Osteostatin improves the osteogenic activity of fibroblast growth factor-2 immobilized in Si-doped hydroxyapatite in osteoblastic cells

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• 作者：Daniel Lozano^a ; ^{dlozano@fjd.es} ; Marí ; a José ; Feito^b ; Sergio Portal-Nú ; ñ ; ez^a ; Rosa Marí ; a Lozano^c ; Marí ; a Concepció ; n Matesanz^b ; Marí ; a Concepció ; n Serrano^d ; Marí ; a Vallet-Regí ; ^e ; ^f ; Marí ; a Teresa Portolé ; s^b ; Pedro Esbrit^a
• 关键词：Osteostatin ; Fibroblast growth factor-2 ; Osteoblastic function ; Parathyroid hormone-related protein ; Si-based hydroxyapatite
• 刊名：Acta Biomaterialia
• 出版年：2012
• 期刊代码：1_17427061
• 类别：ce
• 出版时间：July, 2012
• 卷：8
• 期：7
• 页码：2770-2777
• 文件大小：779 K

摘要

Si-doped hydroxyapatite (Si-HA) is a suitable ceramic for the controlled release of agents to improve bone repair. We recently showed that parathyroid hormone-related protein (PTHrP) (107-111) (osteostatin) has remarkable osteogenic features in various in vitro and in vivo systems. Fibroblast growth factor (FGF)-2 modulates osteoblastic function and induces angiogenesis, and can promote osteoblast adhesion and proliferation after immobilization on Si-HA. In the present study we examined whether osteostatin might improve the biological efficacy of FGF-2-coated Si-HA in osteoblastic MC3T3-E1 cells in vitro. We found that Si-HA/FGF-2 in the presence or absence of osteostatin (100 nM) similarly increased cell growth (by about 50%). However, addition of the latter peptide to Si-HA/FGF-2 significantly enhanced gene expression of Runx2, osteocalcin, vascular endothelial growth factor (VEGF) and the VEGF receptors 1 and 2, without significantly affecting that of FGF receptors in these cells. Moreover, secreted VEGF in the MC3T3-E1 cell conditioned medium, which induced the proliferation of pig endothelial-like cells, was also enhanced by these combined factors. The synergistic action of osteostatin and Si-HA/FGF-2 on the VEGF system was abrogated by a mitogen-activated protein kinase inhibitor (U0126) and by the calcium antagonist verapamil. This action was related to an enhancement of alkaline phosphatase activity and matrix mineralization in MC3T3-E1 cells, and also in primary human osteoblastic cells. These in vitro data show that osteostatin increases the osteogenic efficacy of a Si-HA/FGF-2 biomaterial by a mechanism involving mitogen-activated protein kinases and intracellular Ca²⁺. These findings provide an attractive strategy for bone tissue engineering.