Polymorphisms and gene expression of metalloproteinases and their inhibitors associated with cerebral ischemic stroke in young patients with sickle cell anemia.

BACKGROUND: Sickle cell anemia (SCA) is a genetic disease with great clinical heterogeneity and few viable strategies for treatment; hydroxyurea (HU) is the only widely used drug. Thus, the study of single nucleotide polymorphisms (SNPs) and the gene expression of MMPs 1, 2, 9, 7 and TIMPs 1 and 2, which are involved in the regulation of extracellular matrix, inflammation, and neuropathies, may provide further insights into the pathophysiology of the disease and elucidate biomarkers and molecules as potential therapeutic targets for patients with SCA. METHODS AND RESULTS: We evaluated 251 young individuals with SCA from northeastern Brazil. The groups were divided according to vaso-occlusive crisis (VOC) and cerebrovascular disease (CVD), compared to control individuals. SNP detection and gene expression assays were performed by real-time PCR, TaqMan system®. Both the expression levels of MMP1 gene, and the SNP MMP1-1607 1G/2G were associated with the risk of cerebral ischemic stroke (IS), and the expression of MMP1 was also associated with a higher frequency of VOC/year. Expression levels of MMP7, TIMP1, and TIMP2 were increased in patients conditioned to IS. The SNP 372T>C (rs4898) TIMP1 T alleles were more frequent in patients with > 5 VOC events/year. The SNP rs17576 of MMP9 showed differences in gene expression levels; it was increased in the genotypes AG, and AG+GG. CONCLUSION: The findings of this study, the SNPs, and expression provide initial support for understanding the role of MMPs-TIMPs in the pathophysiology of SCA in young patients.

Solar radiation leads to increased collagenase gene expression (MMP1) in HERDA (Hereditary equine regional dermal asthenia) affected horses and may explain the typical dorsal distribution of their lesions.

BACKGROUND: Hereditary equine regional dermal asthenia (HERDA) is a genetic disease that alters collagen biosynthesis. Affected horses exhibit fragile, hyperextensible skin, especially over the dorsal region. Although ultraviolet (UV) radiation seems to contribute to the regional distribution of lesions and worsening of clinical signs, the molecular mechanisms involved are largely unknown. OBJECTIVES: To evaluate the effect of solar radiation on matrix metalloproteinase MMP1, MMP8 and MMP13 gene expression in the dorsal and ventral skin of HERDA-affected and HERDA-unaffected horses [wild-type (WT) horses]. ANIMALS: Six HERDA-affected and six unaffected Quarter horses (WT) were paired according to age, sex and coat colour. MATERIALS AND METHODS: Horses were submitted to 30 day sunlight restriction, followed by 15 day sunlight exposure. Dorsal and ventral skin biopsies were obtained at six sampling times over 45 days. The expression of MMP1, MMP8 and MMP13 genes was measured by quantitative PCR. RESULTS: Although solar radiation modulated MMP1, MMP8 and MMP13 expression, the effects were more pronounced on MMP1. Sun exposure for three days significantly upregulated MMP1 in the dorsal region when compared to the ventral skin in both unaffected and HERDA-affected horses. CONCLUSIONS AND CLINICAL RELEVANCE: This study shows that solar irradiation leads to upregulation of skin collagenase genes particularly MMP1 in the dorsal, sun-exposed skin of horses. Furthermore, this was more marked in HERDA-affected horses. The increased activity of collagenases on the disorganised collagen present in HERDA affected horses would explain why UV radiation leads to deterioration of clinical signs in affected individuals.

Maca Root (Lepidium meyenii) Extract Increases the Expression of MMP-1 and Stimulates Migration of Triple-Negative Breast Cancer Cells.

Maca root (Lepidium meyenii) extract is a worldwide consumed food supplement for sexual dysfunctions, increasing sperm production and its motility, and alleviating menopausal symptoms. Once maca root has a role in cell proliferation and motility, and its consumption may increase along with age, mainly in menopausal women, we aimed to investigate the plant effects on triple-negative breast cancer (TNBC) cell lines. Standardized maca root powdered extract showed significant cytotoxic activity in both MDA-MB-231 and Hs578T cells, and the IC50s were 2000 µg/ml and 3000 µg/ml, respectively. Both cell lines showed an increase in migratory capacity. Using bioinformatics tools, we established genes involved in the metastatic process, CAV1, LAMA4, and MMP-1, and the mRNAs expression was assessed by qPCR. Comparing the treated cells to the negative control, CAV1 presented a decreased expression by 2-fold in MDA-MB-231. LAMA4 presented a decrease by 4-fold in Hs578T cells. MMP-1 showed substantially increase mRNA expression in MDA-MB-231 by 86-fold and in Hs578T by 5-fold. To the best of our knowledge, this is the first study indicating that the human consumption of maca may be dangerous due to the upregulation in MMP-1 expression and the increase in TNBC migrated cells.

