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Hematopoietic stem-cell contribution to ectopic skeletogenesis.
J Bone Joint Surg Am. 2007 Feb; 89(2):347-57.JB

Abstract

BACKGROUND

Fibrodysplasia ossificans progressiva is a rare genetic disorder of ectopic skeletogenesis associated with dysregulation of bone morphogenetic protein (BMP) signaling. Hematopoietic cells have been implicated in the ectopic skeletogenesis of fibrodysplasia ossificans progressiva, and their replacement has been postulated as a possible cure. However, the definitive contribution of hematopoietic cells to the pathogenesis of ectopic skeletogenesis remains obscure.

METHODS

We employed both careful clinical observation and in vivo murine transplantation studies to more precisely determine the contribution of hematopoietic cells to ectopic skeletogenesis. We identified a patient with fibrodysplasia ossificans progressiva who had undergone bone marrow transplantation for the treatment of intercurrent aplastic anemia twenty-five years earlier and investigated whether the clinical course of the fibrodysplasia ossificans progressiva had been influenced by bone marrow replacement or immunosuppression, or both. In complementary studies, we transplanted hematopoietic stem cells from constitutively expressing LacZ transgenic mice to identify the contribution of hematopoietic cells to BMP4-induced heterotopic ossification, a histopathologic model of fibrodysplasia ossificans progressiva.

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.

Authors+Show Affiliations

Center for Research in Fibrodyplasia Ossificans Progressiva and Related Disorders, Department of Orthopaedic Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6081, USA. frederick.kaplan@uphs.upenn.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17272450

Citation

Kaplan, Frederick S., et al. "Hematopoietic Stem-cell Contribution to Ectopic Skeletogenesis." The Journal of Bone and Joint Surgery. American Volume, vol. 89, no. 2, 2007, pp. 347-57.
Kaplan FS, Glaser DL, Shore EM, et al. Hematopoietic stem-cell contribution to ectopic skeletogenesis. J Bone Joint Surg Am. 2007;89(2):347-57.
Kaplan, F. S., Glaser, D. L., Shore, E. M., Pignolo, R. J., Xu, M., Zhang, Y., Senitzer, D., Forman, S. J., & Emerson, S. G. (2007). Hematopoietic stem-cell contribution to ectopic skeletogenesis. The Journal of Bone and Joint Surgery. American Volume, 89(2), 347-57.
Kaplan FS, et al. Hematopoietic Stem-cell Contribution to Ectopic Skeletogenesis. J Bone Joint Surg Am. 2007;89(2):347-57. PubMed PMID: 17272450.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hematopoietic stem-cell contribution to ectopic skeletogenesis. AU - Kaplan,Frederick S, AU - Glaser,David L, AU - Shore,Eileen M, AU - Pignolo,Robert J, AU - Xu,Meiqi, AU - Zhang,Yi, AU - Senitzer,David, AU - Forman,Stephen J, AU - Emerson,Stephen G, PY - 2007/2/3/pubmed PY - 2007/3/22/medline PY - 2007/2/3/entrez SP - 347 EP - 57 JF - The Journal of bone and joint surgery. American volume JO - J Bone Joint Surg Am VL - 89 IS - 2 N2 - BACKGROUND: Fibrodysplasia ossificans progressiva is a rare genetic disorder of ectopic skeletogenesis associated with dysregulation of bone morphogenetic protein (BMP) signaling. Hematopoietic cells have been implicated in the ectopic skeletogenesis of fibrodysplasia ossificans progressiva, and their replacement has been postulated as a possible cure. However, the definitive contribution of hematopoietic cells to the pathogenesis of ectopic skeletogenesis remains obscure. METHODS: We employed both careful clinical observation and in vivo murine transplantation studies to more precisely determine the contribution of hematopoietic cells to ectopic skeletogenesis. We identified a patient with fibrodysplasia ossificans progressiva who had undergone bone marrow transplantation for the treatment of intercurrent aplastic anemia twenty-five years earlier and investigated whether the clinical course of the fibrodysplasia ossificans progressiva had been influenced by bone marrow replacement or immunosuppression, or both. In complementary studies, we transplanted hematopoietic stem cells from constitutively expressing LacZ transgenic mice to identify the contribution of hematopoietic cells to BMP4-induced heterotopic ossification, a histopathologic model of fibrodysplasia ossificans progressiva. 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. SN - 0021-9355 UR - https://www.unboundmedicine.com/medline/citation/17272450/Hematopoietic_stem_cell_contribution_to_ectopic_skeletogenesis_ L2 - https://doi.org/10.2106/JBJS.F.00472 DB - PRIME DP - Unbound Medicine ER -