Matrix metalloproteinases (MMPs), also called matrixins, function in the extracellular environment of cells and degrade both matrix and non-matrix proteins. They play central roles in morphogenesis, wound healing, tissue repair and remodelling in response to injury, e.g. after myocardial infarction, and in progression of diseases such as atheroma, arthritis, cancer and chronic tissue ulcers. They are multi-domain proteins and their activities are regulated by tissue inhibitors of metalloproteinases (TIMPs). This review introduces the members of the MMP family and discusses their domain structure and function, proenyme activation, the mechanism of inhibition by TIMPs and their significance in physiology and pathology.

Structure and function of matrix metalloproteinases and TIMPs

Application of the experimental design of genome-wide association studies (GWASs) is now 10 years old (young), and here we review the remarkable range of discoveries it has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics. We predict the likely discoveries in the next 10 years, when GWASs will be based on millions of samples with array data imputed to a large fully sequenced reference panel and on hundreds of thousands of samples with whole-genome sequencing data.

10 Years of GWAS Discovery: Biology, Function, and Translation

An Expanded View of Complex Traits: From Polygenic to Omnigenic

Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here we analyze a broad set of functional elements, including cell type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits with an average sample size of 73,599. To enable this analysis, we introduce a new method, stratified LD score regression, for partitioning heritability from GWAS summary statistics while accounting for linked markers. This new method is computationally tractable at very large sample sizes and leverages genome-wide information. Our findings include a large enrichment of heritability in conserved regions across many traits, a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers and many cell type-specific enrichments, including significant enrichment of central nervous system cell types in the heritability of body mass index, age at menarche, educational attainment and smoking behavior.

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Partitioning heritability by functional annotation using genome-wide association summary statistics.

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci6 and pathway analyses7, 8, 9—as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes—to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

/pdf/genetics-of-rheumatoid-arthritis-contributes-to-biology-and-4wuv6x8yle.pdf

Genetics of rheumatoid arthritis contributes to biology and drug discovery

Failure to confirm association between SLC22A4 polymorphism and rheumatoid arthritis in a Japanese population

Objective. To analyze sex difference in the effect of smoking on remission proportions in patients with rheumatoid arthritis (RA). Methods. Subjects were Japanese patients with RA who participated in the IORRA survey conducted in April 2011 and reported smoking status. Clinical characteristics, treatment status, and the percentages achieving remission were compared between subjects stratified by sex and smoking status. To confirm the differential effects of sex and smoking status on remission, we used multivariate logistic regression models with the dependent variable as 28-joint Disease Activity Score (DAS28) remission. Results. Among 810 men and 4206 women, 162 (20.0%) and 3173 (75.4%), respectively, were never smokers; 208 (25.7%) and 314 (7.5%), respectively, were current smokers. In men, never smokers tended to have higher remission proportions than past and current smokers. In contrast, smoking status seemed not to affect remission in women. Except for lower corticosteroid dose in male never smokers, no significant differences were observed in comparing treatment status. By multivariate analyses, male past and current smokers were negatively associated with DAS28-erythrocyte sedimentation rate remission compared to male never smokers [OR 0.66 and 0.61, 95% CI (0.44–0.98) and (0.39–0.96), respectively]. However, female past and current smokers were not associated with remission compared to female never smokers [OR 1.04 and 1.19, 95% CI (0.86–1.25) and (0.91–1.54), respectively]. Conclusion. We demonstrated that the effect of smoking on remission proportions differed between men and women. Our findings suggest that both sex and smoking status are important considerations when planning a treatment strategy for patients with RA.

https://www.jrheum.org/content/jrheum/early/2015/03/10/jrheum.140376.full.pdf

Effect of Smoking on Remission Proportions Differs Between Male and Female Patients with Rheumatoid Arthritis: A Study Based on the IORRA Survey

We attempted to determine whether the A1330V polymorphism of the low-density lipoprotein receptor-related protein 5 (LRP5) gene is associated with a risk of self-reported incident fractures and hypercholesterolemia in Japanese patients with rheumatoid arthritis (RA). DNA samples, laboratory data, and clinical data were obtained from 563 female RA patients who participated in the Institute of Rheumatology Rheumatoid Arthritis (IORRA) observational cohort study. A1330V genotyping was performed using a custom TaqMan assay. Multiple logistic regression analyses showed that any incident fracture was significantly associated with older age (P = 0.000000036), high Japanese Health Assessment Questionnaire (J-HAQ) score (P = 0.016), and high daily prednisolone dose (P = 0.031), but not with the A1330V polymorphism, while serum total cholesterol levels ≥220 mg/100 mL were independently correlated with baseline older age (P = 0.00011), low J-HAQ score (P = 0.0098), high body mass index (P = 0.024), 1330VV genotype (P = 0.027), and high daily prednisolone dose (P = 0.031). Our results suggest that this LPR5 polymorphism does not appear to be a clinically useful marker for the prediction of fracture risk in Japanese female RA patients, although it is associated with increased serum total cholesterol levels.

A1330V polymorphism of low-density lipoprotein receptor-related protein 5 gene and self-reported incident fractures in Japanese female patients with rheumatoid arthritis.

Background The purpose of this study was to evaluate the effect of mobile-bearing implant design and activity on knee arthroplasty kinematics during three activities of daily living. Methods In vivo kinematics were analyzed using 3D model registration from fluoroscopic images of non-weightbearing knee flexion-extension, weight-bearing squatting and stair activities in 20 knees in 10 patients with bilateral total knee arthroplasty. Each patient had one rotating-platform and one meniscal-bearing variant of the same prosthesis design. Results Anteroposterior translations in meniscal-bearing knees were larger than those in rotating-platform knees for the different dynamic conditions. Meniscal-bearing knees showed more posterior femoral locations with activities that increased demand on the quadriceps. Condylar translations changed little in rotating-platform knees with different activities. Conclusions Activity dynamics can have a significant influence on knee kinematics, and have a greater effect on the kinematics of unconstrained meniscal-bearing prostheses than rotating-platform knee prostheses. Level of evidence Level II.

Does mobile-bearing knee arthroplasty motion change with activity?

Objectives: To evaluate usage patterns for methotrexate (MTX) and/or glucocorticoids in rheumatoid arthritis (RA) patients receiving biological disease-modifying antirheumatic drugs (bDMARDs) in da...

Reduction of methotrexate and glucocorticoids use after the introduction of biological disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis in daily practice based on the IORRA cohort

Shigeki Momohara

Papers

Failure to confirm association between SLC22A4 polymorphism and rheumatoid arthritis in a Japanese population

Effect of Smoking on Remission Proportions Differs Between Male and Female Patients with Rheumatoid Arthritis: A Study Based on the IORRA Survey

A1330V polymorphism of low-density lipoprotein receptor-related protein 5 gene and self-reported incident fractures in Japanese female patients with rheumatoid arthritis.

Does mobile-bearing knee arthroplasty motion change with activity?

Reduction of methotrexate and glucocorticoids use after the introduction of biological disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis in daily practice based on the IORRA cohort