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Resume La maladie de Dupuytren (MDD) est une fibrose progressive de l’aponevrose palmaire caracterisee par la formation d’un nodule palmaire evoluant vers une corde. La MDD est la plus frequente maladie hereditaire du tissu conjonctif affectant preferentiellement les caucasoides originaires d’Europe du Nord. Certains facteurs environnementaux sont associes a la MDD, notamment la consommation d’alcool, de tabac et possiblement les activites manuelles. Le diabete et l’epilepsie constituent les associations pathologiques les plus frequemment rapportees. Le mode de transmission genetique de la MDD demeure mal connu et semble heterogene : le plus souvent autosomique dominant avec une penetrance variable et rarement, autosomique recessif ou maternel (matrilineaire) evoquant une heredite mitochondriale. Tout d’abord, une suggestion de liaison avec le locus DUPC1 en 16q a ete mise en evidence. Ensuite, parmi les variations genomiques dans la MDD, ont ete rapportees une alteration du nombre de copies des genes dans les regions chromosomiques 10q22, 16p12.1 et 17p12, une association avec l’allele HLA-DRB1*15 et une mutation dans le gene de l’ARNr 16S, observee dans les formes avec heredite matrilineaire. Enfin, une etude pangenomique a montre une association genetique de la MDD avec les chromosomes 6, 11 et 16. La physiopathologie de la MDD implique principalement les myofibroblastes et la matrice extracellulaire de collagene. Les etudes d’expression genique et proteique ont confirme le role central des voies de la β-catenine et du TGFβ dans la pathogenie de la MDD.

Genetic factors contribute to the development of digital osteoarthritis, whose heritability has been estimated at 48 to 65%. Among the manifestations of digital osteoarthritis, only Heberden's nodes are transmitted by Mendelian inheritance, as a dominant trait in women and a recessive trait in men. The other forms of digital osteoarthritis are multifactorial, with a major gene and a residual multifactorial component that probably interacts with environmental factors. Hindrances to molecular studies include the absence to date of a universally accepted definition of the phenotype and the late onset of the manifestations. Genetic association studies of selected class I and II HLA genes produced conflicting results. The T303M polymorphism of the MATN3 gene, which was initially described as associated with hand osteoarthritis, may be more closely linked to trapeziometacarpal osteoarthritis than to digital osteoarthritis. Genome-wide scans have identified numerous loci linked to digital osteoarthritis. Replication has been achieved for some of these loci, most notably those located at 2p, 2q, 3p, 4q, and 7p. A recently published genome-wide association study showed that an A2BP1 gene polymorphism was significantly associated with hand osteoarthritis. Many candidate-gene studies found associations with AGC1, ASPN, ENPP1, HFE, KL, VDR, IL-1 cluster, and IL-6, although the results were not consistently reproducible. In one study, women with hand osteoarthritis had significant telomere shortening. Telomere shortening has also been reported in other age-related conditions.

Resume Il existe une certaine composante genetique dans l’arthrose digitale avec une heritabilite estimee entre 48 et 65 %. Seuls les nodules d’Heberden sont transmis sur un mode mendelien, dominant chez les femmes et recessif chez les hommes. Les autres formes d’arthrose digitale sont multifactorielles avec un gene majeur et un composant residuel multifactoriel en interaction avec de probables facteurs environnementaux. Les etudes moleculaires s’averent complexes en raison de difficultes a definir un phenotype consensuel et de la revelation tardive du phenotype. Les etudes d’association avec certains genes du HLA de classes I et II demeurent contradictoires. Le polymorphisme T303 M du gene MATN3, initialement associe a l’arthrose de la main, semblerait finalement etre plus associe a la rhizarthrose qu’a l’arthrose digitale. Les criblages du genome entier ont montre une liaison de nombreux locus avec l’arthrose digitale. Certains de ces locus, notamment ceux situes en 2p, 2q, 3p, 4q et 7p, ont ete repliques avec succes. Une large etude d’association a l’echelle du genome entier vient d’etre publiee, montrant une association significative d’un polymorphisme du gene A2BP1 avec l’arthrose de la main. De nombreuses etudes de genes candidats ont rapporte des associations, pas toujours repliquees, avec les genes AGC1, ASPN, ENPP1, HFE, KL, VDR, le cluster de l’IL-1 et le gene de l’IL-6. Enfin, une etude a rapporte une diminution significative de la longueur des telomeres chez des femmes atteintes d’arthrose de la main. Des observations similaires sur la longueur des telomeres ont ete rapportees dans d’autres pathologies liees au vieillissement.

