Matrix metalloproteinase 8 : genetic, diagnostic, and therapeutic approaches

Matrix metalloproteinases (MMPs) are enzymes that are responsible for the degradation of the extracellular matrix (ECM) during development, repair, and remodeling of tissues. MMP-8, also known as neutrophil collagenase, is released from neutrophils when they enter the tissues at the site of inflammation. An imbalance in MMP-8 activity leads to excess degradation of tissues and destructive inflammation, such as periodontitis. Elevated concentrations of MMP-8 in serum and plasma are also associated with cardiovascular diseases (CVDs). Doxycycline has inhibitory effects against MMPs in addition to its well-known property of being antimicrobial. This thesis investigated the genetics of MMP-8, the effect of MMP-8 and its inhibitors on lipid metabolism, and the potential of salivary MMP-8 in diagnostics of periodontitis. We performed a genome-wide association study (GWAS) in two independent populations with a total of 6049 individuals to identify genetic variants and molecular mechanisms that affect serum MMP-8 concentrations. In addition, we studied whether MMP-8-associated genetic variants are related to increased risk of CVDs in over 20 000 individuals. We discovered that genetic polymorphism in the gene of complement factor H (CFH) is strongly associated with the concentrations of MMP-8 in serum. By conducting functional experiments with isolated neutrophils, we found that genetic variation of CFH affected the release of MMP-8 from neutrophils in response to complement activation. In addition, genetic polymorphism in the locus containing the genes of S100 calcium binding proteins A8, A9, and A12 was associated with serum and plasma MMP-8 levels and also with the prevalence and incidence of CVDs. We studied the effect of MMP-8 and its inhibitors on lipid metabolism by conducting cell experiments, in an MMP-8-knockout mouse model, and in a placebo-controlled clinical trial of two years. We discovered that MMP-8 cleaved apolipoprotein A-I (apoA-I), the main protein component of HDL. MMP-8 significantly reduced the ability of HDL to promote cholesterol efflux from cholesterol-loaded macrophages. The cleavage of apoA-I by MMP-8 and the reduction in its cholesterol efflux capacity was inhibited by doxycycline at clinically attainable doses. MMP-8 deficient mice had significantly lower serum triglyceride levels and larger HDL particle size compared to wild type mice. In the clinical trial, the subjects treated with subantimicrobial-dose doxycycline (SDD) displayed a significant increase in cholesterol efflux from macrophages to the serum compared to the baseline, whereas the efflux levels did not change in the placebo group over the study period. We studied the association of three salivary biomarkers, MMP-8, interleukin-1β, and Porphyromonas gingivalis, with periodontal status in 463 subjects. The salivary concentrations of MMP-8, interleukin-1β, and P. gingivalis were associated with the number of deepened periodontal pockets and the extent of alveolar bone loss. The combination of the biomarkers was more strongly associated with moderate to severe periodontitis than any of the biomarkers alone. Our results indicate that activation of the complement system, especially the alternative pathway, contributes significantly to the concentrations of MMP-8 in serum. Genetic polymorphism in S100A8/A9/A12 locus affects circulating MMP-8 levels, and is associated with CVDs. These results emphasize the role of inflammation and the immune system in CVDs. Proteolysis of apoA-I by MMP-8 may disturb HDL