Multiple approaches to oral epithelial dysplasia degree analyses: a pilot study.

BACKGROUND: Oral epithelial dysplasia (OED) is the presence of cells of an abnormal type within a tissue, which may signify a stage preceding the development of cancer. Our aim was to determine the interrelation between the expression of multiple molecular markers and the histological features of oral dysplasia. METHODS: Fifteen samples of OED (five for each severity degree) were analyzed through software assisted image cytometry nuclear morphology. p53 (wild-type and mutated form), Bax and Bcl2 expression was immunohistochemically determined, and the gene expression of MMP1, MMP2, MMP9 and hTERT was determined by RT-PCR. The mean, standard deviation, ANOVA and Fisher's Exact Test (P<0.05) were performed. RESULTS: Our analysis indicated congruence between the software-assisted measurement of nuclear morphology and severity degree. Only five samples were positive to p53-mutated form; and Bax was more expressed than Bcl-2. hTERT expression was significantly expressed in relation to severity, and MMP1 was predominantly expressed, followed by MMP9 and MMP2. CONCLUSIONS: Our results reinforce that software-assisted measurement is an alternative to severity degree determination. MMP1 is an important marker for severity dysplasia degree; however, the predominant expression of Bax over Bcl-2 suggests that this pro-apoptotic state could be used to minorize the progression, perhaps, as a future therapeutic target.

The 1G/1G+1G/2G Genotypes of MMP1 rs1799750 Are Associated with Higher Levels of MMP-1 and Are Both Associated with Lipodystrophy in People Living with HIV on Antiretroviral Therapy.

In HIV-infected patients, antiretroviral therapy (ART) is associated to adipose tissue redistribution known as lipodystrophy (LD). This study aimed at verifying the association between the polymorphism of the MMP1 gene (rs1799750) (1G/2G) and the serum levels of matrix metalloproteinase 1 (MMP-1) with LD and its subtypes in people living with HIV on ART. This is a cross-secional study. LD was self-reported. The determination of the MMP1 rs1799750 gene polymorphism was performed by real-time PCR, and the serum concentrations of MMP-1 were quantified by the enzyme-linked immunosorbent assay (ELISA) method. Of 404 participants, 204 (51%) were diagnosed with LD, of whom 89 (43%) had mixed lipodystrophy (ML), 72 (35%) had lipohypertrophy (LH), and 43 (22%) had lipoatrophy (LA). There was an association between the genotypes 1G/1G+1G/2G and higher serum levels of MMP-1 (p = .025). There was no association of MMP1 (1G/2G) with LD. Other factors associated with LD were current CD4 ≤ 350 [odds ratio (OR) = 4.85, confidence interval (CI) = 1.78-47.99, p = .0033] and serum MMP-1 levels >6.81 (OR = 2.67, CI = 1.21-6.08, p = .0165). Factors associated with ML: current CD4 ≤ 350 (OR = 5.59, CI = 1.69-20.39, p = .006); with LH: number of antiretroviral regimens used: 2 (OR = 2.06, CI = 1.01-4.20, p = .0460) and 3+ (OR = 2.09, CI = 1.00-4.35, p = .0477), and current CD4 ≤ 350 (OR = 2.08, CI = 1.00-4.24, p = .0461); and with LA: current viral load >40 (OR = 2.52, CI = 1.03-5.91, p = .0372) and current use of zidovudine (OR = 2.97, CI = 1.32-6.54, p = .0074). Higher levels of MMP-1 were associated with genotypes 1G/2G+1G/1G and with LD. Other individual risk factors were independently associated with LD, and its subtypes, suggesting that the pathogenesis itself is differently manifested for each type of LD.

