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.

/pdf/partitioning-heritability-by-functional-annotation-using-13dk84e4b8.pdf

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

Objective Tumor necrosis factor-a inhibitors have been available in recent years for treating early and established rheumatoid arthritis (RA). Twice-weekly administration of 25 mg etanercept (ETN) has demonstrated efficacy and safety. The objective of this study was to evaluate the efficacy of once-weekly administration of 50 mg ETN (ETN50), and to compare it with that of twice-weekly administration of 25 mg ETN (ETN25). Methods The ETN50 group comprised 29 patients and the ETN25 group 26. The analysis compared changes from baseline in Disease Activity Score in 28 joints (DAS28)‐C reactive protein (CRP) and DAS28‐erythrocyte sedimentation rate (ESR) between the ETN50 and ETN25 groups. Results Overall, 42.3 % of ETN50 patients achieved DAS28‐ESR remission (\2.6), and 76.9 % experienced low disease activity at 24 weeks. Patients in the ETN50 group also experienced more significant improvement in DAS28‐ESR at 4 weeks, higher DAS28‐ESR remission rates, and lower disease activity rates than ETN25 group patients. No serious adverse events were experienced in the safety analysis set (ETN50 group). Conclusion These results suggest that ETN50 can lead to earlier remission and higher remission rates compared with ETN25 in patients with RA.

Evaluation of the efficacy and safety of etanercept 50 mg once weekly in Japanese patients with rheumatoid arthritis and comparison with 25 mg etanercept twice weekly

Ulcerative colitis (UC) is commonly associated with peripheral joint disease which correlates with the activity and extent of the inflammatory bowel disorder. They are generally divided into three clinical categories; peripheral arthritis, spondylitis, and sacroiliitis. The arthritis is usually pauciarticular, generally asymmetric, transient, and nondestructive. However, the peripheral arthritis becomes chronic and destructive in some cases. Rheumatoid arthritis has been reported to be seldom associated with UC. Inflammatory joint disease is considered an enteropathic arthritis if the gastrointestinal tract is directly involved in the pathogenesis. The occurrence of rheumatologic manifestations in UC is reviewed in this paper.

Arthritic manifestations in ulcerative colitis

Objectives: This study aimed to identify the prevalence of scoliosis and scoliosis-related factors of rheumatoid arthritis (RA).Methods: In this study, 411 patients who underwent coronal total spine and lower limb radiography were enrolled. Patients with a Cobb angle ≥10° were diagnosed with scoliosis. Statistical analysis was performed to compare between patients with and those without scoliosis, and between patients without scoliosis and those with a Cobb angle >20°.Results: The prevalence of scoliosis in patients with RA was 30.7%. The mean Cobb angles were 8.5° ± 7.2° in all the patients, 16.1° ± 8.6° in patients with scoliosis, and 5.1° ± 2.3° in patients without scoliosis. According to a multivariate analysis, the scoliosis-related factors of RA were age and vertebral fracture. Significant differences in age, corticosteroid use, and malalignment of lower limbs were observed between patients with a Cobb angle >20° and those without scoliosis.Conclusions: With RA treatment, the need for cortic...

Scoliosis-related factors in patients with rheumatoid arthritis: A cross-sectional study

Serine proteinase in articular cartilage, subchondral bone marrow and synovial fluid in human osteoarthritis and rheumatoid arthritis

Behcet's disease is a systemic disease characterized by oral aphta, genital ulcers, and ocular lesions, and arthritic manifestations also appear to be common. However, this disease rarely produces loss of function or deformity in arthritic joints. We report the case of a 52-year-old woman with Behcet's disease who had a history of recurrent oral aphta, genital ulcerations, and intestinal lesions for almost 30 years. When she was about 30 years old, she began to notice significant morning stiffness and polyarthritis, and progressive destructive arthritic changes in the bilateral fingers, wrists, and left ankle. Behcet's disease with severe destructive arthritic changes is rare, and the underlying mechanism is still unknown.

Shigeki Momohara

Papers

Evaluation of the efficacy and safety of etanercept 50 mg once weekly in Japanese patients with rheumatoid arthritis and comparison with 25 mg etanercept twice weekly

Arthritic manifestations in ulcerative colitis

Scoliosis-related factors in patients with rheumatoid arthritis: A cross-sectional study

Serine proteinase in articular cartilage, subchondral bone marrow and synovial fluid in human osteoarthritis and rheumatoid arthritis

Behçet's disease with severe destructive arthritis.