The interplay of matrix metalloproteinase-8, transforming growth factor-beta 1 and vascular endothelial growth factor-C cooperatively contributes to the aggressiveness of oral tongue squamous cell carcinoma

Background: Matrix metalloproteinase-8 (MMP-8) has oncosuppressive properties in various cancers. We attempted to assess MMP-8 function in oral tongue squamous cell carcinoma (OTSCC). Methods: MMP-8 overexpressing OTSCC cells were used to study the effect of MMP-8 on proliferation, apoptosis, migration, invasion and gene and protein expression. Moreover, MMP-8 functions were assessed in the orthotopic mouse tongue cancer model and by immunohistochemistry in patient samples. Results: MMP-8 reduced the invasion and migration of OTSCC cells and decreased the expression of MMP-1, cathepsin-K and vascular endothelial growth factor-C (VEGF-C). VEGF-C was induced by transforming growth factor-beta 1 (TGF-beta 1) in control cells, but not in MMP-8 overexpressing cells. In human OTSCC samples, low MMP-8 in combination with high VEGF-C was an independent predictor of poor cancer-specific survival. TGF-beta 1 treatment also restored the migration of MMP-8 overexpressing cells to the level of control cells. In mouse tongue cancer, MMP-8 did not inhibit metastasis, possibly because it was eliminated in the peripheral carcinoma cells. Conclusions: The suppressive effects of MMP-8 in OTSCC may be mediated through interference of TGF-beta 1 and VEGF-C function and altered proteinase expression. Together, low MMP-8 and high VEGF-C expression have strong independent prognostic value in OTSCC.Peer reviewe

Hemodialysis Removes Uremic Toxins That Alter the Biological Actions of Endothelial Cells

Chronic kidney disease is linked to systemic inflammation and to an increased risk of ischemic heart disease and atherosclerosis. Endothelial dysfunction associates with hypertension and vascular disease in the presence of chronic kidney disease but the mechanisms that regulate the activation of the endothelium at the early stages of the disease, before systemic inflammation is established remain obscure. In the present study we investigated the effect of serum derived from patients with chronic kidney disease either before or after hemodialysis on the activation of human endothelial cells in vitro, as an attempt to define the overall effect of uremic toxins at the early stages of endothelial dysfunction. Our results argue that uremic toxins alter the biological actions of endothelial cells and the remodelling of the extracellular matrix before signs of systemic inflammatory responses are observed. This study further elucidates the early events of endothelial dysfunction during toxic uremia conditions allowing more complete understanding of the molecular events as well as their sequence during progressive renal failure

Salivary Biomarkers for Detection of Systemic Diseases

Peer reviewe

Matrix metalloproteinase-8 as a diagnostic tool for the inflammatory and malignant diseases

