To examine the effect of tissue inhibitor of metalloproteinase-2 (TIMP-2) on conjunctival filtering bleb scarring.

Myogenesis in vitro involves myoblast cell cycle arrest, migration, and fusion to form multinucleated myotubes. Extracellular matrix (ECM) integrity during these processes is maintained by the opposing actions of matrix metalloproteinase (MMP) proteases and their inhibitors, the tissue inhibitor of metalloproteinases (TIMPs). Here, we report that TIMP-2, MMP-2, and MT1-MMP are differentially expressed during mouse myoblast differentiation in vitro. A specific role for TIMP-2 in myogenesis is demonstrated by altered TIMP-2(-/-) myotube formation. When differentiated in horse serum-containing medium, TIMP-2(-/-) myotubes are larger than wild-type myotubes. In contrast, when serum-free medium is used, TIMP-2(-/-) myotubes are smaller than wild-type myotubes. Regardless of culture condition, myotube size is directly correlated with MMP activity and inversely correlated with beta1 integrin expression. Treatment with recombinant TIMP-2 rescues reduced TIMP-2(-/-) myotube size and induces increased MMP-9 activation and decreased beta1 integrin expression. Treatment with either MMP-2 or MMP-9 similarly rescues reduced myotube size, but has no effect on beta1 integrin expression. These data suggest a specific regulatory relationship between TIMP-2 and beta1 integrin during myogenesis. Elucidating the role of TIMP-2 in myogenesis in vitro may lead to new therapeutic options for the use of TIMP-2 in myopathies and muscular dystrophies in vivo.

The imbalance between MMPs and TIMPs is associated with the HIV dissemination tissue damage pathology neurodegenerative disorders, including HAND. Genetic variations in the TIMP gene may modulate the neurocognitive disorder in HIV patients. Hence, we evaluated the genetic variants of TIMP-2 (-418G/C, 303G/A) gene with the risk of HAND. Genotyping of TIMP-2 polymorphism was performed in 50 patients with HAND, 100 no HAND, and 154 healthy controls by PCR-RFLP. TIMP-2 -418GC and 303AA genotypes represented a predominant risk for HAND severity (OR = 1.55, P = 0.30; OR = 4.58, P = 0.24). The variant -418CC genotype, -418A allele, had exhibited a significant risk for the acquisition of HAND (OR = 12.55, P = 0.026; OR = 2.66, P = 0.004). TIMP-2 303GA, 303AA genotype, and 303A allele evinced a higher risk for HAND severity (OR = 1.82, P = 0.14; OR = 1.70, P = 0.63; and OR = 1.68, P = 0.12). In HIV patients, TIMP-2 -418CC genotype and -418C allele significantly occurred in comparison to healthy controls (OR = 10.10, P = 0.006; OR = 2.02, P = 0.009). In the intermediate and early HIV disease stage, TIMP-2 -418CC genotype was significantly increased compared with healthy controls (11.1% vs. 1.3%, OR = 14.63, P = 0.01; 16.9% vs. 1.3%, OR = 14.51, P = 0.002). In patients with HAND among tobacco and alcohol users, TIMP-2 -418CC genotype displayed a risk for HAND severity (OR = 3.96, P = 0.26; OR = 4.83, P = 0.19). On multivariate logistic regression, TIMP-2 303AA genotype, advanced stage, and gender had a risk for HAND severity (OR = 28.98, P = 0.02; OR = 2.35, P = 0.070; and OR = 2.36, P = 0.04). In conclusion, TIMP-2 -418G/C polymorphism independently, along with alcohol and tobacco, may have an impact on the acquisition of HAND and its severity. TIMP-2 303G/A polymorphism bare a risk for HAND severity.

Metalloproteinases and their tissue inhibitors play an important role in the metastases formation. A multistage process of carcinogenesis requires the involvement of numerous enzymes and compounds that facilitate the expansion of tumor cells. The formation of metastases depends on both metalloproteinases and tissue inhibitors activation leading to the activation of neoangiogenesis. The changes of the expression in stromal and tumor proteins could be prognostic factors in patients with oropharyngeal squamous cell carcinoma.

