Autogenous regulation of a network of bone morphogenetic proteins (BMPs) mediates the osteogenic differentiation in murine marrow stromal cells

被引:91
作者
Edgar, Cory M. [1 ]
Chakravarthy, Vinay [1 ]
Barnes, George [1 ]
Kakar, Sanjeev [1 ]
Gerstenfeld, Louis C. [1 ]
Einhorn, Thomas A. [1 ]
机构
[1] Boston Univ, Med Ctr, Dept Orthopaed Surg, Orthopaed Res Lab, Boston, MA 02118 USA
关键词
marrow stromal stem cells; bone morphogenctic proteins; BMP; osteoinduction; noggin;
D O I
10.1016/j.bone.2007.01.001
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The expression patterns of (bone morphogenetic proteins) BMPs during fracture repair and pre-natal bone development suggest that these processes are regulated through the coordinated actions of multiple BMPs. Marine bone marrow stromal cells (MSCs) in culture provide a well recognized ex vivo system of mesenchymal stem cell differentiation in which the effects of BMPs can be examined. Studies were performed to determine if MSC differentiation is dependent on the endogenous expression of multiple BMPs and to characterize their interactions. MSCs were harvested from the bone marrow of tibiae and femora of 8 to 10-week-old male C57/136 mice and prepared by standard methods. Osteogenic differentiation was assessed by histological assays, alkaline phosphatase enzyme activity and assays for the expression of multiple mRNAs for BMPs and osteogenic development. The role of autogenously expressed BMPs in controlling the osteogenic differentiation of marrow stromal cells in vitro was assessed in both gain-of-function and loss-of-function experiments. Gain of function experiments were carried out in the presence of exogenously added BMP-2 or -7 and loss-of-function experiments were carried out by BMP antagonism with noggin and BMP-2 antibody blockade. Osteogenic differentiation was concurrent with and proportional to increases in the expression of BMPs-2, -3, -4, -5, -6 and -8A. BMP antagonism with either noggin or BMP-2 antibody blockade inhibited osteogenic differentiation by 50% to 80%, respectively, and reduced the expression of endogenous levels of BMPs-2, -3, -5 and -8A. In contrast, antagonism induced the expression of BMP-4 and -6. The addition of rhBMP-2 or -7 enhanced osteogenic differentiation and produced a reciprocal expression profile in the endogenous BMPs expression as compared to BMP antagonism. BMP antagonism could be rescued through the competitive addition of rhBMP-2. These studies demonstrated that osteogenic differentiation was regulated by a complex network of multiple BMPs that showed selective increased and decreased expression during differentiation. They further demonstrated that BMP-2 was a central regulator in this network. (c) 2007 Elsevier Inc. All rights reserved.
引用
收藏
页码:1389 / 1398
页数:10
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