title: Hematopoietic stem-cell contribution to ectopic skeletogenesis.
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.affiliation: 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.edu
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Kaplan
authors.forename: David L
authors.initials: DL
authors.lastname: Glaser
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Shore
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Pignolo
authors.forename: Meiqi
authors.initials: M
authors.lastname: Xu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: David
authors.initials: D
authors.lastname: Senitzer
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Forman
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Emerson
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics; D000328:Adult; D000741:Anemia, Aplastic / Q000601:surgery; D000818:Animals; D016026:Bone Marrow Transplantation; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics; D004252:DNA Mutational Analysis; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009221:Myositis Ossificans / Q000235:genetics / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D009999:Ossification, Heterotopic / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA
chemical_list: C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I