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Bone Marrow Transplantation for Treatment of the Col1a2+/G610C Osteogenesis Imperfecta Mouse Model

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Abstract

Bone marrow transplantation (BMT) of healthy donor cells has been postulated as a strategy for treating osteogenesis imperfecta (OI) and other bone fragility disorders. The effect of engraftment by tail vein injection and/or marrow ablation by 6 Gy whole body irradiation were tested in Col1a2+/G610C (OI) mice as a model of mild-moderate OI. Dual-emission X-ray absorptiometry, microCT, and 4-point bending were used to measure bone volume (BV), bone mineral density (BMD), and biomechanical strength. BV, BMD, and mechanical strength were reduced in OI mice compared to wild type (WT) controls. BMT with and without irradiation yielded no difference in BV and BMD outcomes for both OI and WT mice, at 3 weeks. Transplantation of OI cells into OI mice to test for paracrine effects of BMT also showed no difference with non-transplanted OI mice. In a parallel cell tracking study, donor marrow was taken from transgenic mice constitutively expressing tdTomato and transplanted into WT mice. Lineage tracking demonstrated that irradiation considerably enhanced engraftment of tdTomato+ cells. However, tdTomato+ cells predominantly expressed TRAP and not AP, indicating engrafted donor cells were chiefly from the hematopoietic lineages. These data show that whole marrow transplantation fails to rescue the bone phenotype of Col1a2+/G610C (OI) mice and that osteopoietic engraftment is not significantly enhanced by irradiation. These findings are highly relevant to modern approaches focused on the gene repair of patient cells ex vivo and their subsequent reintroduction into the osteopoietic compartment via the circulation.

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References

  1. Thomas IH, DiMeglio LA (2016) Advances in the classification and treatment of osteogenesis imperfecta. Curr Osteoporos Rep 14(1):1–9

    Article  PubMed  Google Scholar 

  2. Hoyer-Kuhn H, Netzer C, Semler O (2015) Osteogenesis imperfecta: pathophysiology and treatment. Wien Med Wochenschr 165(13):278–284

    Article  PubMed  Google Scholar 

  3. Chan JK, Götherström C (2014) Prenatal transplantation of mesenchymal stem cells to treat osteogenesis imperfecta. Front Pharmacol 5:223. https://doi.org/10.3389/fphar.2014.00223

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Hilfiker A, Kasper C, Hass R, Haverich A (2011) Mesenchymal stem cells and progenitor cells in connective tissue engineering and regenerative medicine: is there a future for transplantation? Langenbeck’s Arch Surg 396(4):489–497

    Article  Google Scholar 

  5. Cabral WA, Marini JC (2004) High proportion of mutant osteoblasts is compatible with normal skeletal function in mosaic carriers of osteogenesis imperfecta. Am J Hum Genet 74(4):752–760

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Horwitz EM, Gordon PL, Koo WK, Marx JC, Neel MD, McNall RY, Muul L, Hofmann T (2002) Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: implications for cell therapy of bone. Proc Natl Acad Sci USA 99(13):8932–8937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M, Sussman M, Orchard P, Marx JC, Pyeritz RE (1999) Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 5(3):309–313

    Article  CAS  PubMed  Google Scholar 

  8. Horwitz EM, Prockop DJ, Gordon PL, Koo WW, Fitzpatrick LA, Neel MD, McCarville ME, Orchard PJ, Pyeritz RE, Brenner MK (2001) Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta. Blood 97(5):1227–1231

    Article  CAS  PubMed  Google Scholar 

  9. Ricci P, Tauchmanova L, Risitano AM, Carella C, Mazziotti G, Lombardi G, Colao A, Rotoli B, Selleri C (2006) Imbalance of the osteoprotegerin/RANKL ratio in bone marrow microenvironment after allogeneic hemopoietic stem cell transplantation. Transplantation 82(11):1449–1456

    Article  PubMed  Google Scholar 

  10. Otsuru S, Desbourdes L, Guess AJ, Hofmann TJ, Relation T, Kaito T, Dominici M, Iwamoto M, Horwitz EM (2017) Extracellular vesicles released from mesenchymal stromal cells stimulate bone growth in osteogenesis imperfecta. Cytotherapy 20(1):62–73

    Google Scholar 

  11. Daley E, Streeten EA, Sorkin JD, Kuznetsova N, Shapses SA, Carleton SM, Shuldiner AR, Marini JC, Phillips CL, Goldstein SA (2010) Variable bone fragility associated with an Amish COL1A2 variant and a knock-in mouse model. J Bone Miner Res 25(2):247–261