metabolism and reverse cholesterol transport, which leads to accumulation of cholesterol in the vessel walls and accelerated atherosclerosis. Inhibition of MMP-8 by doxycycline may reduce the risk of CVDs, especially in vulnerable individuals such as periodontitis patients. Saliva MMP-8, particularly when combined with other biomarkers, has great potential in the diagnostics of periodontitis. MMP-8 in saliva reflects the health of the oral cavity, whereas circulating MMP-8 is associated with systemic diseases such as CVDs. Our results suggest that MMP-8 functions as a link between inflammatory disorders, such as periodontitis, and cardiovascular disorders.Matriksin metalloproteinaasit (MMPt) ovat soluväliainetta eli matriksia muokkaavia ja hajottavia proteiineja. MMP-8 on erityisesti neutrofiilisten valkosolujen tuottama entsyymi, joka auttaa puolustussoluja tunkeutumaan verenkierrosta kudoksiin ja liikkumaan tulehduspaikalla. MMP-8:n vapautuminen ja aktiivisuus lisääntyvät useissa patologisissa tiloissa, etenkin kroonisissa tulehduksissa. Parodontiitti on hampaiden kiinnityskudosten tulehdussairaus, jossa MMP-8 aiheuttaa kudostuhoa. MMP-8:n pitoisuudet veressä yhdistyvät myös sydän- ja verisuonitauteihin. Väitöskirjassa tutkittiin MMP-8:n toimintaa ja merkitystä mahdollisena parodontiittia ja sydän- ja verisuonitauteja yhdistävänä tekijänä. Genominlaajuisessa analyysissä selvitettiin geneettisiä tekijöitä, jotka vaikuttavat MMP-8:n pitoisuuteen verenkierrossa ja sydän- ja verisuonitautien riskiin. Tutkimuksessa havaittiin, että variaatio komplementtitekijä H proteiinia koodaavassa geenissä vaikutti selvästi MMP-8:n vapautumiseen neutrofiileistä ja sen pitoisuuteen seerumissa. Variaatio geenialueella, jossa sijaitsee tulehdusta ja immuunipuolustusta säätelevää S100A9-proteiinia koodaava geeni, oli myös yhteydessä MMP-8:n pitoisuuteen seerumissa ja plasmassa sekä sydän- ja verisuonitautien riskiin. Sekä parodontiittiin että sydän- ja verisuonitauteihin liittyy rasva-aineenvaihdunnan häiriöitä. MMP-8:n ja sen inhibiittorien vaikutuksia rasva-aineenvaihduntaan tutkittiin solukokeilla, hiirimallilla ja lumelääkekontrolloidussa potilastutkimuksessa. MMP-8:n havaittiin hajottavan apolipoproteiini A-I:tä, joka on HDL-lipoproteiinipartikkelien tärkein proteiini. MMP-8 myös heikensi HDL-partikkelien kykyä poistaa kolesteroliylimääriä soluista. Nämä vaikutukset saatiin kumottua doksisykliinillä, joka estää MMP-8:n toimintaa. Potilastutkimuksessa havaittiin, että hoito matala-annoksisella doksisykliinillä paransi seerumin kykyä poistaa kolesterolia soluista. Syljen MMP-8-tasot yhdistyivät parodontiitin oireisiin eli ienverenvuotoon ja patologisesti syventyneisiin ientaskuihin. MMP-8 yhdistyi parodontiittiin erityisesti kun se yhdistettiin muihin tulehdusta ja bakteerikuormaa kuvaaviin merkkiaineisiin syljessä. Väitöskirjan tulokset osoittivat, että komplementtijärjestelmän aktivoituminen vaikuttaa MMP-8:n vapautumiseen neutrofiileistä. Lisäksi variaatio S100A9-geenin alueella yhdistyi MMP-8:aan ja sydän- ja verisuonitautien riskiin. MMP-8 heikensi HDL-lipoproteiinipartikkelien valtimonkovettumataudilta suojaavia ominaisuuksia. Syljen MMP-8 on hyvä parodontiitin merkkiaine. Sylkinäytteen ottaminen on hyvin yksinkertaista, joten sylkidiagnostiikkaa voitaisiin käyttää parodontiitin toteamiseen esimerkiksi seulontatutkimuksissa tai terveyden edistämisessä. Tulosten perusteella MMP-8 voisi olla lääkityksen kohde sekä parodontiitissa että sydän- ja verisuonitaudeissa. Väitöskirjan havainnot korostavat tulehdusten ja immuunijärjestelmän yhteyttä sydän- ja verisuonitauteihin

