Overexpression of MMP13 in human osteoarthritic cartilage is associated with the SMAD-independent TGF-β signalling pathway.
Overexpression of MMP13 in human osteoarthritic cartilage is associated with the SMAD-independent TGF-β signalling pathway.
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DOI：
10.1186/s13075-015-0788-x
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发表时间：
2015-09-23
影响因子：
4.9
通讯作者：
Zhai G
中科院分区：
文献类型：
--
作者：
Aref-Eshghi E;Liu M;Harper PE;Doré J;Martin G;Furey A;Green R;Rahman P;Zhai G
骨关节炎（OA）的体外和动物模型研究表明TGF-β信号参与OA，但人体数据有限。我们通过比较作为配体的TGFB1和BMP2、作为细胞内介质的SMAD3和作为靶基因的MMP13在人骨关节炎和健康软骨中的表达水平，开展了这项研究，以阐明TGF-β信号通路在OA中的作用。作为对照，从因原发性OA或髋部骨折而接受全髋关节/膝关节置换术的患者中收集人体软骨样本。从软骨组织中提取RNA。实时荧光定量PCR检测基因表达。采用Mann-Whitney检验比较OA患者与对照组软骨组织中TGFB1、BMP2、SMAD3和MMP13的表达水平。计算Spearman等级相关系数（rho）来检验所研究的四个基因表达水平之间的相关性，并使用非参数回归来调整协变量。共纳入32例OA病例（25例髋关节OA， 7例膝关节OA）和21例健康对照。在OA影响的软骨中，TGFB1、SMAD3和MMP13的表达分别比对照组平均高出70%、46%和355%，而BMP2的表达比对照组低88%（均p < 0.03），但在髋关节和膝关节OA之间没有差异（均p < 0.04）。TGFB1的表达与oa影响软骨组织中SMAD3 （rho = 0.50, p = 0.003）、MMP13 （rho = 0.46, p = 0.007）的表达相关，调整年龄、性别、BMI后，其相关性更强。在健康软骨中，BMP2的表达与TGFB1 （rho = - 0.50, p = 0.02）和MMP13 （rho = - 0.48, p = 0.02）均呈负相关，但校正协变量后，其显著性改变。SMAD3与MMP13的表达无相关性。我们的研究结果表明，MMP13的表达与oa影响软骨中TGFB1的表达增加有关，可能是通过smad独立的TGF-β途径。此外，TGF-β/SMAD3在OA软骨中过度激活；然而，这种过度激活的后果仍有待确定。
In vitro and animal model of osteoarthritis (OA) studies suggest that TGF-β signalling is involved in OA, but human data is limited. We undertook this study to elucidate the role of TGF-β signalling pathway in OA by comparing the expression levels of TGFB1 and BMP2 as ligands, SMAD3 as an intracellular mediator, and MMP13 as a targeted gene between human osteoarthritic and healthy cartilage. Human cartilage samples were collected from patients undergoing total hip/knee joint replacement surgery due to primary OA or hip fractures as controls. RNA was extracted from the cartilage tissues. Real-time quantitative PCR was performed to measure gene expression. Mann-Whitney test was utilized to compare the expression levels of TGFB1, BMP2, SMAD3 and MMP13 in human cartilage between OA cases and controls. Spearman’s rank correlation coefficient (rho) was calculated to examine the correlation between the expression levels of the four genes studied and non-parametric regression was used to adjust for covariates. A total of 32 OA cases (25 hip OA and 7 knee OA) and 21 healthy controls were included. The expression of TGFB1, SMAD3, and MMP13 were on average 70 %, 46 %, and 355 % higher, respectively, whereas the expression of BMP2 was 88 % lower, in OA-affected cartilage than that of controls (all p < 0.03), but no difference was observed between hip and knee OA (all p > 0.4). The expression of TGFB1 was correlated with the expression of SMAD3 (rho = 0.50, p = 0.003) and MMP13 (rho = 0.46, p = 0.007) in OA-affected cartilage and the significance became stronger after adjustment for age, sex, and BMI. The expression of BMP2 was negatively correlated with both TGFB1 (rho = −0.50, p = 0.02) and MMP13 (rho = −0.48, p = 0.02) in healthy cartilage, but the significance was altered after adjustment for the covariates. There was no correlation between the expression of SMAD3 and MMP13. Our results demonstrate that MMP13 expression is associated with an increased expression of TGFB1 in OA-affected cartilage, possibly through SMAD-independent TGF-β pathway. Furthermore, TGF-β/SMAD3 is overactivated in OA cartilage; yet, the consequence of this overactivation remains to be established.