Summary Paget's disease (PD) is characterized by abnormal osteoclasts (OCL) that secrete high IL-6 levels and induce exuberant bone formation. Because measles virus nucleocapsid gene (MVNP) and the p62 P392L mutation are implicated in PD, marrows from 12 PD patients harboring p62 P392L and eight normals were tested for MVNP expression and pagetic OCL formation. Eight out of twelve patients expressed MVNP and formed pagetic OCL in vitro, which were inhibited by antisense-MVNP. Four out of twelve patients lacked MVNP and formed normal OCL that were hyperresponsive to RANKL but unaffected by antisense-MVNP. Similarly, mice expressing only p62 P394L formed normal OCL, while mice expressing MVNP in OCL, with or without p62 P394L , developed pagetic OCL and expressed high IL-6 levels dependent on p38MAPK activation. IL-6 deficiency in MVNP mice abrogated pagetic OCL development in vitro. Mice coexpressing MVNP and p62 P394L developed dramatic Paget's-like bone lesions. These results suggest that p62 P394L and IL-6 induction by MVNP play key roles in PD.

Resume L’identification d’un nombre croissant de facteurs genetiques dans les maladies articulaires et osseuses conduit legitimement a se questionner sur l’utilite clinique de ces nouvelles informations. La consultation de genetique permet de diagnostiquer une affection genetique et d’evaluer les risques d’avoir une maladie genetique, et/ou d’en transmettre les genes de predisposition. Chez l’adulte, la consultation de genetique est le plus souvent realisee a visee diagnostique chez un individu symptomatique, ou a visee de diagnostic de predisposition chez un individu indemne ayant des antecedents familiaux d’affection genetique. A la difference des autres consultations specialisees, la consultation de genetique presente de nombreuses specificites, notamment la duree prolongee de la consultation afin de reconstituer l’histoire detaillee de la maladie presente dans la famille et d’en predire le risque de transmission dans la famille lors du conseil genetique, et la prise en charge pluridisciplinaire. En fonction du caractere genetique ou non de l’affection, du risque estime par le conseil genetique et communique au patient, du risque percu et compris par le patient et de l’existence d’un test genetique ayant une utilite clinique, un test genetique peut etre propose. En France, les tests genetiques a visee diagnostique chez un individu atteint peuvent etre prescrits, apres recueil d’un consentement specifique, par un geneticien ou un medecin specialiste connaissant bien les aspects genetiques, alors que les tests a visee predictive chez les apparentes indemnes, dans le but d’offrir une meilleure prise en charge preventive et/ou therapeutique, doivent etre conduits dans le cadre d’une consultation de genetique.

Resume La deacetylation des histones, la methylation de l’ADN et les microARN sont les trois principaux mecanismes epigenetiques de regulation de l’expression des genes. Cette modulation epigenetique permet de reguler finement toutes les etapes physiologiques du remodelage osseux. Dans cette mise au point, sont abordes les principaux types de modifications epigenetiques dans les maladies osseuses non tumorales et tumorales, en accordant une large part aux microARN. Ces differents mecanismes regulateurs de l’expression des genes seront illustres dans les maladies osseuses les plus frequentes en s’appuyant sur la litterature la plus recente dans ce domaine. Dans les maladies osseuses multifactorielles comme l’osteoporose, de nombreux biomarqueurs epigenetiques, seuls ou en combinaison, ont ete associes avec la densite minerale osseuse ou comme predicteurs des fractures osteoporotiques. De plus, des agents therapeutiques visant a moduler le remodelage osseux en ciblant selectivement la fonction de certains microARN sont aussi a l’etude. Dans les autres maladies osseuses non tumorales, y compris dans les maladies osseuses d’origine genetique et transmises sur un mode mendelien, une meilleure connaissance de leur regulation epigenetique permet de mieux en comprendre la physiopathologie. Enfin, dans les tumeurs osseuses primitives comme dans les metastases osseuses, de nombreuses avancees ont ete realisees ces dernieres annees dans la comprehension de la regulation epigenetique de l’oncogenese et ses liens avec le tissu osseux localement. Ces nouvelles donnees pourraient conduire au developpement de biomarqueurs epigenetiques pronostiques tres en demande dans ces affections, mais aussi d’agents therapeutiques novateurs via la modulation des microARN.

Paget's disease of bone (PDB) is a common metabolic bone disorder with a significant genetic component. To date, only one gene associated with PDB has been identified, the p62-Sequestosome1 gene (SQSTM1), and more than 20 mutations of this gene have been reported in PDB, the most common being the P392L substitution. In order to search for differentially expressed genes in PDB, we investigated the relative gene expression profile of candidate genes in osteoclast (OCL) cultures from 12 PDB patients and six unmatched healthy controls with known genetic status regarding p62, including healthy carriers of the P392L mutation. We selected 48 OCL-expressed candidate genes that may be involved in relevant pathways of PDB pathogenesis, such as OCL signaling, survival, bone resorption activity, or adhesion. In OCL cultures derived from peripheral blood mononuclear cells, total RNA extraction was performed, followed by real-time PCR experiments. Relative quantification analysis utilized the qBase method where relative expression levels were normalized with respect to a set of reference primer pairs for three housekeeping genes. When compared to non-mutated healthy controls, OCL cultures from PDB patients displayed a significant down-regulation in genes involved in apoptosis (CASP3 and TNFRSF10A), in cell signaling (TNFRSF11A), in the OCL bone resorbing function (ACP5 and CTSK) and in the gene coding for Tau protein (MAPT) (all comparisons, p