Association between matrix metalloproteinase-1 (MMP-1) protein level and the risk of rheumatoid arthritis and osteoarthritis: a meta-analysis

Recent publications have investigated the potential role of the protein level of matrix metalloproteinase-1 (MMP-1) in the susceptibility to rheumatoid arthritis (RA) and osteoarthritis (OA). However, no unanimous conclusion was obtained. Therefore, we carried out a meta-analysis to explore the association between MMP-1 expression and these two clinical disorders. After database searching and screening, we enrolled a total of eighteen articles for the pooled analysis. We observed a significant association between RA cases and controls in the whole population [SMD (standard mean difference)=1.01, P=0.017]. There were similar positive results in the subgroup analysis of "population-based control" (SMD=1.50, P=0.032) and "synovial fluid" (SMD=1.32, P=0.049). In addition, we observed an increased risk in OA cases, compared with controls, in the overall analysis (SMD=0.47, P=0.004) and subsequent subgroup analysis of "knee OA" (SMD=0.86, P<0.001), "Asian/China" (SMD=0.76, P=0.003), "cartilage-Asian/China" (SMD=1.21, P<0.001), and "synovial fluid-Asian/China" (SMD=0.73, P=0.004). In summary, a high protein level of MMP-1 in synovial fluid may be associated with the susceptibility to RA, and the high MMP-1 level in the cartilage tissue or synovial fluid may be related to the pathogenesis of knee OA in the Chinese population. This should be confirmed by larger sample sizes.

Association between matrix metalloproteinase-1 (MMP-1) protein level and the risk of rheumatoid arthritis and osteoarthritis: a meta-analysis.

Recent publications have investigated the potential role of the protein level of matrix metalloproteinase-1 (MMP-1) in the susceptibility to rheumatoid arthritis (RA) and osteoarthritis (OA). However, no unanimous conclusion was obtained. Therefore, we carried out a meta-analysis to explore the association between MMP-1 expression and these two clinical disorders. After database searching and screening, we enrolled a total of eighteen articles for the pooled analysis. We observed a significant association between RA cases and controls in the whole population [SMD (standard mean difference)=1.01, P=0.017]. There were similar positive results in the subgroup analysis of "population-based control" (SMD=1.50, P=0.032) and "synovial fluid" (SMD=1.32, P=0.049). In addition, we observed an increased risk in OA cases, compared with controls, in the overall analysis (SMD=0.47, P=0.004) and subsequent subgroup analysis of "knee OA" (SMD=0.86, P<0.001), "Asian/China" (SMD=0.76, P=0.003), "cartilage-Asian/China" (SMD=1.21, P<0.001), and "synovial fluid-Asian/China" (SMD=0.73, P=0.004). In summary, a high protein level of MMP-1 in synovial fluid may be associated with the susceptibility to RA, and the high MMP-1 level in the cartilage tissue or synovial fluid may be related to the pathogenesis of knee OA in the Chinese population. This should be confirmed by larger sample sizes.

Tannic acid, a promising anti-photoaging agent: Evidences of its antioxidant and anti-wrinkle potentials, and its ability to prevent photodamage and MMP-1 expression in L929 fibroblasts exposed to UVB.

Chronic and unprotect UV exposure leads to skin oxidative stress, following accumulation of damaged cellular components and downstream activation of specific signaling pathways, culminating in premature skin aging (photoaging). In this concern, polyphenols have been proposed for the prevention of skin disorders UV-generated. In the present study, we compared gallic acid (GA) and tannic acid (TA) regarding their potentials in prevent photoaging, using cell-free assays. The most promising compound was further investigated for its photoprotection abilities in UVB-irradiated L929 fibroblasts. TA was more efficient in scavenging radicals DPPH•, superoxide anion, peroxyl, nitric oxide and peroxynitrite, and to reduce ferric ions. Although GA and TA exhibited similar inhibitory activity towards collagenase, TA was more potent in inhibit elastase. In addition, TA presented a broader UV absorption spectrum. Furthermore, TA treatment in UVB-irradiated cells attenuated redox imbalance, as observed by its ability to inhibit ROS production, NADPH oxidase activation and depletion of endogenous antioxidant defense system. Moreover, TA treatment prevented cellular photodamage and subsequently photoaging, by inhibiting lipid peroxidation, depolarization of mitochondrial transmembrane potential, DNA damage, and MMP-1 expression, a protein closely related to the structural degeneration of the dermis extracellular matrix. In conclusion, the results indicate the potential of TA in act as anti-photoaging agent, due to its potent antioxidant, anti-collagenase and anti-elastase activities, and UV-absorption effects, and its ability in prevent oxidative stress, oxidative damages and MMP-1 induction in UVB-irradiated L929 fibroblasts.

