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In Vivo Somatic Cell Gene Transfer of an Engineered Noggin Mutein Prevents BMP4-Induced Heterotopic Ossification.
- Source :
- Journal of Bone & Joint Surgery, American Volume; Dec2003, Vol. 85 Issue 12, p2332-2342, 11p
- Publication Year :
- 2003
-
Abstract
- The formation of the skeleton requires inductive signals that are balanced with their antagonists in a highly regulated negative feedback system. Inappropriate or excessive expression of BMPs (bone morphogenetic proteins) or their antagonists results in genetic disorders affecting the skeleton, such as fibrodysplasia ossificans progressiva. BMP signaling mediated through binding to its receptors is a critical step in the induction of abnormal ossification. Therefore, we hypothesized that engineering more effective inhibitors of this BMP-signaling process may lead to the development of therapies for such conditions. BMP4-induced heterotopic ossification was used as a model for testing the ability of the BMP antagonist Noggin to block de novo bone formation, either by local or systemic delivery. Since Noggin naturally acts locally, a Noggin mutein, hNOGΔB2, was engineered and was shown to circulate systemically, and its ability to block heterotopic ossification was tested in a mouse model with use of adenovirus-mediated somatic cell gene transfer. BMP4-induced heterotopic ossification can be prevented in vivo either by local delivery of wild-type Noggin or after somatic cell gene transfer of a Noggin mutein, hNOGΔB2. Furthermore, the data in the present study provide proof of concept that a naturally occurring factor can be engineered for systemic delivery toward a desirable pharmacological outcome. Clinical Relevance: Blocking bone formation is clinically relevant to disorders of heterotopic ossification in humans, such as fibrodysplasia ossificans progressiva. Furthermore, development of BMP antagonists as therapeutic agents may provide modalities for the treatment of other pathologic conditions that arise from aberrant expression of BMPs and/or from a lack of their antagonists. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00219355
- Volume :
- 85
- Issue :
- 12
- Database :
- Complementary Index
- Journal :
- Journal of Bone & Joint Surgery, American Volume
- Publication Type :
- Academic Journal
- Accession number :
- 11570790
- Full Text :
- https://doi.org/10.2106/00004623-200312000-00010