Hematopoietic Stem-Cell Contribution to Ectopic Skeletogenesis

Kaplan, Frederick S.; Glaser, David L.; Shore, Eileen M.; Pignolo, Robert J.; Meiqi Xu; Yi Zhang; Senitzer, David; Forman, Stephen J.; Emerson, Stephen G.
February 2007
Journal of Bone & Joint Surgery, American Volume;Feb2007, Vol. 89-A Issue 2, p347
Academic Journal
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 con- tribute 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. Clinical Relevance: Therapeutic regulation of hematopoietic and osteogenic cell populations involved in fibrodysplasia ossificans progressiva lesions holds promise for treatment of fibrodysplasia ossificans progressiva and possibly other disorders of heterotopic ossification.


Related Articles

  • De novo 617G—A nucleotide mutation in the ACVR1 gene in a Taiwanese patient with fibrodysplasia ossificans progressiva. Gau-Tyan Lin; Hsueh-Wei Chang; Chih-Shan Liu; Peng-Ju Huang; Hsien-Chung Wang; Yuh-Min Cheng // Journal of Human Genetics;Dec2006, Vol. 51 Issue 12, p1083 

    Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disease with autosomal dominant transmission characterized by the presence of malformations of the big toes and of postnatal progressive heterotopic endochondral osteogenesis. We report the case of 3-year-old girl with dysplasia of...

  • A Recurrent Mutation c.617G>A in the ACVR1 Gene Causes Fibrodysplasia Ossificans Progressiva in Two Chinese Patients. Yue Sun; Weibo Xia; Yan Jiang; Xiaoping Xing; Mei Li; Ou Wang; Huabing Zhang; Yingying Hu; Huaicheng Liu; Xunwu Meng; Xueying Zhou // Calcified Tissue International;May2009, Vol. 84 Issue 5, p361 

    Fibrodysplasia ossificans progressiva (FOP; OMIM 135100) is a rare heritable disorder of connective tissue characterized by congenital malformations of the great toes and recurrent episodes of painful soft tissue swelling that lead to heterotopic ossifications. Recent studies have shown that the...

  • The Genetic Key to a Rare Disease and Its Impact on Orthopedics. Wolf, Jennifer M. // Orthopedics;Aug2006, Vol. 29 Issue 8, p672 

    Discusses the etiology of fibrodysplasia ossificans progressiva and its impact on orthopedics. Contributions of the disabling formation of heterotopic bone to the development of the disease; Need for the identification of the specific gene mutation that causes bone to form in fibrodysplasia...

  • Myositis Ossificans Progressiva. Kuchey, Gulzar Ahmad; Bhat, Masood Habib; Tantray, Mejrah Din; Mahajan, Sumit; Wali, G. R.; Sharma, Sudesh // Internet Journal of Orthopedic Surgery;2009, Vol. 12 Issue 1, p17 

    Myositis ossificans progressiva (MOP) or fibrodysplasia ossificans progressiva is a severe extremely rare condition of ectopic ossification with primary involvement of the skeletal muscles associated with charecteristic skeletal abnormalities with an average incidence of 1/10million. It was...

  • Pennsylvania Researchers Discover Gene Responsible for Rare Skeletal Disease.  // PT: Magazine of Physical Therapy;Jul2006, Vol. 14 Issue 7, p79 

    The article cites key research findings from Pennsylvania in 2006 pinpointing the cause of the bone growth disease fibrodysplasia ossificans progressiva (FOP). Researchers have located the skeleton key, a gene that causes bone disorders when damaged. The findings show promise for the development...

  • Chin-on-Chest Deformity in Patients with Fibrodysplasia Ossificans Progressiva: A Case Series. Moore, Ryan E.; Dormans, John P.; Drummond, Denis S.; Shore, Eileen M.; Kaplan, Frederick S.; Auerbach, Joshua D. // Journal of Bone & Joint Surgery, American Volume;Jun2009, Vol. 91-A Issue 6, p1497 

    The article presents case studies of patients with fibrodysplasia ossificans progressiva. The patients had severe chin-on-chest deformity due to progressive heterotopic ossification and asymmetric lesions of the neck. The patients underwent a surgery that has been effective in achieving...

  • Fibrodysplasia Ossificans Progressiva – Lessons from Rare Maladies. Connor, J. Michael // New England Journal of Medicine;8/22/96, Vol. 335 Issue 8, p591 

    The author discusses implications of the study reported in this issue, "Overexpression of an osteogenic morphogen in fibrodysplasia ossificans progressiva," by A. B. Shafritz and colleagues. He mentions that studies of rare genetic defects can help define the roles of cellular morphogens and...

  • Mutational analysis of the ACVR1 gene in Italian patients affected with fibrodysplasia ossificans progressiva: confirmations and advancements. Bocciardi, Renata; Bordo, Domenico; Di Duca, Marco; Di Rocco, Maja; Ravazzolo, Roberto // European Journal of Human Genetics;Mar2009, Vol. 17 Issue 3, p311 

    Fibrodysplasia ossificans progressiva (FOP, MIM 135100) is a rare genetic disorder characterized by congenital great toe malformations and progressive heterotopic ossification transforming skeletal muscles and connective tissues to bone following a well-defined anatomic pattern of progression....

  • Skeletal metamorphosis in fibrodysplasia ossificans progressiva (FOP). Frederick Kaplan; Qi Shen; Vitali Lounev; Petra Seemann; Jay Groppe; Takenobu Katagiri; Robert Pignolo; Eileen Shore // Journal of Bone & Mineral Metabolism;Nov2008, Vol. 26 Issue 6, p521 

    Abstract  Metamorphosis, the transformation of one normal tissue or organ system into another, is a biological process rarely studied in higher vertebrates or mammals, but exemplified pathologically by the extremely disabling autosomal dominant disorder fibrodysplasia ossificans...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics