Skip to main content

Advertisement

SpringerLink
Log in

Prognostic potential of precise molecular diagnosis of Autosomal Recessive Osteopetrosis with respect to the outcome of bone marrow transplantation

  • Special Issue Stem Cells
  • Published:
Cytotechnology Aims and scope Submit manuscript

Abstract

Hematopoietic stem cell transplantation (HSCT) is often the only practical approach to fatal genetic defects. One of the first pathologies which HSCT was applied to was Autosomal Recessive Osteopetrosis (ARO), a rare genetic bone disease in which a deficit in bone resorption by osteoclasts leads to increased bone density and secondary defects. The disease is often lethal early in life unless treated with HSCT. In utero transplantation (IUT) of the oc/oc mouse, reproducing the clinical features of a subset of ARO, has demonstrated that the quality of life and the survival of transplanted animals are greatly improved, suggesting that a similar protocol could be applied to humans. However, recently the dissection of the molecular bases of the disease has shown that ARO is genetically heterogeneous and has revealed the presence of subsets of patients which do not benefit from HSCT. This observation highlights the importance of molecular diagnosing ARO to identify and establish the proper therapies for a better prognosis. In particular, on the basis of experimental results in murine models, efforts should be undertaken to develop approaches such as IUT and new pharmacological strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Campos-Xavier AB, Casanova JL, Doumaz Y, Feingold J, Munnich A, Cormier-Daire V (2005) Intrafamilial phenotypic variability of osteopetrosis due to chloride channel 7 (CLCN7) mutations. Am J Med Genet A 133A:216–218. doi:10.1002/ajmg.a.30490

    Article  Google Scholar 

  • Castellano Chiodo D, DiRocco M, Gandolfo C, Morana G, Buzzi D, Rossi A (2007) Neuroimaging findings in malignant infantile osteopetrosis due to OSTM1 mutations. Neuropediatrics 38:154–156. doi:10.1055/s-2007-990267

    Article  CAS  Google Scholar 

  • Chalhoub N, Benachenhou N, Rajapurohitam V, Pata M, Ferron M, Frattini A, Villa A, Vacher J (2003) Grey-lethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human. Nat Med 9:399–406. doi:10.1038/nm842

    Article  CAS  Google Scholar 

  • Cleiren E, Bénichou O, Van Hul E, Gram J, Bollerslev J, Singer FR, Beaverson K, Aledo A, Whyte MP, Yoneyama T, de Vernejoul MC, Van Hul W (2001) Albers-Schönberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Hum Mol Genet 10:2861–2867. doi:10.1093/hmg/10.25.2861

    Article  CAS  Google Scholar 

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

    CAS  Google Scholar 

  • Corbacioglu S, Hönig M, Lahr G, Stöhr S, Berry G, Friedrich W, Schulz AS (2006) Stem cell transplantation in children with infantile osteopetrosis is associated with a high incidence of VOD, which could be prevented with defibrotide. Bone Marrow Transplant 38:547–553. doi:10.1038/sj.bmt.1705485

    Article  CAS  Google Scholar 

  • Corsten MF, Shah K (2008) Therapeutic stem-cells for cancer treatment: hopes and hurdles in tactical warfare. Lancet Oncol 9:376–384R. doi:10.1016/S1470-2045(08)70099-8

    Article  Google Scholar 

  • Driessen GJ, Gerritsen EJ, Fischer A, Fasth A, Hop WC, Veys P, Porta F, Cant A, Steward CG, Vossen JM, Uckan D, Friedrich W (2003) Long-term outcome of haematopoietic stem cell transplantation in autosomal recessive osteopetrosis: an EBMT report. Bone Marrow Transplant 32:657–663. doi:10.1038/sj.bmt.1704194

    Article  CAS  Google Scholar 

  • Flanagan AM, Massey HM, Wilson C, Vellodi A, Horton MA, Steward CG (2002) Macrophage colony-stimulating factor and receptor activator NF-kappaB ligand fail to rescue osteoclast-poor human malignant infantile osteopetrosis in vitro. Bone 30:85–90. doi:10.1016/S8756-3282(01)00656-1

    Article  CAS  Google Scholar 

  • Frattini A, Orchard PJ, Sobacchi C, Giliani S, Abinun M, Mattsson JP, Keeling DJ, Andersson AK, Wallbrandt P, Zecca L, Notarangelo LD, Vezzoni P, Villa A (2000) Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat Genet 25:343–346. doi:10.1038/77131