Tissue inhibitors of metalloproteinases (TIMPs) are known to be endogenous inhibitors of matrix metalloproteinases (MMPs). Our preliminary study showed that TIMP-2 is constitutively expressed in microglia but significantly inhibited by lipopolysaccharide (LPS) treatment. The current study was undertaken to investigate the role of TIMP-2 in microglia.

In this study, 293T cells were genetically engineered to secrete tissue inhibitor of metalloproteinase-2 (TIMP2) and encapsulated into alginate microcapsules to continuously release TIMP2 protein.

Matrix metalloproteinases (MMPs) and tissue inhibitor of MMPs (TIMPs) have been shown to play an important role in the pathogenesis of tissue destruction in periodontitis. The associations between single nucleotide polymorphisms (SNPs) in the promoter regions of MMP-2, MMP-9, and TIMP-2 genes and the risk of aggressive periodontitis (AgP) and chronic periodontitis (CP) were investigated in a Taiwanese population.

The objective of the study was the assessment of serum levels and tissue expression of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of matrix metalloproteinases 2 (TIMP-2) in patients with colorectal cancer (CRC). The study included 72 CRC patients and 68 healthy subjects. The serum levels of MMP-2 and TIMP-2 were measured using enzyme-linked immunosorbent assay (ELISA) method, whereas tissue expression of MMP-2 and TIMP-2 in cancer cells, interstitial inflammatory cells, and adjacent normal colorectal mucosa were examined by immunohistochemical staining of tumor samples. The serum levels of MMP-2 and TIMP-2 in cancer patients were significantly lower than those in control group, but the percentage of positive immunoreactivity of these proteins were higher in malignant and inflammatory cells as compared to normal tissue. There was a significant correlation between MMP-2 immunoreactivity in inflammatory cells and the presence of distant metastases and between TIMP-2 expression in inflammatory cells and tumor size, nodal involvement, and distant metastases. Area under receiver operating characteristic (ROC) curve (AUC) for serum MMP-2 was higher than for serum TIMP-2. Moreover, positive tissue expression of MMP-2 was a significant prognostic factor for CRC patients' survival. Our findings suggest that MMP-2 and TIMP-2 might play a role in the process of colorectal cancer invasion and metastasis, but the significance of their interactions with tumor stroma and interstitial inflammatory infiltration in colorectal neoplasia require further elucidation.

Tissue inhibitor of metalloproteinase-2 (TIMP-2) is an endogenous inhibitor of matrix metalloproteinase-2 and is highly expressed in breast cancer (BC) cases at diagnosis. However, the genetic investigations for the association of TIMP-2 genotypes with BC risk are rather limited. In this study, contribution of TIMP-2 rs8179090, rs4789936, rs2009196 and rs7342880 genotypes to BC risk was examined among Taiwan's BC population. TIMP-2 genotypic profiles were revealed among 1232 BC cases and 1232 controls about their contribution to BC using a PCR-based RFLP methodology. The TIMP-2 rs8179090 homozygous variant CC genotype was significantly higher in BC cases than controls (odds ratio (OR) = 2.76, 95% confidence interval (95%CI) = 1.78-4.28, p = 0.0001). Allelic analysis showed that C allele carriers have increased risk for BC (OR = 1.39, 95%CI = 1.20-1.62, p = 0.0001). Genotypic together with allelic analysis showed that TIMP-2 rs4789936, rs2009196 or rs7342880 were not associated with BC risk. Stratification analysis showed that TIMP-2 rs8179090 genotypes were significantly associated with BC risk among younger (≤55) aged women, not among those of an elder (>55) age. Last, rs8179090 genotypes were also associated with triple negative BC. This study sheds light into the etiology of BC in Taiwanese women. Rs8179090 may be incorporated into polygenic risk scores and risk prediction models, which could aid in stratifying individuals for targeted breast cancer screening.

