Association Study of Matrix Metalloproteinases Gene Polymorphisms with Susceptibility to Rheumatoid Arthritis: A Meta-Analysis

Objective: Association of matrix metalloproteinases (MMPs) gene polymorphisms with rheumatoid arthritis is controversial. We conduct a meta-analysis to clarify this dispute.

Methods: We systematically searched the electronic PUBMED, EMBASE and CNKI databases for research articles about MMPs (MMP-1, MMP-2, MMP-3, MMP-9) gene polymorphisms and rheumatoid arthritis (RA) up to January 2015. According to the heterogeneity, fixed-effects or random-effects models were used to calculate crude odds ratios (ORs) and 95% confidence intervals (95% CIs).

Results: A total of 11 articles involving 2143 cases and 2049 controls were included in this meta-analysis. Overall, no significant associations were observed between MMP-1-1607 1G/2G polymorphism and RA. Stratification by ethnicity, no significant associations were observed in Caucasian populations. Similarly, no significant associations were observed between MMP-3-1171 5A/6A, MMP-9-1562 C/T polymorphisms and RA in overall and Caucasian populations, respectively. However, a weak association was found between MMP-2-1306 C/T polymorphism and RA (C vs. T, OR?=?0.813, 95%CI?=?0.694–0.953, p?=?0.010) in overall populations.

Conclusions: The present meta-analysis suggests that MMP-1-1607 1G/2G, MMP-3-1171 5A/6A, MMP-9-1562 C/T polymorphisms are not associated with the susceptibility of RA, but MMP-2 -1306 C/T is weakly associated with susceptibility to RA. Further studies with more sample size are needed for definitive conclusions.     

Proteases and their inhibitors as prognostic factors for high-grade serous ovarian cancer

Ovarian carcinoma is one of the most lethal malignancies, but only very few prognostic biomarkers are known. The degradome, comprising proteases, protease non-proteolytic homologues and inhibitors, have been involved in the prognosis of many cancer types, including ovarian carcinoma. The prognostic significance of the whole degradome family has not been specifically studied in high-grade serous ovarian cancer. A targeted DNA microarray known as the CLIP-CHIP microarray was used to identify potential prognostic factors in ten high-grade serous ovarian cancer women who had early recurrence (<1.6 years) or late/no recurrence after first line surgery and chemotherapy. In women with early recurrence, we identified seven upregulated genes (TMPRSS4, MASP1/3, SPC18, PSMB1, IGFBP2, CFI – encoding Complement Factor I – and MMP9) and one down-regulated gene (ADAM-10). Using immunohistochemistry, we evaluated the prognostic effect of these 8 candidate genes in an independent cohort of 112 high-grade serous ovarian cancer women. Outcomes were progression, defined according to CA-125 criteria, and death. Multivariate Cox proportional hazard regression models were done to estimate the associations between each protein and each outcome. High ADAM-10 expression (intensity of 2–3) was associated with a lower risk of progression (adjusted hazard ratio (HR): 0.51; 95% confidence interval (CI): 0.29-0.87). High complement factor I expression (intensity 2–3) was associated with a higher risk of progression (adjusted HR: 2.30, 95% CI: 1.17–4.53) and death (adjusted HR: 3.42; 95% CI: 1.72–6.79). Overall, we identified the prognostic value of two proteases, ADAM-10 and complement factor I, for high-grade serous ovarian cancer which could have clinical significance.     

Germline gain-of-function MMP11 variant results in an aggressive form of colorectal cancer

Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.     

Matrix metalloproteinase 9 (MMP9) level and MMP9 -1562C>T in patients with obstructive sleep apnea: a systematic review and meta-analysis of case-control studies

BackgroundThe peripheral level of matrix metalloproteinase (MMP)-9 and polymorphism of MMP9 -1562C>T in patients with obstructive sleep apnea (OSA) remains controversial. Therefore, the aims of this systemic review and meta-analysis are to assess the MMP9 level in OSA patients and identify the relationship between MMP9 -1562C>T and OSA susceptibility.MethodsThis systematic review was performed following the PRISMA guideline. We searched for studies in major databases, identifying those indexed from inception to July 3, 2019 which related to MMP9 level, MMP9 -1562C>T and OSA. The pooled standardized mean differences (SMDs) and 95% confidence interval (CI) of MMP9 levels were calculated. In addition, the relationship between MMP9 -1562C>T and OSA susceptibility was assessed by three genetic models. The heterogeneity analysis and calculation of the pooled odds ratio (OR) were also performed, followed by quality assessment using the Newcastle-Ottawa Scale (NOS).ResultsIn sum, our review included 15 eligible studies regarding MMP9 level and three regarding MMP9 -1562C>T. The pooled results showed that peripheral level of MMP9 was increased in OSA patients (SMD = 1.37; 95% CI = 1.15–1.59). Furthermore, significant difference of MMP9 level can be found between severe and mild-to-moderate OSA patients (SMD = 28.17; 95% CI = 4.23–52.11) or between moderate-severe and mild OSA (SMD = 36.62; 95% CI = 12.19–61.04). However, no relationship was observed between MMP9 -1562C>T and OSA susceptibility in three genetic models (Homozygote model, OR = 1.37; 95% CI = 0.87–2.18); (Recessive model, OR = 1.42; 95% CI = 0.83–2.42); (Allele model, OR = 1.07; 95% CI = 0.96–1.18).ConclusionsThis systemic review and meta-analysis indicated that the level of MMP9 was increased in patients with OSA and this increase is relevant to OSA severity. Moreover, the relationship between MMP9 -1562 C>T and OSA susceptibility has currently not been proven by current merging values. Further analyses with larger sample size are required to verify these associations.     

