The evaluation of ectopic bone formation induced by delivery systems for bone morphogenetic protein-9 or its derived peptide.
ABSTRACT We have earlier shown that a peptide derived from the bone morphogenetic protein-9 (pBMP-9) stimulates mouse preosteoblasts MC3T3-E1 differentiation in vitro. Here, we evaluated the effects of two delivery systems (DSs) for pBMP-9, one based on collagen and the other on chitosan. The release kinetics of BMP-9 (used as control) and pBMP-9 from these DSs were first determined in vitro by using enzyme-linked immunosorbent assay and high performance liquid chromatography assays, respectively. Micro-computerized tomography and histological analysis were then performed to study in vivo the ectopic ossification induced by both DSs containing these molecules in C57BL/6 mouse quadriceps. We found that collagen DS released in vitro about 35% of its BMP-9 within 1 h, whereas chitosan DS released 80%. The pBMP-9 was released from both DSs more slowly for up to 10 days. These release kinetics seemed to fit the Korsmeyer-Peppas model. Only chitosan DS containing BMP-9 induced strong bone formation in all mice quadriceps within 24 days. All mice quadriceps treated by pBMP-9 trapped in this DS also favored bone structures that started to mineralize. However, pBMP-9 in collagen DS failed to promote ectopic ossification within 24 days in vivo. This study highlights the importance to optimize carrier, thus improving the efficiency of pBMP-9 in vivo.
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ABSTRACT: Bone morphogenetic proteins (BMPs) are cytokines with a strong effect on bone and cartilage growth and with important roles during embryonic patterning and early skeletal formation. BMPs have promising potential for clinical bone and cartilage repair, working as powerful bone-inducing components in diverse tissue-engineering products. Synthetic polymers, natural origin polymers, inorganic materials and composites may be used as carriers for the delivery of BMPs. Carriers range from nanoparticles to complex three-dimensional (3D) scaffolds, membranes for tissue-guided regeneration, biomimetic surfaces and smart thermosensitive hydrogels. Current clinical uses include spinal fusion, healing of long bone defects and craniofacial and periodontal applications, amongst others. BMP-2 and BMP-7 have recently received approval by the US Food and Drug Administration (FDA) for specific clinical cases, delivered in absorbable collagen sponges. Considering the expanding number of publications in the field of BMPs, there are prospects of a brilliant future in the field of regenerative medicine of bone and cartilage with the use of BMPs.Journal of Tissue Engineering and Regenerative Medicine 2(2-3):81-96. · 2.83 Impact Factor
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ABSTRACT: As life expectancy increases, so does the need to treat large bone defects. New biomaterials combined with osteogenic cells are now being developed as an alternative to autogenous bone grafts. The goal is to make the stem cells adhere to the scaffold, and then grow to differentiate into functional osteogenic cells and organize into healthy bone as the scaffold degrades. Decisive improvements have been made in the fields of stem cell biology, 3-D scaffold fabrication and tissue engineering, but the ideal bone substitute that fulfils all functional and safety requirements has yet to be developed.Drug Discovery Today 10/2004; 9(18):803-11. · 6.55 Impact Factor
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ABSTRACT: Osterix/Sp7, a member of the Sp1 transcription factor family, plays an essential role in bone formation and osteoblastogenesis. Although Osterix has been shown to be induced by BMP2 in a mesenchymal cell line, the molecular basis of the regulation, expression and function of Osterix during osteoblast differentiation, is not fully understood. Thus we examined the role of BMP2 signaling in the regulation of Osterix using the mesenchymal cell lines C3H10T1/2 and C2C12. Osterix overexpression induced alkaline phosphatase activity and osteocalcin expression in C2C12 cells and stimulated calcification of murine primary osteoblasts. Considering that Runx2 overexpression induces Osterix, these results suggest that Osterix functions as downstream of Runx2. Surprisingly, BMP2 treatment induced Osterix expression and alkaline phosphatase activity in mesenchymal cells derived from Runx2-deficient mice. Furthermore, overexpression of Smad1 and Smad4 up-regulated Osterix expression, and an inhibitory Smad, Smad6, markedly suppressed BMP2-induced Osterix expression in the Runx2-deficient cells. Moreover, overexpression of a homeobox gene, Msx2, which is up-regulated by BMP2 and promotes osteoblastic differentiation, induced Osterix expression in the Runx2-deficient cells. Knockdown of Msx2 clearly inhibited induction of Osterix by BMP2 in the Runx2-deficient mesenchymal cells. Interestingly, microarray analyses using the Runx2-deficient cells revealed that the role of Osterix was distinct from that of Runx2. These findings suggest that Osterix is regulated via both Runx2-dependent and -independent mechanisms, and that Osterix controls osteoblast differentiation, at least in part, by regulating the expression of genes not controlled by Runx2.Journal of Biological Chemistry 09/2008; 283(43):29119-25. · 4.65 Impact Factor