BACKGROUND This study investigated the relationship between the pathological alteration of alveolar septa and (1) pulmonary function and (2) matrix metalloproteinase (MMP)-2, MMP-9, and tissue inhibitor matrix metalloproteinase 1 (TIMP-1) expression in chronic obstructive pulmonary disease (COPD). MATERIAL AND METHODS Sixty patients with pulmonary disease were divided into control (n=20) and COPD (n=40) groups. Postoperative lung tissue specimens were examined. Hematoxylin and eosin and elastin van Gieson staining detected pathological alterations of pulmonary alveolar septa. Septa thickness was measured. MMP-2, MMP-9, and TIMP-1 expression levels were detected by immunohistochemical staining. Correlations were determined by Pearson analysis. RESULTS Forced expiratory volume in 1 s (FEV₁), forced vital capacity, FEV₁ percent predicted (FEV₁%pre), and diffusion capacity of carbon monoxide percent predicted (DLCO%pre) in COPD patients were significantly lower than in those of the control group (P<0.05). MMP-2, MMP-9, and TIMP-1 expression levels were significantly higher in the COPD group than in control, especially the severe group (P<0.05). Septa thickness was negatively correlated with FEV₁%pre (r=-0.335; P<0.05) and positively correlated with MMP-2 and TIMP-1 expression (P<0.05). Proportion of collagenous fiber was negatively correlated with FEV₁%pre and DLCO%pre (P<0.01), and positively correlated with MMP-2, MMP-9, and TIMP-1 expression (P<0.01). Proportion of elastic fibers was negatively correlated with collagenous fiber. CONCLUSIONS The pathological alteration of alveolar septa was correlated with pulmonary function and expression levels of MMP-2, MMP-9, and TIMP-1, which can play vital roles in COPD progression.

The extracellular matrix is important for tumor invasion and metastasis. Normal function of the extracellular matrix depends on the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). The objective of this meta-analysis was to assess the relationship between expression of MMP-9, MMP-2, and TIMP-2 and invasion of pituitary adenomas.We searched Pubmed, Embase, and the Chinese Biomedical Database up to October 2015. RevMan 5.1 software (Cochrane Collaboration, Copenhagen, Denmark) was used for statistical analysis. We calculated the standardized mean difference (SMD) for data expressed as mean ± standard deviation because of the difference in the detection method.Twenty-four studies (1320 patients) were included. MMP-9 expression was higher in the patients with invasive pituitary adenomas (IPAs) than patients with noninvasive pituitary adenomas (NIPAs) with detection methods of IHC [odds ratio (OR) = 5.48, 95% confidence interval (CI) = 2.61-11.50, P < 0.00001), and reverse transcriptase-polymerase chain reaction (SMD = 2.28, 95% CI = 0.91-3.64, P = 0.001). MMP-2 expression was also increased in patients with IPAs at the protein level (OR = 3.58, 95% CI = 1.63-7.87, P = 0.001), and RNA level (SMD = 3.91, 95% CI = 1.52-6.29, P = 0.001). Meta-analysis showed that there was no difference in TIMP-2 expression between invasive and NIPAs at the protein level (OR = 0.38, 95% CI = 0.06-2.26, P = 0.29). MMP-9 expression in prolactinomas and nonfunctioning pituitary adenomas was also no difference (OR = 1.03, 95% CI = 0.48-2.20, P = 0.95).The results indicated that MMP-9 and -2 may be correlated with invasiveness of pituitary adenomas, although their relationship with functional status of pituitary adenomas is still not clear. TIMP-2 expression in IPAs needs to be investigated further.

Using rat conjunctival bleb model, we correlated changes morphology and histology in the bleb with changes in MMP-2 and TIMP-2 levels.

The purpose of this study was to observe and quantify the expression of interleukin-4 (IL-4), interferon-gamma (IFN-gamma), and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) in the gingival tissue of patients with type 2 diabetes mellitus (DM) and healthy adults with chronic periodontitis.

