Molecular effect of an OPTN common variant associated to Paget's disease of bone

Paget's disease of bone (PDB) is a chronic bone disorder and although genetic factors appear to play an important role in its pathogenesis, to date PDB causing mutations were identified only in the Sequestosome 1 (SQSTM1) gene at the PDB3 locus. PDB6 locus, also previously linked to PDB, contains several candidate genes for metabolic bone diseases. We focused our analysis in the most significantly associated variant with PDB, within the Optineurin (OPTN) gene, i.e. the common variant rs1561570. Although it was previously shown to be strongly associated with PDB in several populations, its contribution to PDB pathogenesis remains unclear. In this study we have shown that rs1561570 may contribute to PDB since its Tallele results in the loss of a methylation site in patients' DNA, leading to higher levels of OPTN gene expression and a corresponding increase in protein levels in patients' osteoclasts. This increase in OPTN expression leads to higher levels of NF-KB translocation into the nucleus and increasing expression of its target genes, which may contribute to the overactivity of osteoclasts observed in PDB. We also reported a tendency for a more severe clinical phenotype in the presence of a haplotype containing the rs1561570 T allele, which appear to be re-enforced with the presence of the SQSTM1/P392L mutation. In conclusion, our work provides novel insight towards understanding the functional effects of this variant, located in OPTN intron 7, and its implication in the contribution to PDB pathogenesis.national funds from Foundation for Science and Technology (FCT) [UID/Multi/04326/2013]; Canadian Institutes for Health Research, Canada [MOP130457]; CHU de Quebec Foundation; Canadian Foundation for Innovation; Fonds de recherche du Quebec-sante; Laval University; CHU de Quebec-Universite Laval Research Centre; FCT [SFRH/BD/77227/2011, SFRH/BPD/111898/2015]; Fonds de recherche Quebec-Sante (FRQ-S), Quebec, Canad

High bone mass in adults

International audienceA finding of high bone mineral density (BMD) from routine dual-energy X-ray absorptiometry (DXA) screening is not uncommon. No consensus exists about the definition of high BMD, and T-score and/or Z-score cutoffs of ≥+2.5 or ≥+4 have been suggested. The many disorders that can result in high BMD are usually classified based on whether the BMD changes are focal vs. generalized or acquired vs. constitutional. In over half the cases, careful interpretation of the DXA report and images identifies the cause as an artefact (e.g., degenerative spinal disease, vascular calcifications, or syndesmophytes) or focal lesion (e.g., sclerotic bone metastasis or Paget's disease). Generalized acquired high BMD may be secondary to a diverse range of disorders such as fluorosis, diffuse bone sclerosis related to renal osteodystrophy, hematological diseases, and hepatitis C. Identification of the cause may require additional investigations such as imaging studies, serum tryptase assay, or serological tests for the hepatitis C virus. Finally, high BMD is a feature of many genetic diseases, most notably osteopetrosis and the disorders caused by mutations in the sclerostin gene SOST (sclerosing bone dysplasia and van Buchem disease) or in the LRP5 gene encoding the low-density lipoprotein receptor-related protein 5 (which is the Wnt co-receptor)

HLA Shared Epitope and ACPA: just a marker or an active player?

Autoantibody production is genetically controlled and anti-citrullinated protein/peptide antibodies (ACPA) are not an exception to the rule. ACPA are highly specific markers of rheumatoid arthritis (RA) and are also associated with a more severe disease course. The production of ACPA is almost invariably observed in HLA-shared epitope (SE) positive patients. The DRB1 alleles sharing SE are those conferring susceptibility to RA. SE alleles behave like immune response genes, controlling both the specificity and the amount of ACPA produced. These data suggest a role of SE in the presentation of citrullinated antigens. The ability of SE alleles to bind selectively citrullinated sequences as compared to the native counterparts has been demonstrated in the case of peptides derived from several joint associated proteins (vimentin, fibrinogen and cartilage intermediate-layer protein). On the contrary, EBV-derived citrullinated peptides do not display a biologically relevant binding to SE alleles even if the immune response to VCPs is under the genetic control of these alleles (namely *0401 and *0404). Thus, the presentation of citrullinated epitopes does not represent the only molecular mechanisms underlying the HLA-DRB1 effect on ACPA production