Association Between -1607 1G/2G Polymorphism of MMP1 and Temporomandibular Joint Anterior Disc Displacement with Reduction.

Anterior disc displacement with reduction (DDWR) is considered one of the most common disorders within the temporomandibular joint (TMJ), with a prevalence of 41% in adults. Matrix metalloproteinases play an important role in the degradation of the TMJ and the matrix metalloproteinase 1 (MMP1) 1607 1G/2G polymorphism increases the local expression of MMP1 thus leading to accelerated degradation of the extracellular matrix. The objective of this study was to evaluate the association between the 1607 1G/2G polymorphism of MMP1 gene and DDWR in a group of Mexican individuals from western Mexico. A total of 67 unrelated individuals, between the ages of 18 and 36 years, of both genders, were included in this study. Study participants with DDWR were required to meet the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD), while a second control group of 90 individuals without DDWR were also included. Both groups were required to have paternal and maternal ancestry (grandparents) of the same geographic and ethnic region. Genotypes were determined using the nested PCR technique. The 1G/2G polymorphism was found in 68.7%, followed by 2G/2G in 25.4% and 1G/1G in 6.0% of the cases group. While the prevalence in the control group was 55.5% for the 1G/2G polymorphism, 26.6% for 1G/1G and 17.7% for 2G/2G. An association was found between the 2G allele of the 1607 1G/2G polymorphism of MMP1 gene and the presence of DDWR in the patients of western Mexico.

Association of the polymorphisms of the genes APOC3 (rs2854116), ESR2 (rs3020450), HFE (rs1799945), MMP1 (rs1799750) and PPARG (rs1801282) with lipodystrophy in people living with HIV on antiretroviral therapy: a systematic review.

The aim of this study was to perform a systematic review to identify data reported in the literature concerning the association of APOC3 (rs2854116), ESR2 (rs3020450), HFE (rs1799945), MMP1 (rs1799750) and PPARG (rs1801282) polymorphisms with lipodystrophy in people living with HIV (PLWHIV) on antirretroviral therapy. The research was conducted in six databases and the studies were selected in two steps. First, a search was undertaken in the following electronic databases: PubMed, Science Direct, Medline, World Wide Science, Directory of Open Access Journals, Scielo, Lilacs and Medcarib. The titles and abstracts of 24,859 articles were read to select those that match the elegibilty criteria. Five papers that addressed the association of HAART, lipodystrophy and polymorphisms were selected for the review. There was no association between the polymorphisms of the genes APOC3 and PPARG and lipodystrophy. Another study described an association between the variant allele (G) of HFE and protection concerning the development of lipoatrophy (0.02) when compared with the reference allele (C). On the other hand, the variant allele (T) of the ESR2 gene was associated with the development of lipoatrophy (p = 0.007) when compared with the reference allele (C). In addition, the genotype and the variant allele of the gene MMP1 (2G) were associated with lipodystrophy in PLWHIV on HAART (p = 0.0002 and p = 0.0008, respectively). Therefore, further studies with other populations, involving PLWHIV on HAART are necessary to better understand the role of genetic markers, which may be involved in a predisposition to lipodystrophy.

Association between -1607 1g/2g polymorphism of mmp1 and temporomandibular joint anterior disc displacement with reduction

Abstract Anterior disc displacement with reduction (DDWR) is considered one of the most common disorders within the temporomandibular joint (TMJ), with a prevalence of 41% in adults. Matrix metalloproteinases play an important role in the degradation of the TMJ and the matrix metalloproteinase 1 (MMP1) 1607 1G/2G polymorphism increases the local expression of MMP1 thus leading to accelerated degradation of the extracellular matrix. The objective of this study was to evaluate the association between the 1607 1G/2G polymorphism of MMP1 gene and DDWR in a group of Mexican individuals from western Mexico. A total of 67 unrelated individuals, between the ages of 18 and 36 years, of both genders, were included in this study. Study participants with DDWR were required to meet the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD), while a second control group of 90 individuals without DDWR were also included. Both groups were required to have paternal and maternal ancestry (grandparents) of the same geographic and ethnic region. Genotypes were determined using the nested PCR technique. The 1G/2G polymorphism was found in 68.7%, followed by 2G/2G in 25.4% and 1G/1G in 6.0% of the cases group. While the prevalence in the control group was 55.5% for the 1G/2G polymorphism, 26.6% for 1G/1G and 17.7% for 2G/2G. An association was found between the 2G allele of the 1607 1G/2G polymorphism of MMP1 gene and the presence of DDWR in the patients of western Mexico.

