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

Several studies from different countries suggest that the rates of orthopaedic surgery have decreased for patients with rheumatoid arthritis (RA) in recent years. From the Rochester Epidemiology Project, there was a reduction in the overall rates for all types of joint-related surgery inpatients.1 The California State Hospitalization Database for 1983–2001 reported a decrease in the rate of total knee arthroplasty for patients with RA.2 From Scandinavian countries, there was a decrease of RA-related surgical procedures to the lower limbs in Swedish patients between 1987 and 2001,3 from Denmark a decrease in the incidence rate of total hip arthroplasties due to RA was reported,4 …

https://ard.bmj.com/content/annrheumdis/68/2/291.full.pdf

Declining use of synovectomy surgery for patients with rheumatoid arthritis in Japan.

Objectives: Rheumatoid arthritis (RA) is the most common immune-related inflammatory arthritis affecting 0.5–1.0% of the population. Both genetic and environmental factors are associated with RA onset. Twin studies reported from European countries estimated heritability of RA as 53–65%. However, no twin studies have been reported from Asian countries.Methods: We collected a total of 43 monozygotic and 43 dizygotic twins from 7550 patients with RA and obtained information of RA status in the twin pairs. We characterized RA patients whose twin siblings had RA. Variance components analysis was performed to estimate heritability in RA in the Japanese population.Results: Four and one patients with RA over 43 monozygotic (9.3%) and 43 dizygotic twins (2.3%), respectively, had twin siblings with RA. All the patients whose information of sero-positivity was available and whose twin siblings had RA were sero-positive. Heritability of RA was estimated as 62.2% and 56.1% in the AE and ACE models, respectivel...

A twin study of rheumatoid arthritis in the Japanese population

The aim of this study was to investigate determinants of reduced bone mineral density (BMD) in postmenopausal women with active rheumatoid arthritis (RA) and to evaluate whether there are common markers of bone loss. We evaluated BMD of the femoral neck using dual-energy X-ray absorptiometry, and the measured biochemical markers included serum bone-specific alkaline phosphatase (BALP), serum osteocalcin (OC), and serum cross-linked N-telopeptidases of type I collagen (NTx). Serum BALP and NTx concentrations were measured by enzyme-linked immunsorbent assay, and OC was measured using an immunoradiometric assay. One hundred and forty postmenopausal Japanese women who had not received treatment with bisphosphonates or hormone replacement therapy were entered into the study. Thirty-four patients (41.0%) had femoral osteopenia (T score −1 to −2.5) and 23 patients (27.7%) had osteoporosis (T < −2.5). The body mass index of patients with normal BMD (T score ≥ −1.0) was significantly higher (P < 0.01) than in patients with osteoporosis at the femoral neck. The T score exhibited a significant negative correlation with age and the duration of RA disease. Serum BALP and serum OC, markers of osteoblast function, were negatively related to erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and matrix metalloproteinase-3 (MMP-3). However, serum NTx, a marker of resorptive function, exhibited a positive correlation with ESR, CRP, and MMP-3. From these results, this study suggests that generalized bone loss occurs in active RA and is characterized by evidence of bone resorption that is correlated with the high levels of inflammation. Body mass index, disease duration, and high serum NTx level were common risk factors in osteoporosis of postmenopausal women with RA.

The study of bone mineral density and bone turnover markers in postmenopausal women with active rheumatoid arthritis

Following online first publication, the authors notified the editor that the legend of Figure 1b was written incorrectly: “Of all patients being treated for RA” should read “Of all patients diagnos

ErratumCorrection to: Estimates of the prevalence of and current treatment practices for rheumatoid arthritis in Japan using reimbursement data from health insurance societies and the IORRA cohort (I)

Matrix metalloproteinase 28/epilysin expression in cartilage from patients with rheumatoid arthritis and osteoarthritis: Comment on the article by Kevorkian et al

Shigeki Momohara

Papers

Declining use of synovectomy surgery for patients with rheumatoid arthritis in Japan.

A twin study of rheumatoid arthritis in the Japanese population

The study of bone mineral density and bone turnover markers in postmenopausal women with active rheumatoid arthritis

ErratumCorrection to: Estimates of the prevalence of and current treatment practices for rheumatoid arthritis in Japan using reimbursement data from health insurance societies and the IORRA cohort (I)

Matrix metalloproteinase 28/epilysin expression in cartilage from patients with rheumatoid arthritis and osteoarthritis: Comment on the article by Kevorkian et al