痔组织弹性纤维退变和血管生成的机制及其意义

目的研究痔组织弹性纤维的病理变化及微血管密度(MVD)和血管生成相关蛋白的表达与痔形成的关系。方法利用免疫组织化学染色技术(SP法),对比研究24例Ⅲ度痔患者的正常肛垫和痔两种组织内弹性纤维和MVD的变化,并检测一氧化氮合酶(NOS)的3种亚型、血管内皮生长因子(VEGF)和金属基质蛋白酶(MMP)2、MMP9在两种组织中表达的差异。结果痔组织存在显著的新生血管形成,痔组织与相对正常肛垫组织间的MVD计数、VEGF、MMP9表达差异存在统计学意义(P<0.05)。痔组织中iNOS明显增高,但与正常肛垫组织比较,不具备统计学意义;痔组织弹性纤维出现断裂、扭曲、变形、玻璃样变等异常,而正常肛垫组织中弹性纤维形态较规则、密集,断裂和变形少见。结论新生血管形成可能是痔的发病机制之一;MMP9对肛垫纤维支持结构的直接降解作用可能是痔形成和加重的一个重要机制;痔组织中iNOS表达增高还提示炎症因素和一氧化氮可能参与了痔的病理过程。     

Matrix Metalloproteinase-2 and Tissue Inhibitor of Metalloproteinase-1 in the Retinal Pigment Epithelium and Interphotoreceptor Matrix: Vectorial Secretion and Regulation

Matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) play an essential role in both normal and pathological extracellular matrix degradation, and a TIMP has been associated with at least one type of retinal degeneration. We have studied expression of MMP-2 and TIMP-1 by zymography, immunocytochemistry, and immunoblotting in the retinal pigment epithelium (RPE) from normal, aged and diseased retinas. MMPs and TIMPs were found in the rat RPE, interphotoreceptor matrix (IPM), and in media conditioned by human and rat RPE in culture. In other polarized cells, MMPs and TIMP-2 are secreted vectorially towards the basal lamina. In the RPE, however, MMP-2 and TIMP-1 were secreted preferentially from the apical surface, the surface bordering the IPM. These findings provide new evidence that MMPs and TIMPs could play a role in the turnover of IPM components.Cell homogenates and conditioned media from RPE isolated from mutant Royal College of Surgeons (RCS) rats with inherited retinal dystrophy had similar amounts of MMP-2 and TIMP-1 as those from congenic control rats. The secretion of MMP-2 and TIMP-1 from RPE cell cultures isolated from young and aged human donors varied widely. However, with increasing cell passage number, secretion of MMPs and TIMPs from human RPE increased dramatically. Also, growing human RPE on bovine corneal endothelial cell-generated extracellular matrix instead of plastic reduced the secretion of both MMPs and TIMPs. These data suggest that the integrity of Bruch's membrane may serve to regulate RPE functions in MMP and TIMP secretion and that extracellular matrices contain signals that regulate MMP and TIMP synthesis and/or secretion by the RPE.     

Expression of gelatinases within the trabecular bone compartment of ovariectomized and parathyroidectomized adult female rats

Ovariectomized (ovx) and parathyroidectomized (ptx) rat models of disturbed bone metabolism have been widely used in evaluating bone changes resulting from hormonal depletion, and are characterized by elevated and depressed bone turnover, respectively. We report here the expression of gelatinases extracted from native trabecular bone in these models. Nine-month-old female Sprague-Dawley rats were sacrificed after 3 weeks following ovx or 10 days post ptx to determine the influence of these procedures on the levels of proximal tibial bone tissue gelatinases. Identification and quantitation of these enzymes were performed via gelatin gel zymography of native tissue extracts and laser densitometry of developed gels, respectively. In the ptx model, a reduction in tissue levels of pro- and active-MMP-2 and 45 kDa activated fragment was seen, whereas ovx exhibited significant increases in these enzymes. The MMPs are therefore clearly under the influence of factors known to modulate bone remodeling in vivo. The study of MMP levels directly extracted from bone using these experimental models may assist in developing management regimes for metabolic bone diseases through the use of drugs aimed at controlling turnover.     

Expression of matrix metalloproteinase matrilysin (mmp-7) was induced by activated ki-ras via ap-1 activation in sw1417 colon cancer cells

The matrix metalloproteinase matrilysin (MMP-7) is a member of the matrix metallo-proteinase gene family, which is believed to play an important role in tumor invasion and metastasis. We have previously found that matrilysin mRNA is specifically expressed in colorectal cancers and adenomas and that its message is localized in the tumor cells themselves. We examined the effects of activated Ki-ras oncogene on the expression of matrilysin in colon cancer cells. We showed that both mRNA and the enzymatic activity of matrilysin were induced by the introduction of activated Ki-ras into SW1417 colon cancer cells. To understand the mechanisms regulating this induction, we analyzed alterations of AP-1 activity induced by activated Ki-ras, using the chloramphenicol acetyltransferase assay. AP-1 activity in SW1417 cells expressing activated Ki-ras was higher than that in control cells. The gel-shift assay also showed higher levels of AP-1 binding protein in SW1417 cells expressing activated Ki-ras than those in control cells. Our results suggest that activated Ki-ras may play a role in inducing expression of matrilysin through an AP-1-dependent pathway in colon cancer cells.