Resumo O deslocamento anterior do disco com redução (DADR) é considerado um dos distúrbios mais comuns na articulação temporomandibular (ATM), com prevalência de 41% em adultos. As metaloproteinases da matriz desempenham um papel importante na degradação da ATM e o polimorfismo 1607 1G/2G da metaloproteinase da matriz 1 (MMP1) aumenta a expressão local da MMP1, levando à degradação acelerada da matriz extracelular. O objetivo deste estudo foi avaliar a associação entre o polimorfismo 1607 1G/2G do gene MMP1 e a DADR em um grupo de indivíduos mexicanos do oeste do México. Um total de 67 indivíduos não relacionados, com idades entre 18 e 36 anos, de ambos os sexos, foram incluídos neste estudo. Os participantes do estudo com DADR foram obrigados a cumprir os Critérios de Diagnóstico de Pesquisa para Disfunções Temporomandibulares (CDP/DTM), enquanto um segundo grupo controle de 90 indivíduos sem DADR também foi incluído. Ambos os grupos tinham ascendência paterna e materna (avós) da mesma região geográfica e étnica. Os genótipos foram determinados pela técnica de nested PCR. o polimorfismo 1G/2G foi encontrado em 68,7%, seguido por 2G/2G em 25,4% e 1G/1G em 6,0% do grupo de casos. Enquanto a prevalência no grupo controle foi de 55,5% para o polimorfismo 1G/2G, 26,6% para 1G/1G e 17,7% para 2G/2G. Foi encontrada uma associação entre o alelo 2G do polimorfismo 1607 1G/2G do gene MMP1 e a presença de DADR nos pacientes do oeste do México.

A 4-gene signature from histologically normal surgical margins predicts local recurrence in patients with oral carcinoma: clinical validation.

Prognostic biomarkers for recurrence of Oral Squamous Cell Carcinoma (OSCC) are urgently needed. We aimed to independently validate a 4-gene expression signature (MMP1, COL4A1, P4HA2, THBS2) predictive of OSCC recurrence risk. Gene expression was measured using Nanostring nCounter® in 245 histologically normal surgical resection margins from 62 patients. Association between risk scores for individual patients and recurrence was assessed by Kaplan-Meier analysis. Signature performance was quantified by concordance index (CI), hazard ratio (HR) and the area under receiver operating characteristics (AUC). Risk scores for recurrence were significantly higher than recurrence-free patients (p = 9.58e-7, Welch's t-test). A solid performance of the 4-gene signature was determined: CI = 0.64, HR = 3.38 (p = 1.4E-4; log-rank test), AUC = 0.71. We showed that three margins per patient are sufficient to preserve predictive performance (CI = 0.65; HR = 2.92; p = 2.94e-3; AUC = 0.71). Association between the predicted risk scores and recurrence was assessed and showed HR = 2.44 (p = 9.6E-3; log-rank test, N = 62). Signature performance analysis was repeated using an optimized threshold (70th percentile of risks), resulting in HR = 3.38 (p = 1.4E-4; log-rank test, N = 62). The 4-gene signature was validated as predictive of recurrence risk in an independent cohort of patients with resected OSCC and histologically negative margins, and is potentially applicable for clinical decision making on adjuvant treatment and disease monitoring.

Association of polymorphisms in IL-8, MMP-1 and MMP-13 with the risk and prognosis of oral and oropharyngeal squamous cell carcinoma.