Ientulehdus ja parodontiitti terveysriskeinä

Vertaisarvioitu.Terve suu kuuluu olennaisena osana kokonaisterveyteen. Suun tulehdukselliset sairaudet aiheuttavat ja ylläpitävät lievää tulehdusta, joka liittyy yleissairauksiin. Parodontiitissa epäsuotuisat bakteerit ja niiden virulenssitekijät leviävät muualle elimistöön etenkin verenkierron ja syljen välityksellä. Hampaiden ja ikenien hoito on tärkeää lapsuudesta lähtien niin hampaiden ja hyvän purentatoiminnan säilyttämiseksi kuin tulehduksiin liittyvien riskitekijöiden hallitsemiseksikin. Jatkuvasti lisääntyvä tutkimusnäyttö parodontiitin hoidon yleisterveydellisistä hyödyistä osoittaa, että sillä voidaan aikaansaada esimerkiksi parempi tyypin 2 diabeteksen hoitotasapaino tai matalampi verenpaine. Lääkärille näkyviä merkkejä suun tulehdussairauksista voivat olla pitkälle edennyt hammaspuutos, punoittavat ja turvonneet ikenet tai hampaisiin kertynyt plakki. Tällöin kannattaa muistuttaa potilasta säännöllisten hammaslääkärin tarkastusten tärkeydestä.Peer reviewe

Ientulehdus ja parodontiitti terveysriskinä

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Periodontitis and cardiometabolic disorders : The role of lipopolysaccharide and endotoxemia

Lipopolysaccharide is a virulence factor of gram-negative bacteria with a crucial importance to the bacterial surface integrity. From the host's perspective, lipopolysaccharide plays a role in both local and systemic inflammation, activates both innate and adaptive immunity, and can trigger inflammation either directly (as a microbe-associated molecular pattern) or indirectly (by inducing the generation of nonmicrobial, danger-associated molecular patterns). Translocation of lipopolysaccharide into the circulation causes endotoxemia, which is typically measured as the biological activity of lipopolysaccharide to induce coagulation of an aqueous extract of blood cells of the assay. Apparently healthy subjects have a low circulating lipopolysaccharide activity, since it is neutralized and cleared rapidly. However, chronic endotoxemia is involved in the pathogenesis of many inflammation-driven conditions, especially cardiometabolic disorders. These include atherosclerotic cardiovascular diseases, obesity, liver diseases, diabetes, and metabolic syndrome, where endotoxemia has been recognized as a risk factor. The main source of endotoxemia is thought to be the gut microbiota. However, the oral dysbiosis in periodontitis, which is typically enriched with gram-negative bacterial species, may also contribute to endotoxemia. As endotoxemia is associated with an increased risk of cardiometabolic disorders, lipopolysaccharide could be considered as a molecular link between periodontal microbiota and cardiometabolic diseases.Peer reviewe

Introduced populations of the garden lupine are adapted to local generalist snails but have lost alkaloid diversity

Intraspecific variation in growth and defence among plant populations can be driven by differences in (a)biotic conditions, such as herbivory and resources. Introduction of species to novel environments affects simultaneously herbivory encountered by a plant and resource availability both directly and via altered competitive environment. Here, we address the question of how growth (leaf mass per area (LMA), plant size) and resistance traits (leaf alkaloids, leaf trichomes, resistance to a generalist snail) vary and covary between native and introduced populations of the garden lupine, Lupinus polyphyllus. We focused specifically on evolved differences among populations by measuring traits from plants grown from seed in a common environment. Plants from the introduced populations were more resistant against the generalist snail, Arianta arbustorum, and they had more leaf trichomes and higher LMA than plants from the native populations. The composition of alkaloids differed between native and introduced populations, with the native populations having more diversity in alkaloids among them. Resistance was positively associated with plant size and LMA across all populations. Other trait associations differed between native and introduced areas, implying that certain trade-offs may be fundamentally different between native and introduced populations. Our results suggest that, for the introduced populations, the loss of native herbivores and the alterations in resource availability have led to a lower diversity in leaf alkaloids among populations and may facilitate the evolution of novel trait optima without compensatory trade-offs. Such phytochemical similarity among introduced populations provides novel insights into mechanisms promoting successful plant invasions

