The role of bone morphogenetic protein -9 in skeletal development

By understanding molecular pathways important for bone development, we can gain insight into the pathogenesis of musculoskeletal disease and develop targeted strategies for regenerative medicine in bone. Bone morphogenetic proteins play an important role in the development of bone, as well as other organs. In comprehensive in vitro and in vivo screenings of all fourteen BMPs, Bone Morphogenetic Protein-9 was recently identified one of the most osteogenic of BMPs. BMP-9 is a relatively uncharacterized member of the BMP family.;In this thesis, I investigate the role of BMP-9 in vivo. I present immunohistochemistry of BMP-9 and demonstrate expression of the factor in osteoblasts of bone and in intervertebral discs of the spine. It is also present in the liver and nervous system. I examine the role of BMP-9 in the in vivo skeleton using a transgenic conditional BMP-9 overexpression mouse. By selectively over-expressing BMP-9 in the skeletal system under the control of a Cre-expressing 2.3 kb Col1a1 promoter, I observed mice that have a postnatal spinal curvature reminiscent of idiopathic scoliosis, a human axial skeletal deformity. These mice typically had an ossified deformity of a lower lumbar intervertebral disc. I investigated the mechanism of action of BMP-9 on intervertebral disc cells by creating clonal mouse intervertebral disc cell lines. BMP-9 was effectively able to convert annulus fibrosus disc cells to an osteogenic fate both in vitro and in an in vivo ectopic bone mass model in a Notch pathway dependent fashion. I found that Nucleus pulposus cells were also able to undergo osteogenesis, but to a more limited extent.;These data demonstrate that BMP-9 is expressed in the skeletal system during development and that BMP-9 overexpression can lead to a novel idiopathic scoliosis-like deformity of the axial skeleton. The results suggest that the spinal deformity may be due to BMP-9 induced osteogenic effects on the annulus fibrosus cells of the intervertebral disc. This research highlights a role for osteogenic factors in axial skeletal pathogenesis and role for the Notch pathway in BMP-9 mediated ossification of intervertebral disc cells. I believe that my transgenic mouse model will be of great value in future studies examining the molecular mechanisms behind scoliosis and other disc diseases.