Human papillomavirus (HPV) infection alone is not sufficient for development of cervical cancer and further risk factors are involved, however, the underlying mechanism remains to be elucidated. The authors previously used a microarray assay to reveal microR‑20b (miR‑20b) as a key node in the miRNA‑mRNA network of cervical carcinoma. The present study demonstrated an increased expression of miR‑20b in cervical carcinoma tissue. MiR‑20b was regulated by HPV E6 oncoprotein in cervical cancer. Furthermore, miR‑20b overexpression with mimics induced cell morphological alterations and the epithelial‑mesenchymal transition. Treating cervical cancer cells with the miR‑20b inhibitor decreased the migration and invasion of cervical cancer cells. Tissue inhibitor of metalloproteinase 2 (TIMP‑2), a possible antagonist of matrix metalloproteinase 2, is a metastasis suppressor and predicted to be a potential target of miR‑20b. Fluorescence signals were decreased on transducing HeLa cells with a TIMP‑2 3'‑untranslated region plasmid and miR‑20b mimics compared with control. Finally, TIMP‑2 was identified as a novel target of miR‑20b and was demonstrated to be regulated by the HPV oncoprotein. In addition, miR‑20b and TIMP‑2 were involved in cell invasion regulated by HPV E6. The present study demonstrated a novel pathway of HPV/miR‑20b/TIMP‑2 during the process of invasion in cervical cancer cells.

Acute kidney injury (AKI) is one of the most devastating complications of critical illness in children. Serum creatinine (Scr) is considered the gold standard for AKI diagnosis yet noted to be late and inaccurate. This raises the need for an early and accurate biochemical parameter for the early detection of AKI. This research aimed to explore the role of urinary tissue inhibitor metalloproteinase 2 (TIMP-2) in the early prediction of AKI, compared to standard biomarkers, in critically ill children admitted to pediatric intensive care unit (PICU). Urine TIMP2 was previously explored in multiple adult studies and showed promising results; however, the study of its role in pediatric population was limited.

Macrophage colony-stimulating factor (M-CSF), matrix metalloproteinase-2 (MMP-2) and its specific tissue inhibitor (TIMP-2) may play an important role in the pathogenesis of cancer disease. We investigated the plasma levels and diagnostic power (ROC curve analysis) of M-CSF, MMP-2, TIMP-2 and tumor markers CA 125 and SCC-Ag in cervical cancer (CC) patients as compared to control group. The study included 89 patients with cervical cancer. The control group consisted of 50 healthy, untreated women. The plasma levels of M-CSF, MMP-2 and TIMP-2 were determined using ELISA, CA 125 and SCC-Ag - by CMIA method. The median levels of M-CSF, TIMP-2, SCC-Ag and CA 125 in the entire group of CC were significantly different than compared to the healthy women group. MMP-2 showed the highest value of sensitivity from all examined parameters (in stage I of CC - 93.10%, II - 82.76%, III and IV - 96.88%, total group - 92.05%). The highest specificity was obtained by M-CSF (86%). The area under the ROC curve (AUC) of M-CSF (0.8051) was the largest of all the tested parameters (even higher than commonly used tumor markers) in the group of cervical cancer. The combination of M-CSF, MMP-2 or TIMP-2 with SCC antigen resulted in an increase AUCs in all cases (0.8760;0.7880;0.8081;respectively). The findings of this study suggest the usefulness of all examined parameters in the diagnostics of CC patients. Out of the tested substances, M-CSF also appears to be the best candidate for cancer diagnostics in all stages of the disease, based on ROC analysis.

The regulatory role of cytokines and extracellular matrix remodeling factors in congenital intra-abdominal adhesions has not yet been defined. The aim of this study was to assess the presence and relative distribution of tumor necrosis factor α (TNF-α), protein gene product 9.5 (PGP 9.5), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2) in adhesions.