    Article  CAS  Google Scholar 

  • Frattini A, Pangrazio A, Susani L, Sobacchi C, Mirolo M, Abinun M, Andolina M, Flanagan A, Horwitz EM, Mihci E, Notarangelo LD, Ramenghi U, Teti A, Van Hove J, Vujic D, Young T, Albertini A, Orchard PJ, Vezzoni P, Villa A (2003) Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis. J Bone Miner Res 18:1740–1747. doi:10.1359/jbmr.2003.18.10.1740

    Article  CAS  Google Scholar 

  • Frattini A, Blair HC, Sacco MG, Cerisoli F, Faggioli F, Catò EM, Pangrazio A, Musio A, Rucci F, Sobacchi C, Sharrow AC, Kalla SE, Bruzzone MG, Colombo R, Magli MC, Vezzoni P, Villa A (2005) Rescue of ATPa3-deficient murine malignant osteopetrosis by hematopoietic stem cell transplantation in utero. Proc Natl Acad Sci USA 102:14629–14634. doi:10.1073/pnas.0507637102

    Article  CAS  Google Scholar 

  • Gerritsen EJ, Vossen JM, Fasth A, Friedrich W, Morgan G, Padmos A, Vellodi A, Porras O, O’Meara A, Porta F et al (1994) Bone marrow transplantation for autosomal recessive osteopetrosis. A report from the Working Party on Inborn Errors of the European Bone Marrow Transplantation Group. J Pediatr 125:896–902. doi:10.1016/S0022-3476(05)82004-9

    Article  CAS  Google Scholar 

  • Granero-Molto F, Weis JA, Longobardi L, Spagnoli A (2008) Role of mesenchymal stem cells in regenerative medicine: application to bone and cartilage repair. Expert Opin Biol Ther 8:255–268. doi:10.1517/14712598.8.3.255

    Article  CAS  Google Scholar 

  • Guerrini MM, Sobacchi C, Cassani B, Abinun M, Kilic SS, Pangrazio A, Moratto D, Mazzolari E, Clayton-Smith J, Orchard P, Coxon FP, Helfrich MH, Crockett JC, Mellis D, Vellodi A, Tezcan I, Notarangelo LD, Rogers MJ, Vezzoni P, Villa A, Frattini A (2008) Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. Am J Hum Genet 83:64–76

    Article  CAS  Google Scholar 

  • Hadjidakis DJ, Androulakis II (2006) Bone remodeling. Ann NY Acad Sci 1092:385–396. doi:10.1196/annals.1365.035

    Article  CAS  Google Scholar 

  • Jaing TH, Hou JW, Chen SH, Huang IA, Wang CJ, Lee WI (2006) Successful unrelated mismatched cord blood transplantation in a child with malignant infantile osteopetrosis. Pediatr Transplant 10:629–631. doi:10.1111/j.1399-3046.2006.00537.x

    Article  Google Scholar 

  • Kim N, Odgren PR, Kim DK, Marks SC Jr, Choi Y (2000) Diverse roles of the tumor necrosis factor family member TRANCE in skeletal physiology revealed by TRANCE deficiency and partial rescue by a lymphocyte-expressed TRANCE transgene. Proc Natl Acad Sci USA 97:10905–10910. doi:10.1073/pnas.200294797

    Article  CAS  Google Scholar 

  • Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ, Penninger JM (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397:315–323. doi:10.1038/16852

    Article  CAS  Google Scholar 

  • Kornak U, Schulz A, Friedrich W, Uhlhaas S, Kremens B, Voit T, Hasan C, Bode U, Jentsch TJ, Kubisch C (2000) Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis. Hum Mol Genet 9:2059–2063. doi:10.1093/hmg/9.13.2059

    Article  CAS  Google Scholar 

  • Kornak U, Kasper D, Bosl MR, Kaiser E, Schweizer M, Schulz A, Friedrich W, Delling G, Jentsch TJ (2001) Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell 104:205–215. doi:10.1016/S0092-8674(01)00206-9

    Article  CAS  Google Scholar 

  • Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shaloub V, Senaldi G, Guo J, Delaney J, Boyle WJ (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176. doi:10.1016/S0092-8674(00)81569-X

    Article  CAS  Google Scholar 

  • Lange PF, Wartosch L, Jentsch TJ, Fuhrmann JC (2006) ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function. Nature 440:220–223. doi:10.1038/nature04535

    Article  CAS  Google Scholar 

  • Liu G, Shu C, Cui L, Liu W, Cao Y (2008) Tissue-engineered bone formation with cryopreserved human bone marrow mesenchymal stem cells. Cryobiology 56:209–215. doi:10.1016/j.cryobiol.2008.02.008

    Article  CAS  Google Scholar 

  • Maranda B, Chabot G, Décarie JC, Pata M, Azeddine B, Moreau A, Vacher J (2008) Clinical and cellular manifestations of OSTM1-related infantile osteopetrosis. J Bone Miner Res 23:296–300. doi:10.1359/jbmr.071015

    Article  CAS  Google Scholar 

  • Meadows NA, Sharma SM, Faulkner GJ, Ostrowski MC, Hume DA, Cassady AI (2007) The expression of chloride channel 7 (ClCN7) and OSTM1 in osteoclasts is co-regulated by microphtalmia transcription factor. J Biol Chem 282:1891–1904. doi:10.1074/jbc.M608572200

    Article  CAS  Google Scholar 

  • Meyerrose TE, Roberts M, Ohlemiller KK, Vogler CA, Wirthlin L, Nolta JA, Sands MS (2008) Lentiviral-transduced human mesenchymal stem cells persistently express therapeutic levels of enzyme in a xenotransplantation model of human disease. Stem Cells 26:1713–1722

    Article  CAS  Google Scholar 

  • Michigami T, Kageyama T, Satomura K, Shima M, Yamaoka K, Nakayama M, Ozono K (2002) Novel mutations in the a3 subunit of vacuolar H(+)-adenosine triphosphatase in a Japanese patient with infantile malignant osteopetrosis. Bone 30:436–439. doi:10.1016/S8756-3282(01)00684-6

    Article  CAS  Google Scholar 

  • Nicholls BM, Bredius RG, Hamdy NA, Gerritsen EJ, Lankester AC, Hogendoorn PC, Nesbitt SA, Horton MA, Flanagan AM (2005) Limited rescue of osteoclast-poor osteopetrosis after successful engraftment by cord blood from an unrelated donor. J Bone Miner Res 20:2264–2270. doi:10.1359/JBMR.050807

    Article  Google Scholar 

  • Pangrazio A, Poliani PL, Megarbane A, Lefranc G, Lanino E, Di Rocco M, Rucci F, Lucchini F, Ravanini M, Facchetti F, Abinum M, Vezzoni P, Villa A, Frattini A (2006) Mutations in OSTM1 (grey lethal) define a particularly severe form of autosomal recessive osteopetrosis with neural involvement. J Bone Miner Res 21:1098–1105. doi:10.1359/jbmr.060403

    Article  CAS  Google Scholar 

  • Quarello P, Forni M, Barberis L, Defilippi C, Campagnoli MF, Silvestro L, Frattini A, Chalhoub N, Vacher J, Ramenghi U (2004) Severe malignant osteopetrosis caused by a GL gene mutation. J Bone Miner Res 19:1194–1199. doi:10.1359/JBMR.040407

    Article  Google Scholar 

  • Ramirez A, Faupel J, Goebel I, Stiller A, Beyer S, Stockle C, Hasan C, Bode U, Kornak U, Kubisch C (2004) Identification of a novel mutation in the coding region of the grey-lethal gene OSTM1 in human malignant infantile osteopetrosis. Hum Mutat 23:471–476. doi:10.1002/humu.20028

    Article  CAS  Google Scholar 

  • Schulz AS, Classen CF, Mihatsch WA, Sigl-Kraetzig M, Wiesneth M, Debatin KM, Friedrich W, Müller SM (2002) HLA-haploidentical blood progenitor cell transplantation in osteopetrosis. Blood 99:3458–3460. doi:10.1182/blood.V99.9.3458

    Article  CAS  Google Scholar 

  • Scimeca JC, Quincey D, Parrinello H, Romatet D, Grosgeorge J, Gaudray P, Philip N, Fischer A, Carle GF (2003) Novel mutations in the TCIRG1 gene encoding the a3 subunit of the vacuolar proton pump in patients affected by infantile malignant osteopetrosis. Hum Mutat 21:151–157. doi:10.1002/humu.10165

    Article  CAS  Google Scholar 

  • Sobacchi C, Frattini A, Orchard P, Porras O, Tezcan I, Andolina M, Babul-Hirji R, Baric I, Canham N, Chitayat D, Dupuis-Girod S, Ellis I, Etzioni A, Fasth A, Fisher A, Gerritsen B, Gulino V, Horwitz E, Klamroth V, Lanino E, Mirolo M, Musio A, Matthijs G, Nonomaya S, Notarangelo LD, Ochs HD, Superti Furga A, Valiaho J, van Hove JL, Vihinen M, Vujic D, Vezzoni P, Villa A (2001) The mutational spectrum of human malignant autosomal recessive osteopetrosis. Hum Mol Genet 10:1767–1773. doi:10.1093/hmg/10.17.1767

