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Nonablative neonatal bone marrow transplantation rapidly reverses severe murine osteopetrosis despite low level engraftment and lack of selective expansion of the osteoclastic lineage.

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Author

Summary, in English

Infantile malignant osteopetrosis (IMO) is caused by lack of functional osteoclasts leading to skeletal abnormalities, blindness due to compression of the optic nerves, bone marrow (BM) failure and early death. In most patients TCIRG1, a proton pump subunit essential for bone resorption, is mutated. Oc/oc mice represent a model for IMO due to a deletion in Tcirg1 and die around 4 weeks. To determine if hematopoietic stem cell transplantation without prior conditioning can reverse osteopetrosis, neonatal mice were transplanted iv with lineage depleted BM cells. More than 85% of oc/oc mice transplanted with 5 x 10(6) cells survived long term with an engraftment of 3-5% in peripheral blood (PB). At 3 w engraftment in the BM was 1-2% but the cellularity had increased 60-fold compared to non-treated oc/oc and RANKL and M-CSF expression in the BM was normalized. Histopathology and micro-CT revealed almost complete reversal of osteopetrosis after 4 weeks. In vitro studies showed that bone resorption by osteoclasts from transplanted oc/oc mice was 14% of transplanted controls and immunofluorescence microscopy revealed that resorption was mainly associated with osteoclasts of donor origin. Lineage analysis of BM, PB and spleen did not provide any evidence for selective recruitment of cells to the osteoclastic lineage. The vision was also preserved in transplanted oc/oc mice as determined by a visual tracking drum test. In summary, nonablative neonatal transplantation leading to engraftment of only a small fraction of normal cells rapidly reverses severe osteopetrosis in the oc/oc mouse model. (c) 2010 American Society for Bone and Mineral Research.

Publishing year

2010

Language

English

Pages

2069-2077

Publication/Series

Journal of Bone and Mineral Research

Volume

25

Issue

9

Document type

Journal article

Publisher

Wiley-Blackwell

Topic

  • Cancer and Oncology
  • Hematology

Status

Published

ISBN/ISSN/Other

  • ISSN: 1523-4681