br). 1994;76:975–81.

    CAS  Google Scholar 

  119. Polgreen LE, Lund TC, Braunlin E, et al. Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation. Pediatr Res. 2020;87:104–11.

    CAS  PubMed  Google Scholar 

  120. Tomatsu S, Sawamoto K, Almeciga-Diaz CJ, et al. Impact of enzyme replacement therapy and hematopoietic stem cell transplantation in patients with Morquio A syndrome. Drug Design Dev Ther. 2015;9:1937–53.

    CAS  Google Scholar 

  121. Pérez-López J, Morales-Conejo M, López-Rodríguez M, Hermida-Ameijeiras Á, Moltó-Abad M. Efficacy of laronidase therapy in patients with mucopolysaccharidosis type I who initiated enzyme replacement therapy in adult age. A systematic review and meta-analysis. Mol Genet Metab. 2017;121:138–49.

    PubMed  Google Scholar 

  122. Perez-Calvo J, Bergua Sanclemente I, Lopez Moreno MJ, Torralba Cabeza MA, Amores AB. Early response to idursulfase in a 31-year old male patient with Hunter syndrome. Rev Clin Esp. 2011;211:e42–5.

    CAS  PubMed  Google Scholar 

  123. Zuber Z, Rozdzynska-Swiatkowska A, Jurecka A, Tylki-Szymanska A. The effect of recombinant human iduronate-2-sulfatase (idursulfase) on growth in young patients with mucopolysaccharidosis type II. PLoS One. 2014;9:e85074.

    PubMed  PubMed Central  Google Scholar 

  124. Tomatsu S, Almeciga-Diaz CJ, Montano AM, et al. Therapies for the bone in mucopolysaccharidoses. Mol Genet Metab. 2015;114:94–109.

    CAS  PubMed  Google Scholar 

  125. Vellodi A, Young E, Cooper A, Lidchi V, Winchester B, Wraith JE. Long-term follow-up following bone marrow transplantation for Hunter disease. J Inherit Metab Dis. 1999;22:638–48.

    CAS  PubMed  Google Scholar 

  126. Chinen Y, Higa T, Tomatsu S, Suzuki Y, Orii T, Hyakuna N. Long-term therapeutic efficacy of allogenic bone marrow transplantation in a patient with mucopolysaccharidosis IVA. Mol Genet Metab Rep. 2014;1:31–41.

    PubMed  PubMed Central  Google Scholar 

  127. Patel P, Suzuki Y, Tanaka A, Yabe H, Kato S, Shimada T, et al. Impact of enzyme replacement therapy and hematopoietic stem cell therapy on growth in patients with Hunter syndrome. Mol Genet Metab Rep. 2014;1:184–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Vellodi A, Young EP, Cooper A, Wraith JE, Winchester B, Meaney C, et al. Bone marrow transplantation for mucopolysaccharidosis type I: experience of two British centres. Arch Dis Child. 1997;76:92–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Yabe H, Tanaka A, Chinen Y, Kato S, Sawamoto K, Yasuda E, et al. Hematopoietic stem cell transplantation for Morquio A syndrome. Mol Genet Metab. 2016;117:84–94.

    CAS  PubMed  Google Scholar 

  130. Yamada Y, Kato K, Sukegawa K, Tomatsu S, Fukuda S, Emura S, et al. Treatment of MPS VII (Sly disease) by allogeneic BMT in a female with homozygous A619V mutation. Bone Marrow Transplant. 1998;21:629–34.

    CAS  PubMed  Google Scholar 

  131. Sisinni L, Pineda M, Coll MJ, Gort L, Turon E, Torrent M, et al. Haematopoietic stem cell transplantation for mucopolysaccharidosis type VII: a case report. Pediatr Transplant. 2018;22:e13278.

    PubMed  Google Scholar 

  132. Horwitz EM, Prockop DJ, Gordon PL, Koo WW, Fitzpatrick LA, Neel MD, et al. Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta. Blood. 2001;97:1227–31.

    CAS  PubMed  Google Scholar 

  133. Shalitin S, Phillip M, Stein J, Goshen Y, Carmi D, Yaniv I. Endocrine dysfunction and parameters of the metabolic syndrome after bone marrow transplantation during childhood and adolescence. Bone Marrow Transplant. 2006;37:1109–17.

