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.
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.