    Article  CAS  PubMed  Google Scholar 

  12. Masci M, Wang M, Imbert L, Barnes AM, Spevak L, Lukashova L, Huang Y, Ma Y, Marini JC, Jacobsen CM, Warman ML, Boskey AL (2016) Bone mineral properties in growing Col1a2+/G610C mice, an animal model of osteogenesis imperfecta. Bone 87:120–129. https://doi.org/10.1016/j.bone.2016.04.011

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Marino R, Martinez C, Boyd K, Dominici M, Hofmann TJ, Horwitz EM (2008) Transplantable marrow osteoprogenitors engraft in discrete saturable sites in the marrow microenvironment. Exp Hematol 36(3):360–368

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Madisen L, Zwingman TA, Sunkin SM, Oh SW, Zariwala HA, Gu H, Ng LL, Palmiter RD, Hawrylycz MJ, Jones AR (2010) A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci 13(1):133–140

    Article  CAS  PubMed  Google Scholar 

  15. Schwenk F, Baron U, Rajewsky K (1995) A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. Nucleic Acids Res 23(24):5080

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Limaye A (2012) Drishti: a volume exploration and presentation tool. In: Developments in X-ray tomography. International Society for Optics and Photonics, Bellingham, p 85060X

    Chapter  Google Scholar 

  17. Duran-Struuck R, Dysko RC (2009) Principles of bone marrow transplantation (BMT): providing optimal veterinary and husbandry care to irradiated mice in BMT studies. J Am Assoc Lab Anim Sci 48(1):11–22

    PubMed Central  CAS  PubMed  Google Scholar 

  18. Pereira RF, O’Hara MD, Laptev AV, Halford KW, Pollard MD, Class R, Simon D, Livezey K, Prockop DJ (1998) Marrow stromal cells as a source of progenitor cells for nonhematopoietic tissues in transgenic mice with a phenotype of osteogenesis imperfecta. Proc Natl Acad Sci USA 95(3):1142–1147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Guillot PV, Abass O, Bassett JD, Shefelbine SJ, Bou-Gharios G, Chan J, Kurata H, Williams GR, Polak J, Fisk NM (2008) Intrauterine transplantation of human fetal mesenchymal stem cells from first-trimester blood repairs bone and reduces fractures in osteogenesis imperfecta mice. Blood 111(3):1717–1725

    Article  CAS  PubMed  Google Scholar 

  20. Ranzoni AM, Corcelli M, Hau K-L, Kerns JG, Vanleene M, Shefelbine S, Jones GN, Moschidou D, Dala-Ali B, Goodship AE (2016) Counteracting bone fragility with human amniotic mesenchymal stem cells. Sci Rep 6:39656

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Otsuru S, Gordon PL, Shimono K, Jethva R, Marino R, Phillips CL, Hofmann TJ, Veronesi E, Dominici M, Iwamoto M (2012) Transplanted bone marrow mononuclear cells and MSCs impart clinical benefit to children with osteogenesis imperfecta through different mechanisms. Blood 120(9):1933–1941

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Bregou Bourgeois A, Aubry-Rozier B, Bonafé L, Laurent-Applegate LA, Pioletti D, Zambelli P-Y (2016) Osteogenesis imperfecta: from diagnosis and multidisciplinary treatment to future perspectives. Swiss Med Wkly 146:w14322

    PubMed  Google Scholar 

  23. Marom R, Lee YC, Grafe I, Lee B (2016) Pharmacological and biological therapeutic strategies for osteogenesis imperfecta. Am J Med Genet C 4:367–383

    Article  CAS  Google Scholar 

  24. Ou Z, Niu X, He W, Chen Y, Song B, Xian Y, Fan D, Tang D, Sun X (2016) The combination of CRISPR/Cas9 and iPSC technologies in the gene therapy of human β-thalassemia in mice. Sci Rep 6:32463

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Coccia PF, Krivit W, Cervenka J, Clawson C, Kersey JH, Kim TH, Nesbit ME, Ramsay NK, Warkentin PI, Teitelbaum SL (1980) Successful bone-marrow transplantation for infantile malignant osteopetrosis. N Engl J Med 302(13):701–708

    Article  CAS  PubMed  Google Scholar 

  26. Sorell M, Kapoor N, Kirkpatrick D, Rosen JF, Chaganti RS, Lopez C, Dupont B, Pollack MS, Terrin BN, Harris MB (1981) Marrow transplantation for juvenile osteopetrosis. Am J Med 70(6):1280–1287