    CAS  PubMed  Google Scholar 

  134. Staba SL, Escolar ML, Poe M, et al. Cord-blood transplants from unrelated donors in patients with Hurler’s syndrome. N Engl J Med. 2004;350:1960–9.

    CAS  PubMed  Google Scholar 

  135. Koc ON, Peters C, Aubourg P, et al. Bone marrow-derived mesenchymal stem cells remain host-derived despite successful hematopoietic engraftment after allogeneic transplantation in patients with lysosomal and peroxisomal storage diseases. Exp Hematol. 1999;27:1675–81.

    CAS  PubMed  Google Scholar 

  136. Akiyama K, Shimada Y, Higuchi T, et al. Enzyme augmentation therapy enhances the therapeutic efficacy of bone marrow transplantation in mucopolysaccharidosis type II mice. Mol Genet Metab. 2014;111:139–46.

    CAS  PubMed  Google Scholar 

  137. Pievani A, Azario I, Antolini L, et al. Neonatal bone marrow transplantation prevents bone pathology in a mouse model of mucopolysaccharidosis type I. Blood. 2014.

  138. Norrdin RW, Moffat KS, Thrall MA, Gasper PW. Characterization of osteopenia in feline mucopolysaccharidosis VI and evaluation of bone marrow transplantation therapy. Bone. 1993;14:361–7.

    CAS  PubMed  Google Scholar 

  139. Birkenmeier EH, Barker JE, Vogler CA, Kyle JW, Sly WS, Gwynn B, et al. Increased life span and correction of metabolic defects in murine mucopolysaccharidosis type VII after syngeneic bone marrow transplantation. Blood. 1991;78:3081–92.

    CAS  PubMed  Google Scholar 

  140. Clarke LA, Wraith JE, Beck M, Kolodny EH, Pastores GM, Muenzer J, et al. Long-term efficacy and safety of laronidase in the treatment of mucopolysaccharidosis I. Pediatrics. 2009;123:229–40.

    PubMed  Google Scholar 

  141. Brands MMMG, Oussoren E, Ruijter GJG, Vollebregt AAM, van den Hout HMP, Joosten KFM, et al. Up to five years experience with 11 mucopolysaccharidosis type VI patients. Mol Genet Metab. 2013;109:70–6.

    CAS  PubMed  Google Scholar 

  142. Lin HY, Chuang CK, Wang CH, et al. Long-term galsulfase enzyme replacement therapy in Taiwanese mucopolysaccharidosis VI patients: a case series. Mol Genet Metab Rep. 2016;7:63–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Quartel A, Harmatz PR, Lampe C, Guffon N, Ketteridge D, Leão-Teles E, et al. Long-term galsulfase treatment associated with improved survival of patients with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome):15-year follow-up from the survey study. J Inborn Errors Metab Screening. 2018;6:2326409818755800.

    Google Scholar 

  144. Do Cao J, Wiedemann A, Quinaux T, Battaglia-Hsu SF, Mainard L, Froissart R, et al. 30 months follow-up of an early enzyme replacement therapy in a severe Morquio A patient: about one case. Mol Genet Metab Rep. 2016;9:42–5.

    PubMed  PubMed Central  Google Scholar 

  145. Fox JE, Volpe L, Bullaro J, Kakkis ED, Sly WS. First human treatment with investigational rhGUS enzyme replacement therapy in an advanced stage MPS VII patient. Mol Genet Metab. 2015;114:203–8.

    CAS  PubMed  Google Scholar 

  146. Anson DS, McIntyre C, Byers S. Therapies for neurological disease in the mucopolysaccharidoses. Curr Gene Ther. 2011;11:132–43.

    CAS  PubMed  Google Scholar 

  147. Tylki-Szymanska A, Rozdzynska A, Jurecka A, Marucha J, Czartoryska B. Anthropometric data of 14 patients with mucopolysaccharidosis I: retrospective analysis and efficacy of recombinant human alpha-L-iduronidase (laronidase). Mol Genet Metab. 2010;99:10–7.

    CAS  PubMed  Google Scholar 

  148. Arora RS, Mercer J, Thornley M, Tylee K, Wraith JE. Enzyme replacement therapy in 12 patients with MPS I-H/S with homozygous p.Leu490Pro mutation. J Inherit Metab Dis. 2007;30:821.