Aim. To investigate the dynamic changes on the expression of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) in the diabetic chronic refractory cutaneous ulcers after the autologous platelet-rich gel (APG) treatment. Methods. The study was developed at the Diabetic Foot Care Centre, West China Hospital. The granulation tissues from the target wounds were taken before and within 15 days after APG application. The expression of MMP-2 and TIMP-2 as well as transforming growth factor-β1 (TGF-β1) in the granulation tissue was detected by q TR-PCR and IHC. The relationship between the expression level of MMP-2 and TIMP-2 and their ratio and that of TGF-β1 was analyzed. Results. The expression of MMP-2 (P < 0.05) was suppressed, and the expression of TIMP-2 (P < 0.05) was promoted, while the ratio of MMP-2/TIMP-2 (P < 0.05) was decreased after APG treatments. The expression of TGF-β1 had negative correlation with the ratio of MMP-2/TIMP-2 (P < 0.05) and positive correlation with the expression of TIMP-2 (P < 0.05). Conclusions. APG treatment may suppress the expression of MMP-2, promoting that of the TIMP-2 in the diabetic chronic refractory cutaneous wounds. TGF-β1 may be related to these effects.

Intrauterine adhesion (IUA) is a disease characterized by endometrial fibrosis caused by injury to the endometrium. In the present study, decellularized and lyophilized human amniotic membrane (DL-AM) material was transplanted in a rat model to explore the preventive effect against IUA. A total of 24 Sprague Dawley rats were randomly divided into an IUA (n=12) group and an IUA + DL-AM (n=12) group. To establish the model, the endometrium of the left uterus was scraped, while that of the right uterus was used as a control. In the IUA group, scraped uteri were sutured without any other treatment, whereas DL-AM was transplanted onto the scraped uteri in the IUA + DL-AM group. Uteri were resected for histological and immunohistochemical evaluation at 3, 7, 14 and 28 days after surgery. The results confirmed the development of IUA, which was accompanied by an increase in the rate of fibrotic area. Integral optical density (IOD) values of connective tissue growth factor (CTGF) were elevated in the IUA group, while matrix metalloproteinase-2 (MMP-2) decreased relative to the control group (P<0.05). After DL-AM transplantation, the IOD value of CTGF dropped, while MMP-2 increased compared with the IUA group (P<0.05). However, compared with that in the control group, the IOD value of CTGF was still higher, whereas MMP-2 was still lower in the IUA + DL-AM group (P<0.05). Furthermore, no evidence of endometrial regeneration was detected in both the IUA and IUA + DL-AM groups. Overall, these results indicated that in the rat model of IUA, transplantation of DL-AM had the potential to prevent the formation of fibrosis to a certain extent and may thus be an alternative strategy for managing the condition.

Non-small cell lung cancer (NSCLC) is the most frequent cause of cancer-related death worldwide. Although many molecular-targeted drugs for NSCLC have been developed in recent years, the 5-year survival rate of patients with NSCLC remains low. Therefore, an improved understanding of the molecular mechanisms underlying the biology of NSCLC is essential for developing novel therapeutic strategies for the treatment of NSCLC. In this study, we examined the role of miR-130b in NSCLC. Our results showed that high expression of miR-130b in clinical specimens was significantly associated with poor overall survival in patients with NSCLC. Moreover, miR-130b expression was significantly increased in NSCLC clinical specimens from patients with vascular and lymphatic invasion. Consistent with this, overexpression of miR-130b promoted invasion and matrix metalloproteinase-2 (MMP-2) activity in A549 cells. Argonaute2 immunoprecipitation and gene array analysis identified tissue inhibitor of metalloproteinase-2 (TIMP-2) as a target of miR-130b. Invasion activity promoted by miR-130b was attenuated by TIMP-2 overexpression in A549 cells. Furthermore, TIMP-2 concentrations in serum were inversely correlated with relative miR-130b expression in tumor tissues from the same patients with NSCLC. Overall, miR-130b was found to act as an oncomiR, promoting metastasis by downregulating TIMP-2 and invasion activities in NSCLC cells.