    Article  CAS  PubMed  Google Scholar 

  27. Walker DG (1975) Control of bone resorption by hematopoietic tissue. The induction and reversal of congenital osteopetrosis in mice through use of bone marrow and splenic transplants. J Exp Med 142(3):651–663

    Article  CAS  PubMed  Google Scholar 

  28. Orchard PJ, Fasth AL, Le Rademacher J, He W, Boelens JJ, Horwitz EM, Al-Seraihy A, Ayas M, Bonfim CM, Boulad F (2015) Hematopoietic stem cell transplantation for infantile osteopetrosis. Blood 126(2):270–276

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Millard SM, Pettit AR, Ellis R, Chan JK, Raggatt LJ, Khosrotehrani K, Fisk NM (2015) Intrauterine bone marrow transplantation in osteogenesis imperfecta mice yields donor osteoclasts and osteomacs but not osteoblasts. Stem Cell Rep 5(5):682–689

    Article  Google Scholar 

  30. Caplan AI (1991) Mesenchymal stem cells. J Orthop Res 9(5):641–650

    Article  CAS  PubMed  Google Scholar 

  31. Borges I, Sena I, Azevedo P, Andreotti J, Almeida V, Paiva A, Santos G, Guerra D, Prazeres P, Mesquita LL (2017) Lung as a niche for hematopoietic progenitors. Stem Cell Rev Rep 13(5):567–574

    Article  PubMed  Google Scholar 

  32. Pauley P, Matthews BG, Wang L, Dyment NA, Matic I, Rowe DW, Kalajzic I (2014) Local transplantation is an effective method for cell delivery in the osteogenesis imperfecta murine model. Int Orthop 38(9):1955–1962

    Article  PubMed  Google Scholar 

Download references

Funding

This work was supported by philanthropic funding from the Sticks and Stones Foundation.

Author information

Authors and Affiliations

  1. Orthopaedic Research and Biotechnology Unit, Kids Research, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia

    Lucinda R. Lee, Lauren Peacock, Tegan L. Cheng, David G. Little, Craig F. Munns & Aaron Schindeler

  2. Discipline of Child and Adolescent Health, Faculty of Health and Medicine, The University of Sydney, Sydney, NSW, Australia

    Lucinda R. Lee, Laurence C. Cantrill, Tegan L. Cheng, David G. Little, Craig F. Munns & Aaron Schindeler

  3. Gene Therapy Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of Sydney and Sydney Children’s Hospitals Network, Westmead, NSW, Australia

    Samantha L. Ginn

  4. Microscopy Services, Kids Research at The Children’s Hospital at Westmead, Westmead, NSW, Australia

    Laurence C. Cantrill

Authors
  1. Lucinda R. Lee
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  2. Lauren Peacock
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  3. Samantha L. Ginn
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  4. Laurence C. Cantrill
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  7. Craig F. Munns
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  8. Aaron Schindeler
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Contributions

LRL performed the bulk of the experimental research and analysis. LP performed animal injection and animal care. SG carried out total body irradiation. LCC advised on microscopy and captured confocal images, TLC carried out biomechanical testing. DGL, CM, and AS conceived the study and designed the experimental plan. LRL and AS drafted the manuscript, with all authors providing critical feedback.

Corresponding author

Correspondence to Aaron Schindeler.

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Conflict of interest

Aaron Schindeler has received funding support from Amgen, Novartis AG, Celgene Corp, and N8 Medical for research unrelated to this study. Craig F. Munns has received research support from Alexion, Novartis AG and is a consultant for Alexion and Novartis AG for research unrelated to this project. Tegan L. Cheng and David G. Little received philanthropic funding from Hyundai Help for Kids, which is unrelated to this work.

Human and Animal Rights and Informed Consent

Animal experiments were approved by The Children’s Hospital at Westmead/Children’s Medical Research Institute Animal Ethics Committee under protocol K315. Informed Consent was not required as no human was involved.

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Lee, L.R., Peacock, L., Ginn, S.L. et al. Bone Marrow Transplantation for Treatment of the Col1a2+/G610C Osteogenesis Imperfecta Mouse Model. Calcif Tissue Int 104, 426–436 (2019). https://doi.org/10.1007/s00223-018-0504-3

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  • DOI: https://doi.org/10.1007/s00223-018-0504-3

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