    CAS  PubMed  Google Scholar 

  149. Kakkis ED, Muenzer J, Tiller GE, et al. Enzyme-replacement therapy in mucopolysaccharidosis I. N Engl J Med. 2001;344:182–8.

    CAS  PubMed  Google Scholar 

  150. Sifuentes M, Doroshow R, Hoft R, Mason G, Walot I, Diament M, et al. A follow-up study of MPS I patients treated with laronidase enzyme replacement therapy for 6 years. Mol Genet Metab. 2007;90:171–80.

    CAS  PubMed  Google Scholar 

  151. Decker C, Yu ZF, Giugliani R, et al. Enzyme replacement therapy for mucopolysaccharidosis VI: growth and pubertal development in patients treated with recombinant human N-acetylgalactosamine 4-sulfatase. J Pediatr Rehabil Med. 2010;3:89–100.

    PubMed  PubMed Central  Google Scholar 

  152. Al-Sannaa NA, Bay L, Barbouth DS, et al. Early treatment with laronidase improves clinical outcomes in patients with attenuated MPS I: a retrospective case series analysis of nine sibships. Orphanet J Rare Dis. 2015;10:131.

    PubMed  PubMed Central  Google Scholar 

  153. Furujo M, Kubo T, Kosuga M, Okuyama T. Enzyme replacement therapy attenuates disease progression in two Japanese siblings with mucopolysaccharidosis type VI. Mol Genet Metab. 2011;104:597–602.

    CAS  PubMed  Google Scholar 

  154. McGill JJ, Inwood AC, Coman DJ, Lipke ML, De Lore D, Swiedler SJ, et al. Enzyme replacement therapy for mucopolysaccharidosis VI from 8 weeks of age–a sibling control study. Clin Genet. 2010;77:492–8.

    CAS  PubMed  Google Scholar 

  155. Furujo M, Kosuga M, Okuyama T. Enzyme replacement therapy attenuates disease progression in two Japanese siblings with mucopolysaccharidosis type VI: 10-year follow up. Mol Genet Metab Rep. 2017;13:69–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Wang RY, Aminian A, McEntee MF, et al. Intra-articular enzyme replacement therapy with rhIDUA is safe, well-tolerated, and reduces articular GAG storage in the canine model of mucopolysaccharidosis type I. Mol Genet Metab. 2014;112:286–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Sands MS, Vogler C, Kyle JW, Grubb JH, Levy B, Galvin N, et al. Enzyme replacement therapy for murine mucopolysaccharidosis type VII. J Clin Invest. 1994;93:2324–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Chiaro JA, O’Donnell P, Shore EM, Malhotra NR, Ponder KP, Haskins ME, et al. Effects of neonatal enzyme replacement therapy and simvastatin treatment on cervical spine disease in mucopolysaccharidosis I dogs. J Bone Min Res : the official journal of the American Society for Bone and Mineral Research. 2014;29:2610–7.

    CAS  Google Scholar 

  159. Visigalli I, Delai S, Politi LS, et al. Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model. Blood. 2010;116:5130–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Donsante A, Levy B, Vogler C, Sands MS. Clinical response to persistent, low-level beta-glucuronidase expression in the murine model of mucopolysaccharidosis type VII. J Inherit Metab Dis. 2007;30:227–38.

    CAS  PubMed  Google Scholar 

  161. Macsai CE, Derrick-Roberts AL, Ding X, Zarrinkalam KH, McIntyre C, Anderson PH, et al. Skeletal response to lentiviral mediated gene therapy in a mouse model of MPS VII. Mol Genet Metab. 2012;106:202–13.

    CAS  PubMed  Google Scholar 

  162. Derrick-Roberts AL, Pyragius CE, Kaidonis XM, Jackson MR, Anson DS, Byers S. Lentiviral-mediated gene therapy results in sustained expression of beta-glucuronidase for up to 12 months in the gus(mps/mps) and up to 18 months in the gus(tm(L175F)Sly) mouse models of mucopolysaccharidosis type VII. Hum Gene Ther. 2014;25:798–810.