Abstract Matrix metalloproteinases (MMPs) are the zinc-dependent endopeptidases which belong to a large family of proteases. MMPs are responsible for degradation and remodeling of extracellular matrix proteins during growth, organogenesis and tissue turnover. Besides their role in physiological processes, MMPs also influence various pathological processes, i.e., inflammatory diseases and cancers, in which MMPs may ultimately lead to unwanted tissue destruction. One of the most widely studied MMPs is MMP-8. MMP-8 was previously thought to be expressed only by neutrophils. Presently, it is evident that MMP-8 can be expressed in a wide range of cells such as macrophages, plasma cells, T-cells, endothelial cells, smooth muscle cells, oral epithelial cells, fibroblasts etc. MMP-8 has been previously studied in inflammation and malignancies. High serum MMP-8 concentration is associated with the presence of atherosclerosis and poor cardiovascular disease prognosis, while higher plasma MMP-8 levels protect against lymph node metastasis. Certain MMP-8 gene variations can alter promoter activity and subsequent gene expression. MMP-8 gene variation influences obstetrical outcomes, and lung and breast cancer prognosis. For our study, we hypothesized that systemic levels of MMP-8 correlate with its genetic variations and appear as novel risk markers for disease. We aimed to address the potential role of MMPs and their regulators with a special focus on MMP-8 in distinct sets of inflammatory and malignant diseases, i.e. arterial diseases, and head and neck squamous cell cancer (HNSCC). We demonstrated that the combination of high serum MMP-8 and low myeloperoxidase (MPO) levels is an important risk marker for arterial disease. Further, we demonstrated that MMP-8 gene variation is protective against arterial diseases. Interestingly, we were able to demonstrate an association between MMP-8 gene variation and serum MMP-8 concentration in a healthy population. On the other hand, we showed that plasma tissue inhibitor of matrix metalloproteinases (TIMP-1) concentration is associated with survival in HNSCC patients and TIMP-1 genotype is associated with plasma TIMP-1 levels in women only. Collectively, our study showed that serum MMP-8 levels can be used as an important risk marker in arterial disease and TIMP-1 levels in HNSCC patients. Based on our results, the hypothesis raised has been widely confirmed. Additionally, our study has warranted the need for further investigation involving a larger number of patients. If our results are replicable, serum MMP-8 and plasma TIMP-1 could be used to develop diagnostic tools as well as treatment regimes in clinics.Tiivistelmä Matriksin metalloproteinaasit (MMP:t) ovat sinkkiriippuvaisia endopeptidaaseja, jotka kuuluvat laajaan proteiineja pilkkovaan proteolyyttiseen entsyymi perheeseen. MMP:ien tehtävä on pilkkoa ja uudelleen muokata soluväliaineen proteiineja kasvun, elinten kehityksen ja kudosten uusiutumisen aikana, mutta MMP:t toimivat aktiivisesti myös patologisissa prosesseissa, kuten tulehdustiloissa ja syövissä. Syövissä MMP:en vaikutus voi johtaa ei-toivottuun kudostuhoon. Yksi laajimmin tutkituista MMP-ryhmän entsyymeistä on MMP-8, jonka alunpitäen ajateltiin ilmenevän vain neutrofiileissä. Nykytietämyksen mukaan MMP-8:aa ilmentyy myös mm. makrofaageissa, plasmasoluissa, T-soluissa, endoteelisoluissa, sileälihassoluissa, suun limakalvon epiteelisoluissa ja fibroplasteissa. MMP-8:aa on aikaisemmin tutkittu erityisesti tulehdustiloissa ja pahanlaatuisissa kasvaimissa. Korkean MMP-8 seerumipitoisuuden on havaittu liittyvän valtimokovettumatautiin ja huonoon ennusteeseen sydän- ja verisuonisairauksissa, kun taas kohonnut MMP-8:n pitoisuus plasmassa suojaa imusolmuke-etäpesäkkeiltä. Tiedetään, että tietyt muutokset MMP-8:n geenissä voivat muuttaa sen promoottoriaktiviteettia ja täten säädellä geenin ilmentymistä. MMP-8:n geenimuutokset vaikuttanevat raskaudenkulkuun sekä keuhko- ja rintasyövän ennusteeseen. Tutkimushypoteesimme mukaan MMP-8:n seerumipitoisuudet riippuvat vaihtelusta MMP-8:aa koodaavassa geenissä ja niitä voidaan pitää uusina riskinarvioinnin merkkiaineina tautitiloissa. Tavoitteenamme oli osoittaa yleisesti MMP:ien ja erityisesti MMP-8:n sekä näiden proteinaasien säätelytekijöiden merkitys tietyissä tulehdustiloissa ja maligniteeteissa, kuten sepelvaltimotaudissa ja pään ja kaulan alueen syövissä. Havaitsimme, että korkea MMP-8 seerumipitoisuus ja alhainen myeloperoksidaasitaso yhdistyvät vahvasti valtimotautiriskiin. Lisäksi osoitimme, että tietty MMP-8:n geenimuunnos on suojaava tekijä valtimotaudille ja että MMP-8:n seerumikonsentraatio on siitä riippuvainen terveillä tutkituilla. Tämän lisäksi todensimme, että MMP:n kudosestäjän (tissue inhibitor of matrix metalloproteinases, TIMP-1) plasmapitoisuus liittyy pään ja kaulan alueen levyepiteelisyöpää sairastavien potilaiden eloonjääntiin ja että TIMP-1:n genotyyppi liittyy sen plasmapitoisuuteen ainoastaan naisilla. Tulostemme mukaan seerumin MMP-8-pitoisuutta voidaan pitää hyvänä riskinarviointivälineenä verisuonitaudeissa sekä TIMP-1-pitoisuutta vastaavasti pään ja kaulan alueen levyepiteelisyövissä. Saadut tulokset tukevat olettamustamme, jonka mukaan MMP-8 on tärkeä tautimarkkeri. Tämä on lisännyt kiinnostusta selvittää MMP:ien merkitystä laajemmin muissa tulehdustiloissa ja syövissä. Jos tulokset saadaan toistetuksi laajemmassa tutkimusaineistossa, seerumin MMP-8:sta voidaan kehittää kliinisten ja analyyttisten laboratorioiden käyttöön sopiva diagnostinen menetelmä