OBJECTIVE: This study investigated the risk and prognostic value of single nucleotide polymorphisms (SNP) inIL-8, MMP-1 and MMP-13 in oral and oropharyngeal squamous cell carcinomas (SCCs). DESIGN: SNPs rs2227532 and rs4073 inIL-8, rs2071230 and rs470558 in MMP-1, and rs2252070 in MMP-13 were genotyped in 125 oral and oropharyngeal SCC patients and 130 healthy controls, using TaqMan allelic discrimination assays. Multiple logistic regression models were used to explore the association between SNPs and cancer development, as well as SNP-SNP interaction and gene-environmental factor (GxE) interaction. Univariate and multivariate methods were applied for survival analyses. RESULTS: With exception of rs2227532, all the SNPs were in Hardy-Weinberg equilibrium in the control. No associations between rs4073 in IL-8 and rs2071230 and rs470558 in MMP-1 were observed, but rs2252070 in MMP-13, in the dominant model, was associated in a protective manner to oral and oropharyngeal SCC (OR: 0.20, 95% CI: 0.06-0.71, p = 0.007). All SNPs interact significantly with cigarette smoking and alcohol consumption on susceptibility to oral and oropharyngeal SCC, but they showed no influence on survival of the patients. CONCLUSIONS: Our results show that rs2252070 inMMP-13 may confer protection effect against oral and oropharyngeal SCC. In addition, the combined effects of IL-8 (rs4073), MMP-1 (rs2071230 and rs470558) and MMP-13 (rs2252070) with environmental carcinogens, such as tobacco and alcohol, are related to increased risk for oral and oropharyngeal SCC development.

Matrix metalloproteinases gene polymorphism haplotype is a risk factor to implant loss: A case-control study.

BACKGROUND: Dental implants consist in the treatment of choice to replace tooth loss. The knowledge that implant loss tends to cluster in subsets of individuals may indicate that host response is influenced by genetic factors. Matrix metalloproteinases (MMPs) are enzymes that contribute to degradation and removal of collagen from extracellular matrix. PURPOSE: This case-control study aimed to investigate the haplotypic combination of MMP polymorphism (rs1144393, rs1799750, rs3025058, and rs11225395) and implant loss. MATERIALS AND METHODS: Two hundred nonsmokers subjects were matched by gender, age, implant number and position and divided in control group, 100 patients with one or more healthy implants, and test group, and 100 patients with one or more implant failures. Genomic DNA was extracted from saliva and genotypes were obtained by PCR-RFLP. RESULTS: A significant association of rs1799750 (MMP-1) and rs11225395 (MMP-8) polymorphism on early implant loss was demonstrated (P ≤ 0.001). Global haplotype analysis indicated a significant difference between both groups (P < 0.0001). Haplotype T-A-GG-5A-C had a statistically significant risk effect, while haplotype C-A-G-6A-C andT-G-2G-5A-C had a protective effect in implant loss. CONCLUSIONS: The results of this study showed that MMPs haplotype are a risk factor to early implant loss.

Matrix metalloproteinase-1 (MMP-1) and (MMP-8) gene polymorphisms promote increase and remodeling of the collagen III and V in posterior tibial tendinopathy.

Posterior tibial tendinopathy (PTT) can lead to acquired flatfoot in adults. Many patients develop PTT without any identifiable risk factors. Molecular changes in extracellular matrix (ECM) and matrix metalloproteinase (MMP) polymorphism may influence the risk of developing PTT. We aim to investigate the association between matrix metalloproteinase-1 (MMP-1) and (MMP-8) gene polymorphisms with changes in collagen I, III and V in PTT. A case-control study with 22 patients and 5 controls was performed. The MMP-1 (2G/2G) and MMP-8 (T/T) genotypes were determined by PCR-restriction fragment length polymorphism. Tendon specimens were evaluated by a histologic semiquantitative score, immunofluorescence and histomorphometry for collagen I, III and V. Tendon specimens from PTT demonstrated marked distortion of the architecture with necrosis, large basophilic areas with disruption of the normal linear orientation of collagen bundles, infiltration of inflammatory cells, dystrophic calcification and ossification. Under immunofluorescence, PTT tendon specimens showed weak green fluorescence and diffuse distribution of collagen I fibers, but strong fluorescence of collagen III and V. The collagen I fibers were significantly decreased whereas an increase of collagen III and V were found in PTT compared to control groups. In addition, PTT group presented a significant association with MMP-1 and MMP-8 gene polymorphisms. Patients with PTT matrix metalloproteinase-1 (MMP-1) and (MMP-8) gene polymorphisms presented an increase of the collagen III and V ratio, suggesting that the higher proportion in degenerated tendons could contribute to a decrease in the mechanical resistance of the tissue. Still, functional and association studies are needed to elucidate evident roles of MMPs in PTT.