    CAS  PubMed  Google Scholar 

  163. Smith LJ, Martin JT, O’Donnell P, Wang P, Elliott DM, Haskins ME, et al. Effect of neonatal gene therapy on lumbar spine disease in mucopolysaccharidosis VII dogs. Mol Genet Metab. 2012;107:145–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Orii K, Lim A, Tomatsu S, Stapleton M, Suzuki Y, Simonaro CM, Schuchman EH, Fukao T, Matsumoto T. Safety study of sodium pentosan polysulfate for adult patients with mucopolysaccharidosis type II. Diagnostics (Basel, Switzerland). 2019;9.

  165. Coutinho MF, Santos JI, Alves S. Less is more: substrate reduction therapy for lysosomal storage disorders. Int J Mol Sci. 2016;17.

  166. Derrick-Roberts ALK, Jackson MR, Pyragius CE, Byers S. Substrate deprivation therapy to reduce glycosaminoglycan synthesis improves aspects of neurological and skeletal pathology in MPS I mice. Diseases. 2017;5:5.

    PubMed Central  Google Scholar 

  167. Simonaro CM, Tomatsu S, Sikora T, et al. Pentosan polysulfate: oral versus subcutaneous injection in mucopolysaccharidosis type I dogs. PLoS One. 2016;11:e0153136.

    PubMed  PubMed Central  Google Scholar 

  168. Polgreen LE, Thomas W, Orchard PJ, Whitley CB, Miller BS. Effect of recombinant human growth hormone on changes in height, bone mineral density, and body composition over 1-2 years in children with Hurler or Hunter syndrome. Mol Genet Metab. 2014;111:101–6.

    CAS  PubMed  Google Scholar 

  169. Cattoni A, Motta S, Masera N, Gasperini S, Rovelli A, Parini R. The use of recombinant human growth hormone in patients with mucopolysaccharidoses and growth hormone deficiency: a case series. Ital J Pediatr. 2019;45:93.

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Rogers DG, Nasomyont N. Growth hormone treatment in a patient with Hurler-Scheie syndrome. J Pediatr Endocrinol Metab : JPEM. 2014;27:957–60.

    PubMed  Google Scholar 

  171. Daly TM, Ohlemiller KK, Roberts MS, Vogler CA, Sands MS. Prevention of systemic clinical disease in MPS VII mice following AAV-mediated neonatal gene transfer. Gene Ther. 2001;8:1291–8.

    CAS  PubMed  Google Scholar 

  172. Elliger SS, Elliger CA, Lang C, Watson GL. Enhanced secretion and uptake of beta-glucuronidase improves adeno-associated viral-mediated gene therapy of mucopolysaccharidosis type VII mice. Mol Ther : the journal of the American Society of Gene Therapy. 2002;5:617–26.

    CAS  Google Scholar 

  173. Mango RL, Xu L, Sands MS, Vogler C, Seiler G, Schwarz T, et al. Neonatal retroviral vector-mediated hepatic gene therapy reduces bone, joint, and cartilage disease in mucopolysaccharidosis VII mice and dogs. Mol Genet Metab. 2004;82:4–19.

    CAS  PubMed  Google Scholar 

  174. Cotugno G, Tessitore A, Capalbo A, et al. Different serum enzyme levels are required to rescue the various systemic features of the mucopolysaccharidoses. Hum Gene Ther. 2010;21:555–69.

    CAS  PubMed  Google Scholar 

  175. Derrick-Roberts AL, Marais W, Byers S. Rhodamine B and 2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoro-D-glucopyranose (F-GlcNAc) inhibit chondroitin/dermatan and keratan sulphate synthesis by different mechanisms in bovine chondrocytes. Mol Genet Metab. 2012;106:214–20.

    CAS  PubMed  Google Scholar 

  176. Entchev E, Jantzen I, Masson P, Bocart S, Bournique B, Luccarini JM, et al. Odiparcil, a potential glycosaminoglycans clearance therapy in mucopolysaccharidosis VI-evidence from in vitro and in vivo models. PLoS One. 2020;15:e0233032.

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Nikitovic D, Tsatsakis AM, Karamanos NK, Tzanakakis GN. The effects of genistein on the synthesis and distribution of glycosaminoglycans/proteoglycans by two osteosarcoma cell lines depends on tyrosine kinase and the estrogen receptor density. Anticancer Res. 2003;23:459–64.

