Thymidine Kinase-Mediated Shut Down of Bone Morphogenetic Protein-4 Expression Allows Regulated Bone Production
Maria T. Esposito,
Bone morphogenetic Proteins (BMPs) are growth factors also involved in ossification and chondrogenesis that
have generated interest for their efficiency in inducing bone neo-synthesis. BMPs expression in engineered cells has been
successful in stimulating osteoblastic differentiation and ectopic and orthotopic bone formation in vivo. We have previously
shown that an adenoviral vector expressing bone morphogenetic protein type-4 (BMP-4) is able to efficiently drive
bone formation in a rabbit model of discontinuous bone lesions. However, unregulated secretion of BMPs has also been
implicated in bone overproduction and exostosis. We have constructed a replication-defective first generation adenoviral
(FG-Ad) vector containing a cassette for the expression of BMP-4 associated with the Herpes Simplex virus thymidine
kinase (TK) gene (FG-B4TK) in order to shut down BMP-4 expression and, therefore, regulate bone production. TK expression
does not interfere with BMP-4 ability to induce ectopic bone formation in athymic nude mice. Administration of
ganciclovir blocks ectopic bone production in quadriceps muscle transduced with the FG-B4TK with no effect on the contralateral
muscle transduced with a vector expressing only BMP-4. Histological findings confirmed the pro-apoptotic activity
of TK and the reduction of mineralized areas in the quadriceps transduced with FG-B4TK in mice treated with ganciclovir.
We have generated a system to block BMP-4 secretion by inducing apoptosis in transduced cells therefore blocking
unwanted bone formation. This system is an additional tool to generate regulated amount of bone in discontinuous
bone lesions and can be easily coupled with biomaterials capable of recruiting cells and generating a local bioreactor.
Keywords: FG-B4, FG-B4TK, bone production regulation.
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