Cyclic compressive mechanical stimulation induces sequential catabolic and anabolic gene changes in chondrocytes resulting in increased extracellular matrix accumulation
Cyclic compressive mechanical stimulation induces sequential catabolic and anabolic gene changes in chondrocytes resulting in increased extracellular matrix accumulation
复制标题
DOI：
10.1016/j.matbio.2006.03.005
复制
发表时间：
2006-08-01
期刊：
影响因子：
6.9
通讯作者：
Kandel, R. A.
中科院分区：
文献类型：
--
作者：
De Croos, J. N. A.;Dhaliwal, S. S.;Kandel, R. A.
通过组织工程克服关节软骨自我修复能力有限的问题是可能的。然而，使用现有方法形成的生物工程软骨与天然软骨的物理特性不匹配。在先前的研究中，我们证明了机械刺激可促进软骨组织形成。本研究探讨了这种情况发生的机制。与未受刺激的细胞相比，施加单轴循环压缩（1千帕，1赫兹，30分钟）在2小时时显著增加了基质金属蛋白酶（MMP）-3和MMP - 13基因的表达。到6小时时，这些表达恢复到本底水平。在6小时时检测到MMP - 13的蛋白水平（包括前体形式和活性形式）升高，到24小时时降低。这与组织降解有关，因为与未受刺激的细胞相比，在6小时时有更多的蛋白聚糖和胶原蛋白释放到培养基中。这种分解代谢变化之后，在刺激后12小时，Ⅱ型胶原蛋白和聚集蛋白聚糖基因表达显著增加，并且在24小时时这些基质分子的合成和积累增加。机械刺激激活了丝裂原活化蛋白激酶（MAP）激酶途径，因为细胞外调节蛋白激酶1/2（ERK1/2）和应激活化蛋白激酶（JNK）的磷酸化增加，以及激活蛋白-1（AP - 1）结合增加。在JNK抑制剂SP600125存在的情况下进行机械刺激，可阻断AP - 1结合，从而阻止在2小时时MMP - 3和 - 13以及在12小时时Ⅱ型胶原蛋白和聚集蛋白聚糖基因表达的增加，以及基质合成和积累的增加。鉴于这些变化的顺序，循环压缩负荷似乎启动了一种涉及MAPK和AP - 1信号传导的重塑效应，从而改善了软骨的体外形成。（c）2006爱思唯尔B.V. / 国际基质生物学学会。保留所有权利。
Overcoming the limited ability of articular cartilage to self-repair may be possible through tissue engineering. However, bioengineered cartilage formed using current methods does not match the physical properties of native cartilage. In previous studies we demonstrated that mechanical stimulation improved cartilage tissue formation. This study examines the mechanisms by which this occurs. Application of uniaxial, cyclic compression (1 kPa, 1 Hz, 30 min) significantly increased matrix metalloprotease (MMP)-3 and MMP-13 gene expression at 2 h compared to unstimulated cells. These returned to constitutive levels by 6 h. Increased MMP-13 protein levels, both pro- and active forms, were detected at 6 h and these decreased by 24 h. This was associated with tissue degradation as more proteoglycans and collagen had been released into the culture media at 6 h when compared to the unstirnulated cells. This catabolic change was followed by a significant increase in type 11 collagen and aggrecan gene expression at 12 h post-stimulation and increased synthesis and accumulation of these matrix molecules at 24 h. Mechanical stimulation activated the MAP kinase pathway as there was increased phosphorylation of ERK1/2 and JNK as well as increased AP-1 binding. Mechanical stimulation in the presence of the JNK inhibitor, SP600125, blocked AP-1 binding preventing the increased gene expression of MMP-3 and -13 at 2 h and type 11 collagen and aggrecan at 12 h as well as the increased matrix synthesis and accumulation. Given the sequence of changes, cyclic compressive loading appears to initiate a remodelling effect involving MAPK and AP-1 signalling resulting in improved in vitro formation of cartilage. (c) 2006 Elsevier B.V./Intemational Society of Matrix Biology. All rights reserved.