    CAS  PubMed  Google Scholar 

  178. Roberts AL, Rees MH, Klebe S, Fletcher JM, Byers S. Improvement in behaviour after substrate deprivation therapy with rhodamine B in a mouse model of MPS IIIA. Mol Genet Metab. 2007;92:115–21.

    CAS  PubMed  Google Scholar 

  179. Roberts ALK, Thomas BJ, Wilkinson AS, Fletcher JM, Byers S. s. Pediatr Res. 2006;60:309–14.

    CAS  PubMed  Google Scholar 

  180. Mohanalakshmi P, V. M, S. M. Hurler-Scheie syndrome with subclinical hypothyroidism: a case report. 2014. 2014;5:3.

  181. Sederquist B, Fernandez-Vojvodich P, Zaman F, Sävendahl L. Recent research on the growth plate: impact of inflammatory cytokines on longitudinal bone growth. J Mol Endocrinol. 2014;53:T35.

    CAS  PubMed  Google Scholar 

  182. Tummolo A, Gabrielli O, Gaeta A, Masciopinto M, Zampini L, Pavone LM, et al. Bisphosphonate treatment in a patient affected by MPS IVA with osteoporotic phenotype. Case Rep Med. 2013;2013:891596–6.

  183. Wenstrup RJ, Bailey L, Grabowski GA, Moskovitz J, Oestreich AE, Wu W, et al. Gaucher disease: alendronate disodium improves bone mineral density in adults receiving enzyme therapy. Blood. 2004;104:1253–7.

    CAS  PubMed  Google Scholar 

  184. Clement-Lacroix P, Ai M, Morvan F, Roman-Roman S, Vayssiere B, Belleville C, et al. Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice. Proc Natl Acad Sci U S A. 2005;102:17406–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Peck SH, Lau YK, Bendigo JR, et al. Lithium treatment improves vertebral trabecular bone architecture in mucopolysaccharidosis I dogs during postnatal growth. Austin: Orthopedic Research Society; 2019.

    Google Scholar 

  186. Ullah I, Subbarao RB, Rho GJ. Human mesenchymal stem cells - current trends and future prospective. Biosci Rep. 2015;35:e00191.

    PubMed  PubMed Central  Google Scholar 

  187. Koc ON, Day J, Nieder M, Gerson SL, Lazarus HM, Krivit W. Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH). Bone Marrow Transplant. 2002;30:215–22.

    CAS  PubMed  Google Scholar 

  188. Jackson M, Derrick Roberts A, Martin E, Rout-Pitt N, Gronthos S, Byers S. Mucopolysaccharidosis enzyme production by bone marrow and dental pulp derived human mesenchymal stem cells. Mol Genet Metab. 2015;114:584–93.

    CAS  PubMed  Google Scholar 

  189. Espiner EA, Prickett TCR. New prospects for restoring skeletal growth in mucopolysaccharidoses. Endocrinology. 2020;161.

  190. Yamashita T, Fujii T, Yamauchi I, Ueda Y, Hirota K, Kanai Y, Yasoda A, Inagaki N. C-type natriuretic peptide restores growth impairment under enzyme replacement in mice with mucopolysaccharidosis VII. Endocrinology. 2020;161.

  191. Nakao K, Osawa K, Yasoda A, et al. The local CNP/GC-B system in growth plate is responsible for physiological endochondral bone growth. Sci Rep. 2015;5:10554.

    PubMed  PubMed Central  Google Scholar 

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Funding

ZJ, MLC, and LJS received support from the National Institutes of Health (R01DK054481 and R01AR071975), the Lisa Dean Moseley Foundation, and the University of Pennsylvania Department of Orthopaedic Surgery.

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Authors and Affiliations

  1. Department of Orthopedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Zhirui Jiang & Lachlan J. Smith

  2. Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, 371 Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA, 19104, USA

    Zhirui Jiang & Lachlan J. Smith

  3. Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia

    Sharon Byers

  4. Paediatrics, The University of Adelaide, Adelaide, SA, Australia

    Sharon Byers

  5. Genetics and Evolution, The University of Adelaide, Adelaide, SA, Australia

    Sharon Byers

  6. Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Margret L. Casal

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Jiang, Z., Byers, S., Casal, M.L. et al. Failures of Endochondral Ossification in the Mucopolysaccharidoses. Curr Osteoporos Rep 18, 759–773 (2020). https://doi.org/10.1007/s11914-020-00626-y

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