文献类型：期刊文献

英文题名：Strontium attenuates rhBMP-2-induced osteogenic differentiation via formation of Sr-rhBMP-2 complex and suppression of Smad-dependent signaling pathway

作者：Zhang, Wenjing[1,2];Tian, Yu[1,2];He, Hongyan[3];Chen, Rui[1,3];Ma, Yifan[1];Guo, Han[4];Yuan, Yuan[1,3];Liu, Changsheng[1,2,3]

机构：[1]E China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]E China Univ Sci & Technol, Minist Educ, Key Lab Ultrafine Mat, Shanghai 200237, Peoples R China;[3]E China Univ Sci & Technol, Minist Educ, Engn Res Ctr Biomed Mat, Shanghai 200237, Peoples R China;[4]Chinese Acad Sci, Shanghai Inst Appl Phys, Shanghai 201800, Peoples R China

年份：2016

卷号：33

起止页码：290

外文期刊名：ACTA BIOMATERIALIA

收录：;EI(收录号：20215111345034);WOS:【SCI-EXPANDED(收录号:WOS:000372688700029)】；

基金：The authors declare they have no conflicts of interest. This work was supported by grants from the National Basic Research Program of China (973 Program, No. 2012CB933600), the 111 Project (B14018), the National Natural Science Foundation of China (No. 31100679, 31330028 and 31470924).

语种：英文

外文关键词：Sr ions; rhBMP-2; Sr-rhBMP-2 complex; Bone formation

摘要：Strontium (Sr2+) has pronounced effects on stimulating bone formation and inhibiting bone resorption in bone regeneration. In this current study, the effect and the underlying mechanism involved of Sr2+ on the biological activity of bone morphogenetic protein-2 (BMP-2) were studied in detail with pluripotent skeletal muscle myogenic progenitor C2C12 model cell line. The results indicated that Sr2+ could bind recombinant human BMP-2 (rhBMP-2) rapidly, even in the presence of Ca2+ and Mg2+, and inhibited rhBMP-2-induced osteogenic differentiation in vitro and osteogenetic efficiency in vivo. Further studies demonstrated that Sr2+ treatment undermined the binding capacity of rhBMP-2 with its receptor BMPRIA and thus attenuated Smad 1/5/8 phosphorylation without affecting their dephosphorylation in C2C12 cells. Furthermore, circular dichroism spectroscopy, fluorescence spectroscopy and X-ray photoelectron spectroscopy all revealed that the inhibitory effect of Sr2+ on the rhBMP-2 osteogenic activity was associated with the formation of Sr-rhBMP-2 complex and ensuing enhancement of (3-sheet structure. Our work suggests the activity of rhBMP-2 to induce osteogenic differentiation was decreased by directly interaction with free Sr ions in solution, which should provide guide and assist for development of BMP-2-based materials for bone regeneration. Statement of Significance Due to easy denaturation and ensuing the reduced activity of rhBMP-2, preserving/enhancing the capacity of rhBMP-2 to induce osteogenic differentiation is of critical importance in developing the protein based therapy. Cations as effective elements influence the conformation and thereby the bioactivity of protein. Strontium (Sr2+), stimulating bone formation and inhibiting bone resorption, has been incorporated into biomaterials/scaffold to improve the bioactivity for bone-regeneration applications. However, Sr2+-induced changes in the conformation and bioactivity of BMP-2 have never been investigated. In this study, the formation of Sr-rhBMP-2 complex inhibited the osteogenic differentiation in vitro and osteogenetic efficiency in vivo through the inhibition of BMP/Smad signaling pathway, providing guidance for development of Sr-containing BMP-2-based bone scaffold/matrice and other Sr-dopped protein therapy. (C) 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.