Molecular characterization of matrix metalloproteinase-1 (MMP-1) in Lucilia sericata larvae for potential therapeutic applications

Background: The salivary glands of Lucilia sericata are the first organs to express specific endopeptidase enzymes. These enzymes play a central role in wound healing, and they have potential to be used therapeutically. Methods: Rapid amplification of cDNA ends and rapid amplification of genomic ends were used to identify the coding sequence of MMP-1 from L. sericata. Different segments of MMP1 gene, namely the middle part, 3' end, and 5' end, were cloned, sequenced, and analyzed using bioinformatics tools to determine the distinct features of MMP-1 protein. Results: Assembling the different segments revealed that the complete mRNA sequence of MMP-1 is 1932 bp long. CDS is 1212 bp long and is responsible for the production of MMP-1 of 404 amino acid residues with a predicted molecular weight of 45.1 kDa. The middle part, 3' end, and 5' end sequences were 933, 503, and 496 bp. In addition, it was revealed that the MMP-1 genomic sequence includes three exons and two introns. Furthermore, the three-dimensional structure of L. sericata MMP-1 protein was evaluated, and its alignment defined that it has high similarity to chain A of human MMP-2 with 100% confidence, 72% coverage, and 38% identity according to the SWISS-MODEL modeling analysis. Conclusions: MMP-1 of L. sericata has a close relationship with its homologs in invertebrates and other insects. The present study significantly contributes to understanding the function, classification, and evolution of the characterized MMP-1 from L. sericata and provides basic required information for the development of an effective medical bioproduct.

The Role of Proteinase-Activated Receptors 1 and 2 in the Regulation of Periodontal Tissue Metabolism and Disease.

Proteinase-activated receptors 1 (PAR1) and 2 (PAR2) are the most highly expressed members of the PAR family in the periodontium. These receptors regulate periodontal inflammatory and repair processes through their activation by endogenous and bacterial enzymes. PAR1 is expressed by the periodontal cells such as human gingival fibroblasts, gingival epithelial cells, periodontal ligament cells, osteoblasts, and monocytic cells and can be activated by thrombin, matrix metalloproteinase 1 (MMP-1), MMP-13, fibrin, and gingipains from Porphyromonas gingivalis. PAR2 is expressed by neutrophils, osteoblasts, oral epithelial cells, and human gingival fibroblasts, and its possible activators in the periodontium are gingipains, neutrophil proteinase 3, and mast cell tryptase. The mechanisms through which PARs can respond to periodontal enzymes and result in appropriate immune responses have until recently been poorly understood. This review discusses recent findings that are beginning to identify a cardinal role for PAR1 and PAR2 on periodontal tissue metabolism.

Matrix Metalloproteases 1 and 3 Promoter Gene Polymorphism Is Associated With Rotator Cuff Tear.

BACKGROUND: Studies suggest that the collagen degeneration and disordered arrangement of collagen fibers in rotator cuff tears are associated with an increase in activity of matrix metalloproteases 1 and 3 (MMP-1 and MMP-3), and that MMP activity may be in part genetically mediated. The degree to which this might be clinically relevant in patients with rotator cuff tears has not been well characterized. QUESTIONS/PURPOSES: (1) Is genetic polymorphism of MMP-1 and MMP-3 associated with rotator cuff tears? (2) Are there haplotypes of MMP-1 and MMP-3 correlated with rotator cuff tears? (3) Compared with control subjects, do patients with rotator cuff tears have a higher proportion of relatives with the same disease? METHODS: We evaluated 64 patients with full-thickness rotator cuff tears and 64 asymptomatic control subjects. Patients younger 65 years, with nontraumatic tears, were included. The tear or integrity of the rotator cuff tear was evaluated by MRI or ultrasonography in all individuals. The patients and control subjects were paired by age. MMP-1 and MMP-3 genotypes were determined using the PCR-restriction fragment length polymorphism assays. RESULTS: Genetic polymorphisms in MMP-1 and MMP-3 are associated with rotator cuff tear, in which individuals with rotator cuff tears have associated genotypes 1G/2G (patients, 32 of 64 [50%], control subjects, 16 of 64 [25%]; odds ratio [OR], 4.8; 95% CI, 2.1-11.0; p < 0.001) and 2G/2G were at great risk (patients, 15 of 64 [23%], control subjects, seven of 64 [11%]; OR, 5.2; 95% CI,1.8-14.9; p < 0.001), and patients with rotator cuff tears were associated with a higher proportion of 2G allele distribution (62 of 128 [48%] versus 30 of 128 [23%]; p < 0.001). Patients with the 5A/5A genotype are at greater risk of rotator cuff tear (patients, 15 of 64 [23%]; control subjects, four of 64 [6%]; OR, 5.5; 95% CI, 1.4-20.9; p = 0.021), and there was higher 5A allele distribution in patients with rotator cuff tears (patients, 68 of 128 [53%]; control subjects, 52 of 128 [41%]; p = 0.045). Individuals with the haplotype 2G/5A were more likely to have rotator cuff tears develop (patients, 42 of 64 [66%]; control subjects, 17 of 64 [27%]; OR, 5.3; 95% CI, 2.5-11.3; p < 0.001). Patients with rotator cuff tears reported, in higher number, the existence of relatives who previously had treatment for rotator cuff tears (19 of 64 [30%] versus four of 64 [6%]; OR, 6.3; 95% CI, 2.0-19.9; p = 0.001). CONCLUSIONS: The genetic polymorphism of MMP-1 and MMP-3 is associated with rotator cuff tear. Individuals with haplotype 2G/5A were more susceptible to rotator cuff tears in the population studied. CLINICAL RELEVANCE: Knowledge of the genetic markers related to rotator cuff tears can enable identification of susceptible individuals and increase understanding of the pathogenesis of tendon degeneration.