Immunological and microbiological profiling of cumulative risk score for periodontitis

Abstract The cumulative risk score (CRS) is a mathematical salivary diagnostic model to define an individual’s risk of having periodontitis. In order to further validate this salivary biomarker, we investigated how periodontal bacteria, lipopolysaccharide (LPS), and systemic and local host immune responses relate to CRS. Subgingival plaque, saliva, and serum samples collected from 445 individuals were used in the analyses. Plaque levels of 28 microbial species, especially those of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Porphyromonas endodontalis, Prevotella intermedia, and Tannerella forsythia, and serum and salivary levels of IgA and IgG against these five species were determined. Additionally, LPS activity was measured. High CRS associated strongly with all IgA/IgG antibody and LPS levels in saliva, whereas in serum the associations were not that obvious. In the final logistic regression model, the best predictors of high CRS were saliva IgA burden against the five species (OR 7.04, 95% CI 2.25–22.0), IgG burden (3.79, 1.78–8.08), LPS (2.19, 1.38–3.47), and the sum of 17 subgingival Gram-negative species (6.19, 2.10–18.3). CRS is strongly associated with microbial biomarker species of periodontitis and salivary humoral immune responses against them

MMP-1 and -3 haplotype is associated with congenital anomalies of the kidney and urinary tract

Congenital anomalies of the kidney and urinary tract (CAKUT) are a common cause of progressive chronic kidney disease that may lead to end-stage renal disease and renal replacement therapy in childhood. Altered expression or activity of matrix metalloproteinases (MMPs) have been found in CAKUT. The MMP-1, -3, and -8 polymorphisms studied here are located in the gene promoters and alter expression. Our aim was to investigate associations of MMP polymorphisms, solely and in haplotypes, with CAKUT in children. A case-control study with 101 pediatric patients and 281 controls was performed. The MMP-1 (-1607 1G/2G), -3 (5A/6A), and -8 (-799 C/T) genotypes were determined by PCR-restriction fragment length polymorphism. We found statistically significant associations of MMP-3 5A/6A polymorphism (p LT 0.0001) and 1G(-1607)-6A haplotype, with no preferences for MMP-8 -799C or T alleles, with CAKUT (OR = 2.93, 95 % CI 1.43-5.98, adjusted for gender, p = 0.003) and with obstructive uropathies in a subgroup of patients (OR = 4.57, 95 % CI 2.74-7.61, adjusted for gender, p LT 0.0001). MMP-3 genotypes and MMP-3 and -1 haplotypes encompassing either MMP-8 -799C or T alleles were associated with CAKUT and obstructive uropathies in pediatric patients. Still, functional and association studies are needed to elucidate evident roles of MMPs in CAKUT