期刊
SCIENTIFIC REPORTS
卷 5, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep12694
关键词
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资金
- National Basic Research Program of China (973 Program) [2012CB933600]
- 111 Project [B14018]
- National Natural Science Foundation of China [31100679, 31330028, 31470924]
- Program for New Century Excellent Talents in University [NCET-11-0640]
- National Special Fund for the State Key Laboratory of Bioreactor Engineering [2060204]
Preserving bioactivity of bone morphogenetic protein 2 (BMP-2) still remains a challenge in protein-based therapy. It is not known how Ca2+ released from extracellular matrix or existing in physiological environment influences bioactivity in situ till now. Here, effects of extracellular Ca2+ on conformation and osteogenic bioactivity of recombinant human BMP-2 (rhBMP-2) were investigated systematically. In vitro results indicated that Ca2+ could bind rhBMP-2 rapidly and had no obvious effect on cell behaviors. Low concentration of Ca2+ (0.18 mM) enhanced rhBMP-2-induced osteogenic differentiation, while high Ca2+ concentration (>1.80 mM) exerted negative effect. In vivo ectopic bone formation exhibited similar trend. Further studies by circular dichroism spectroscopy, fluorescence spectroscopy, together with cell culture experiments revealed at low concentration, weak interaction of Ca2+ and rhBMP-2 slightly increased beta-sheet/-turn content and facilitated recognition of BMP-2 and BMPRIA. But, high Ca2+ concentration (>1.8 mM) induced formation of CarhBMP-2 complex and markedly increased content of beta-sheet/-turn, which led to inhibition binding of rhBMP-2 and BMPRIA and thus suppression of downstream Smad1/5/8, ERK1/2 and p38 mitogen-associated protein kinase signaling pathways. Our work suggests osteogenic bioactivity of BMP-2 can be adjusted via extracellular Ca2+, which should provide guide and assist for development of BMP-2-based materials for bone regeneration.
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