Integrative miRNA and mRNA analysis in penile carcinomas reveals markers and pathways with potential clinical impact.

Penile carcinoma (PeCa) is an important public health issue in poor and developing countries, and has only recently been explored in terms of genetic and epigenetic studies. Integrative data analysis is a powerful method for the identification of molecular drivers involved in cancer development and progression. miRNA and mRNA expression profiles followed by integrative analysis were investigated in 23 PeCa and 12 non-neoplastic penile tissues (NPT). Expression levels of eight miRNAs and 10 mRNAs were evaluated in the same set of samples used for microarray and in a validation set of cases (PeCa = 36; NPT = 27). Eighty-one miRNAs and 2,697 mRNAs were identified as differentially expressed in PeCa. Integrative data analysis revealed 255 mRNAs potentially regulated by 68 miRNAs. Using RT-qPCR, eight miRNAs and nine transcripts were confirmed as altered in PeCa. We identified that MMP1, MMP12 and PPARG and hsa-miR-31-5p, hsa-miR-224-5p, and hsa-miR-223-3p were able to distinguish tumors from NPT with high sensitivity and specificity. Higher MMP1 expression was detected as a better predictor of lymph node metastasis than the clinical-pathological data. In addition, PPARG and EGFR were highlighted as potential pathways for targeted therapy in PeCa. The analysis based on HPV positivity (7 of 23 cases) revealed five miRNA and 13 mRNA differentially expressed. Although in a limited number of cases, HPV positive PeCa presented less aggressive phenotype in comparison with negative cases. Overall, an integrative analysis using mRNA and miRNA profiles revealed markers related with tumor development and progression. Furthermore, MMP1 expression level was a predictive marker for lymph node metastasis in patients with PeCa.

Analysis of expression of FLI1 and MMP1 in American cutaneous leishmaniasis caused by Leishmania braziliensis infection.

FLI1 (Friend leukemia virus integration 1) and IL6 (interleukin 6; IL-6) are associated with Leishmania braziliensis susceptibility. Cutaneous lesions show exaggerated matrix metalloproteinase 1 (MMP1). In other skin diseases, FLI1 promoter methylation reduces FLI1 expression, and low FLI1 down-regulates MMP1. IL-6 increases FLI1 expression. We hypothesized that epigenetic regulation of FLI1 in cutaneous leishmaniasis, together with IL-6, might determine MMP1 expression. While generally low (<10%), percent FLI1 promoter methylation was lower (P=0.001) in lesion biopsies than normal skin. Contrary to expectation, a strong positive correlation occurred between FLI1 methylation and gene expression in lesions (r=0.98, P=0.0005) and in IL-6-treated L. braziliensis-infected macrophages (r=0.99, P=0.0004). In silico analysis of the FLI1 promoter revealed co-occurring active H3K27ac and repressive DNA methylation marks to enhance gene expression. FLI1 expression was enhanced between 3 and 24hour post infection in untreated (P=0.0002) and IL-6-treated (P=0.028) macrophages. MMP1 was enhanced in lesion biopsies (P=0.0002), induced (P=0.007) in infected macrophages, but strongly inhibited by IL-6. No correlations occurred between FLI1 and MMP1 expression in lesions or infected macrophages (with/without IL-6). We conclude that MMP1 is regulated by factors other than FLI1, and that the influence of IL-6 on MMP1 was independent of its effect on FLI1.