Hematopoietic stem-cell contribution to ectopic skeletogenesis.
Abstract | BACKGROUND: METHODS: RESULTS: We found that replacement of hematopoietic cells was not sufficient to prevent ectopic skeletogenesis in the patient with fibrodysplasia ossificans progressiva but pharmacologic suppression of the apparently normal donor immune system following transplantation in the new host modulated the activity of the fibrodysplasia ossificans progressiva and diminished the expression of skeletal ectopia. In complementary murine transplantation studies, we found that cells of hematopoietic origin contributed to the early inflammatory and late marrow-repopulating stages of BMP4-induced heterotopic ossification but were not represented in the fibroproliferative, chondrogenic, or osteogenic stages of heterotopic ossification. Interestingly, both recombinant human BMP4 induction in an animal model and the dysregulated BMP signaling pathway in a patient with fibrodysplasia ossificans progressiva were sufficient to recruit at least two populations of cells, one of hematopoietic origin and at least one of non-hematopoietic origin, that contribute to the formation of an ectopic skeleton. CONCLUSIONS: Taken together, these findings demonstrate that bone marrow transplantation did not cure fibrodysplasia ossificans progressiva in the patient in this study, most likely because the hematopoietic cell population is not the site, or at least not the dominant site, of the intrinsic dysregulation of the BMP signaling pathway in fibrodysplasia ossificans progressiva. However, following transplantation of bone marrow from a presumably normal donor, immunosuppression of the immune system appeared to ameliorate activation of ectopic skeletogenesis in a genetically susceptible host. Thus, cells of hematopoietic origin may contribute to the formation of an ectopic skeleton, although they are not sufficient to initiate the process alone.
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Authors | Frederick S Kaplan, David L Glaser, Eileen M Shore, Robert J Pignolo, Meiqi Xu, Yi Zhang, David Senitzer, Stephen J Forman, Stephen G Emerson |
Journal | The Journal of bone and joint surgery. American volume
(J Bone Joint Surg Am)
Vol. 89
Issue 2
Pg. 347-57
(Feb 2007)
ISSN: 0021-9355 [Print] United States |
PMID | 17272450
(Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- BMP4 protein, human
- Bmp4 protein, mouse
- Bone Morphogenetic Protein 4
- Bone Morphogenetic Proteins
- ACVR1 protein, human
- Activin Receptors, Type I
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Topics |
- Activin Receptors, Type I
(genetics)
- Adult
- Anemia, Aplastic
(surgery)
- Animals
- Bone Marrow Transplantation
- Bone Morphogenetic Protein 4
- Bone Morphogenetic Proteins
(administration & dosage, adverse effects, genetics)
- DNA Mutational Analysis
- Humans
- Male
- Mice
- Mice, Transgenic
- Myositis Ossificans
(genetics, pathology, physiopathology, surgery)
- Ossification, Heterotopic
(etiology, genetics, pathology)
- Sequence Analysis, DNA
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