    Article  CAS  Google Scholar 

  • Sobacchi C, Frattini A, Guerrini MM, Abinun M, Pangrazio A, Susani L, Bredius R, Mancini G, Cant A, Bishop N, Grabowski P, Del Fattore A, Messina C, Errigo G, Coxon FP, Scott DI, Teti A, Rogers MJ, Vezzoni P, Villa A, Helfrich MH (2007) Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Genet 39:960–962. doi:10.1038/ng2076

    Article  CAS  Google Scholar 

  • Souraty N, Noun P, Djambas-Khayat C, Chouery E, Pangrazio A, Villa A, Lefranc G, Frattini A, Mégarbané A (2007) Molecular study of six families originating from the Middle-East and presenting with autosomal recessive osteopetrosis. Eur J Med Genet 50:188–199. doi:10.1016/j.ejmg.2007.01.005

    Article  Google Scholar 

  • Susani L, Pangrazio A, Sobacchi C, Taranta A, Mortier G, Savarirayan R, Villa A, Orchard P, Vezzoni P, Albertini A, Frattini A, Pagani F (2004) TCIRG1-dependent recessive osteopetrosis: mutation analysis, functional identification of the splicing defects and in vitro rescue by U1snRNA. Hum Mutat 24:225–235. doi:10.1002/humu.20076

    Article  CAS  Google Scholar 

  • Tolar J, Bonfim C, Grewal S, Orchard P (2006) Engraftment and survival following hematopoietic stem cell transplantation for osteopetrosis using a reduced intensity conditioning regimen. Bone Marrow Transplant 38:783–787. doi:10.1038/sj.bmt.1705533

    Article  CAS  Google Scholar 

  • Tsuji Y, Ito S, Isoda T, Kajiwara M, Nagasawa M, Morio T, Mizutani S (2005) Successful nonmyeloablative cord blood transplantation for an infant with malignant infantile osteopetrosis. J Pediatr Hematol Oncol 27:495–498. doi:10.1097/01.mph.0000179961.72889.bf

    Article  Google Scholar 

  • Van Wesenbeeck L, Odgren PR, Coxon FP, Frattini A, Moens P, Perdu B, MacKay CA, Van Hul E, Timmermans JP, Vanhoenacker F, Jacobs R, Peruzzi B, Teti A, Helfrich MH, Rogers MJ, Villa A, Van Hul W (2007) Involvement of PLEKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans. J Clin Invest 117:919–930. doi:10.1172/JCI30328

    Article  Google Scholar 

  • Weinberg KI, Kapoor N, Shah AJ, Crooks GM, Kohn DB, Parkman R (2001) Hematopoietic stem cell transplantation for severe combined immune deficiency. Curr Allergy Asthma Rep 1:416–420R. doi:10.1007/s11882-001-0026-2

    Article  CAS  Google Scholar 

  • Xu YQ, Liu ZC (2008) Therapeutic potential of adult bone marrow stem cells in liver disease and delivery approaches. Stem Cell Rev 4:101–112

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from Eurostells (STELLAR) and FIRB/MIUR to P.V. (RBIN04CHXT), from the Fondazione Telethon to C.S. (grant GGP07059), from the Fondazione Cariplo to A.F and from ISS Malattie Rare (New cell therapy approaches for infantile malignant Osteopetrosis) to P.V. The work reported in this paper has also been funded by the N.O.B.E.L. (Network Operativo per la Biomedicina di Eccellenza in Lombardia) Program from Fondazione Cariplo to P.V. and A.V. The technical assistance of Dario Strina and Lucia Susani is acknowledged.

Author information

Authors and Affiliations

  1. Istituto di Tecnologie Biomediche, CNR, via F.lli Cervi 93, 20090, Segrate, Italy

    Anna Villa, Alessandra Pangrazio, Elena Caldana, Matteo Guerrini, Paolo Vezzoni, Annalisa Frattini & Cristina Sobacchi

  2. Istituto Clinico Humanitas, via Manzoni 113, 20089, Rozzano, Italy

    Anna Villa, Alessandra Pangrazio, Elena Caldana, Matteo Guerrini, Paolo Vezzoni, Annalisa Frattini & Cristina Sobacchi

  3. Telethon Institute for Gene Therapy, Università Vita e Salute San Raffaele, via Olgettina 58, 20090, Milan, Italy

    Anna Villa

Authors
  1. Anna Villa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alessandra Pangrazio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elena Caldana
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Matteo Guerrini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paolo Vezzoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Annalisa Frattini
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Cristina Sobacchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anna Villa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Villa, A., Pangrazio, A., Caldana, E. et al. Prognostic potential of precise molecular diagnosis of Autosomal Recessive Osteopetrosis with respect to the outcome of bone marrow transplantation. Cytotechnology 58, 57–62 (2008). https://doi.org/10.1007/s10616-008-9165-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10616-008-9165-9

Keywords

Search

Navigation