The Factor VII-activating Protease (FSAP) Enhances the Activity of Bone Morphogenetic Protein-2 (BMP-2)*
The Factor VII-activating Protease (FSAP) Enhances the Activity of Bone Morphogenetic Protein-2 (BMP-2)*
复制标题
因子 VII 激活蛋白酶 (FSAP) 增强骨形态发生蛋白 2 (BMP-2) 的活性*
DOI：
10.1074/jbc.m112.433029
复制
发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Kanse SM
中科院分区：
文献类型：
--
作者：
Roedel EK;Schwarz E;Kanse SM
因子VII激活蛋白酶（FSAP）是一种循环蛋白酶，参与动脉粥样硬化、钙化和纤维化过程的发病机制。为了了解FSAP如何控制局部生长因子的平衡，我们研究了其对骨形态发生蛋白（BMPs）的调节作用。BMP-2作为大的前体形式产生，并且在通过前蛋白转化酶（PC）的细胞内加工后作为成熟的肝素结合生长因子分泌。在这项研究中，我们发现FSAP增强了成熟BMP-2及其前体的生物活性，如C2 C12成肌细胞的成骨分化所示。这些发现得到了肝细胞中FSAP敲低的补充，这揭示了内源性FSAP对BMP-2的加工。N端测序表明，pro-BMP-2在典型的PC切割位点被FSAP切割，产生成熟BMP-2（Arg 282 ↓ Gln 283），以及在成熟BMP-2的N端肝素结合区，产生截短的成熟BMP-2肽（Arg 289 ↓ Lys 290）。类似地，成熟BMP-2也在其N-末端区域内被切割成截短的肽（Arg 289 ↓ Lys 290）。纤溶酶具有类似的活性，但与FSAP相比较弱。凝血酶、凝血因子VIIa、凝血因子Xa和活化蛋白C无效。这些结果进一步得到了观察结果的支持，即BMP-2的肝素结合区的突变抑制了FSAP的加工，但不抑制PC的加工。因此，FSAP对pro-BMP-2和成熟BMP-2的蛋白水解和激活可以调节血管中细胞的分化和钙化，并可能解释为什么FSAP基因编码的多态性与血管疾病有关。背景：因子VII激活蛋白酶（FSAP）基因编码的多态性是动脉粥样硬化和血管钙化的危险因素。FSAP调节BMP-2依赖的增殖和成骨分化的几种细胞types.Significance：激活BMP-2的FSAP提供了一种新的机制洞察FSAP的行动在重塑相关疾病。
Factor VII-activating protease (FSAP) is a circulating protease involved in the pathogenesis of atherosclerosis, calcification, and fibrotic processes. To understand how FSAP controls the balance of local growth factors, we have investigated its effect on the regulation of bone morphogenetic proteins (BMPs). BMP-2 is produced as a large pro-form and secreted as a mature heparin-binding growth factor after intracellular processing by pro-protein convertases (PCs). In this study, we discovered that FSAP enhances the biological activity of mature BMP-2 as well as its pro-form, as shown by osteogenic differentiation of C2C12 myoblasts. These findings were complemented by knockdown of FSAP in hepatocytes, which revealed BMP-2 processing by endogenous FSAP. N-terminal sequencing indicated that pro-BMP-2 was cleaved by FSAP at the canonical PC cleavage site, giving rise to mature BMP-2 (Arg282↓Gln283), as well as in the N-terminal heparin binding region of mature BMP-2, generating a truncated mature BMP-2 peptide (Arg289↓Lys290). Similarly, mature BMP-2 was also cleaved to a truncated peptide within its N-terminal region (Arg289↓Lys290). Plasmin exhibited a similar activity, but it was weaker compared with FSAP. Thrombin, Factor VIIa, Factor Xa, and activated protein C were not effective. These results were further supported by the observation that the mutation of the heparin binding region of BMP-2 inhibited the processing by FSAP but not by PC. Thus, the proteolysis and activation of pro-BMP-2 and mature BMP-2 by FSAP can regulate cell differentiation and calcification in vasculature and may explain why polymorphisms in the gene encoding for FSAP are related to vascular diseases.Background:Polymorphisms in the gene encoding for Factor VII-activating protease (FSAP) are a risk factor for atherosclerosis and vascular calcification.Results:FSAP mediates proteolytic cleavage and activation of bone morphogenetic protein-2 (BMP-2).Conclusion:FSAP regulates BMP-2-dependent proliferation and osteogenic differentiation of several cell types.Significance:Activation of BMP-2 by FSAP provides a novel mechanistic insight into the actions of FSAP in remodeling-associated diseases.
登录
查看更多内容
动脉粥样硬化基因治疗的新思路：TGF-β家族细胞信号转导的调节。
DOI：
--
发表时间：
2006
期刊：
Current Pharmaceutical Design 12・7
影响因子：
--
作者：
Koda M;Yamazaki M;Yamazaki M;Koshizuka S;Kamada T;et al.;古川 宏 編;Akira Ishisaki
通讯作者：
Akira Ishisaki
DOI：
10.1084/jem.20052546
发表时间：
2006-12-25
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Sedding D;Daniel JM;Muhl L;Hersemeyer K;Brunsch H;Kemkes-Matthes B;Braun-Dullaeus RC;Tillmanns H;Weimer T;Preissner KT;Kanse SM
通讯作者：
Kanse SM
影响因子：
6.6
作者：
Etscheid, M;Beer, N;Dodt, J
通讯作者：
Dodt, J
影响因子：
3.3
作者：
Degnin, C;Jean, F;Christian, JL
通讯作者：
Christian, JL
转化生长因子 β (TGFβ) 超家族成员的前结构域指定不同的功能
影响因子：
4.8
作者：
G. Sengle;R. Ono;Takako Sasaki;L. Sakai
通讯作者：
L. Sakai