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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.

Flores Bjurström, Carmen LU ; de Vries, Teun J; Moscatelli, Ilana LU ; Askmyr, Maria LU ; Schoenmaker, Ton; Langenbach, Geerling E J; Ehinger, Mats LU ; Everts, Vincent and Richter, Johan LU (2010) In Journal of Bone and Mineral Research 25(9). p.2069-2077
Abstract
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... (More)
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. (Less)
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organization
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Contribution to journal
publication status
published
subject
in
Journal of Bone and Mineral Research
volume
25
issue
9
pages
2069 - 2077
publisher
AMBMR
external identifiers
  • wos:000281620900019
  • pmid:20568230
  • scopus:77956830716
ISSN
1523-4681
DOI
10.1002/jbmr.90
language
English
LU publication?
yes
id
e3922aa4-02b5-4d8d-b718-a61da0315196 (old id 1625830)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20568230?dopt=Abstract
date added to LUP
2010-07-05 21:31:01
date last changed
2018-05-29 11:21:15
@article{e3922aa4-02b5-4d8d-b718-a61da0315196,
  abstract     = {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.},
  author       = {Flores Bjurström, Carmen and de Vries, Teun J and Moscatelli, Ilana and Askmyr, Maria and Schoenmaker, Ton and Langenbach, Geerling E J and Ehinger, Mats and Everts, Vincent and Richter, Johan},
  issn         = {1523-4681},
  language     = {eng},
  number       = {9},
  pages        = {2069--2077},
  publisher    = {AMBMR},
  series       = {Journal of Bone and Mineral Research},
  title        = {Nonablative neonatal bone marrow transplantation rapidly reverses severe murine osteopetrosis despite low level engraftment and lack of selective expansion of the osteoclastic lineage.},
  url          = {http://dx.doi.org/10.1002/jbmr.90},
  volume       = {25},
  year         = {2010},
}