IRF5 rs2004640‐T allele, the new genetic factor for systemic lupus erythematosus, is not associated with rheumatoid arthritis

International audienceBackground: Recently, a new genetic factor within the interferon regulatory factor 5 (IRF5) gene was demonstrated for systemic lupus erythematosus (SLE) through linkage and association: the rs2004640-T allele. IRF5 is involved in the production of rheumatoid arthritis (RA) cytokines, and SLE already shares with RA one genetic factor within the tyrosine phosphatase PTPN22 gene. Aim: To test the hypothesis that the SLE IRF5 genetic factor could also be shared with RA. Patients and methods: 100 French Caucasian trio families with RA were genotyped and analysed with the transmission disequilibrium test, the frequency comparison of the transmitted and untransmitted alleles, and the genotype relative risk. 97% power was available to detect at least a trend in favour of a factor similar to that reported for SLE. Results: The analysis showed the absence of linkage and association globally and in "autoimmune" RA subsets, with a weak non-significant trend against the IRF5 rs20046470-T allele. Given the robustness of familial-based analysis, this slight negative trend provided strong evidence against even a weaker factor than that reported for SLE. Conclusion: Our results exclude the IRF5 rs2004640-T allele as a major genetic factor for RA in this French Caucasian population

Clinical peripheral enthesitis in the DESIR prospective longitudinal axial spondyloarthritis cohort

Objectives: We aimed to describe the prevalence and characteristics of peripheral enthesitis in recent onset axial spondyloarthritis, estimate the incidence of peripheral enthesitis over time, and determine the factors associated with the presence of peripheral enthesitis. Methods: 708 patients with recent onset axial spondyloarthritis were enrolled in the DESIR cohort ( prospective multi-centre, longitudinal). Data regarding the patients and spondyloarthritis characteristics at baseline with a specific focus on enthesitis and occurrence of peripheral enthesitis were collected during the five years of follow-up. Results: At inclusion, 395 patients (55.8%) reported peripheral enthesitis. The locations were mainly the plantar fascia (53.7%) and the Achilles tendon (38.5%). During the 5-year follow-up period, 109 additional patients developed peripheral enthesitis resulting in an estimated (Kaplan-Meier method) percentage of 71% (95% CI: 68-75). Variables associated with peripheral enthesitis in the univariate analysis were: older age, male gender, absence of HLA B27, MRI sacroiliitis and fulfilled Modified NY criteria, presence of anterior chest wall pain, peripheral arthritis, dactylitis, psoriasis, high BASDAI, BASFI, mean score ASAS-and the use of NSAIDs. Only the history of anterior chest wall pain and of peripheral arthritis were retained in the multivariate analysis (odds ratio (OR)=1.6 [95% confidence interval [1.1-2.3], and OR=2.1 [1.4-3.0], respectively)

ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor

Paget disease of bone (PDB) is a skeletal disorder characterized by focal abnormalities of bone remodeling, which result in enlarged and deformed bones in one or more regions of the skeleton. In some cases, the pagetic tissue undergoes neoplastic transformation, resulting in osteosarcoma and, less frequently, in giant cell tumor of bone (GCT). We performed whole-exome sequencing in a large family with 14 PDB-affected members, four of whom developed GCT at multiple pagetic skeletal sites, and we identified the c.2810C>G (p.Pro937Arg) missense mutation in the zinc finger protein 687 gene (ZNF687). The mutation precisely co-segregated with the clinical phenotype in all affected family members. The sequencing of seven unrelated individuals with GCT associated with PDB (GCT/PDB) identified the same mutation in all individuals, unravelling a founder effect. ZNF687 is highly expressed during osteoclastogenesis and osteoblastogenesis and is dramatically upregulated in the tumor tissue of individuals with GCT/PDB. Interestingly, our preliminary findings showed that ZNF687, indicated as a target gene of the NFkB transcription factor by ChIP-seq analysis, is also upregulated in the peripheral blood of PDB-affected individuals with (n = 5) or without (n = 6) mutations in SQSTM1, encouraging additional studies to investigate its potential role as a biomarker of PDB risk