Common complement factor H polymorphisms are linked with periodontitis in elderly patients

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Endotoxemia is associated with an adverse metabolic profile

Our aim was to analyze whether endotoxemia, i.e. translocation of LPS to circulation, is reflected in the serum metabolic profile in a general population and in participants with cardiometabolic disorders. We investigated three Finnish cohorts separately and in a meta-analysis (n = 7178), namely population-based FINRISK97, FinnTwin16 consisting of young adult twins, and Parogene, a random cohort of cardiac patients. Endotoxemia was determined as serum LPS activity and metabolome by an NMR platform. Potential effects of body mass index (BMI), smoking, metabolic syndrome (MetS), and coronary heart disease (CHD) status were considered. Endotoxemia was directly associated with concentrations of VLDL, IDL, LDL, and small HDL lipoproteins, VLDL particle diameter, total fatty acids (FA), glycoprotein acetyls (GlycA), aromatic and branched-chain amino acids, and Glc, and inversely associated with concentration of large HDL, diameters of LDL and HDL, as well as unsaturation degree of FAs. Some of these disadvantageous associations were significantly stronger in smokers and subjects with high BMI, but did not differ between participants with different CHD status. In participants with MetS, however, the associations of endotoxemia with FA parameters and GlycA were particularly strong. The metabolic profile in endotoxemia appears highly adverse, involving several inflammatory characters and risk factors for cardiometabolic disorders.Peer reviewe

Increasing self–other similarity modulates ethnic bias in sensorimotor resonance to others’ pain

The tendency to simulate the pain of others within our own sensorimotor systems is a vital component of empathy. However, this sensorimotor resonance is modulated by a multitude of social factors including similarity in bodily appearance, e.g. skin colour. The current study investigated whether increasing self–other similarity via virtual transfer to another colour body reduced ingroup bias in sensorimotor resonance. A sample of 58 white participants was momentarily transferred to either a black or a white body using virtual reality technology. We then employed electroencephalography to examine event-related desynchronization (ERD) in the sensorimotor beta (13–23 Hz) oscillations while they viewed black, white and violet photorealistic virtual agents being touched with a noxious or soft object. While the noxious treatment of a violet agent did not increase beta ERD, amplified beta ERD in response to black agent’s noxious vs soft treatment was found in perceivers transferred to a black body. Transfer to the white body dismissed the effect. Further exploratory analysis implied that the pain-related beta ERD occurred only when the agent and the participant were of the same colour. The results suggest that even short-lasting changes in bodily resemblance can modulate sensorimotor resonance to others’ perceived pain.Peer reviewe

Anti-epileptic drugs and prostate cancer-specific mortality compared to non-users of anti-epileptic drugs in the Finnish Randomized Study of Screening for Prostate Cancer

Background Drugs with histone deacetylase inhibitory (HDACi) properties have shown to decrease prostate cancer (PCa) cell growth in vitro. Methods A cohort of 9261 PCa cases from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) was used to evaluate prostate cancer-specific mortality in men using anti-epileptic drugs (AEDs). A national subscription database was used to obtain information on medication use. Cox regression with AED use as a time-dependent variable was used to analyse prostate cancer mortality in men using AEDs compared to non-users, and in men using HDACi AEDs compared to users of other AEDs. The analysis was adjusted for age, screening trial arm, PCa risk group, primary treatment of PCa, Charlson co-morbidity score and concomitant use of other drugs. Results The use of AEDs, in general, was associated with an increased risk of PCa death. The use of HDACi AEDs was not significantly associated with decreased PCa mortality compared to use of other AEDs (HR 0.61, 95% CI 0.31-1.23). Conclusions AED usage is associated with elevated PCa mortality compared to non-users, likely reflecting the differences between men with epilepsy and those without. No benefit was observed from HDACi drugs compared to other AEDs.Peer reviewe