Contains fulltext : 71178.pdf (Publisher’s version ) (Closed access) OBJECTIVE: We recently showed, using a candidate gene approach in a case-control association study, that a 65-kb block encompassing tumor necrosis factor receptor-associated factor 1 (TRAF1) and C5 is strongly associated with rheumatoid arthritis (RA). Compared with case-control association studies, family-based studies have the added advantage of controlling potential differences in population structure and are not likely to be hampered by variation in population allele frequencies, as is seen for many genetic polymorphisms, including the TRAF1/C5 locus. The aim of this study was to confirm this association in populations of European origin by using a family-based approach. METHODS: A total of 1,356 western European white individuals from 452 "trio" families were genotyped for the rs10818488 polymorphism, using the TaqMan allelic discrimination assay. RESULTS: We observed evidence for association, demonstrating departure from Mendel's law, with an overtransmission of the rs10818488 A allele (A = 55%; P = 0.036). By taking into consideration parental phenotypes, we also observed an increased A allele frequency in affected versus unaffected parents (A = 64%; combined P = 0.015). Individuals carrying the A allele had a 1.2-fold increased risk of developing RA (allelic odds ratio 1.24, 95% confidence interval 1.04-1.50). CONCLUSION: Using a family-based study that is robust against population stratification, we provide evidence for the association of the TRAF1/C5 rs10818488 A allele and RA in populations of European descent, further substantiating our previous findings. Future functional studies should yield insight into the biologic relevance of this locus to the pathways involved in RA.

Morbidity in Paget’s disease of bone (PDB), mostly related to skeletal and nonskeletal complications, results in an impairment of quality of life. The focal increases in bone turnover which characterizes PDB largely explain the pathogenesis of mechanical, vascular, and metabolic complications. The relative risk of mortality of patients with PDB was found to be increased in England and Wales, but not in the population-based inception cohort of Olmsted County (Minnesota, USA), the three most frequent causes of death being diseases of the circulatory system, cancers, and diseases of the respiratory system. Pain in pagetic bone is the only symptom of PDB for which there is firm evidence that therapy confers a clinical benefit, whereas pharmacological treatment to prevent future complications, such as osteoarthritis, fracture, or neurological complications, is more controversial. The most common complications of PDB are bone pain, bone deformity, fracture, neurological complications, headache, hearing loss, and osteoarthritis.

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.

Paget's disease of bone (PDB) manifests fairly late in life and currently affects up to 3% of individuals older than 55 years of age. An about 60% decline in the prevalence of PDB between 1970 and 1990 was documented in England, particularly in Lancashire, where the disease was initially most common. Although wide regional variations exist, the overall prevalence is decreasing, as confirmed by a recent meta-analysis. This secular decline is associated with a decrease in mortality due to the disappearance of sarcomatous transformation of PDB lesions. Another reported change is a decrease in the severity of the clinical PDB phenotype, with a gradual increase in the age at diagnosis of 4 years per decade. In familial forms related to an SQSTM1 mutation, the first manifestations are detected about 10 years later from one generation to the next, and the disease is less severe, with smaller elevations in serum alkaline phosphatase levels and less extensive lesions. Although incompletely understood, the reasons for these changes might involve environmental factors such as the correction of childhood deficiencies in calcium and/or vitamin D, a less rural lifestyle, and decreased contact with domestic animals and consumption of bovine organ meats during childhood. Childhood exposure to industrial waste and products of combustion has also been incriminated. Finally, although classical, the role for paramyxoviruses such as the measles virus in the pathogenesis of PDB remains debated in the literature.

Osteoimmunology represents a large area of research resulting from the cross talk between bone and immune systems. Many cytokines and signaling cascades are involved in the field of osteoimmunology, originating from various cell types. The RANK/receptor activator of nuclear factor Kappa-B ligand (RANKL)/osteoprotegerin (OPG) signaling has a pivotal role in osteoimmunology, in addition to proinflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1, IL-6, and IL-17. Clinically, osteoimmunological disorders, such as rheumatoid arthritis, osteoporosis, and periodontitis, should be classified according to their pattern of osteoimmunological serum biomarkers. Paget’s disease of bone is a common metabolic bone disorder, resulting from an excessively increased bone resorption coupled with aberrant bone formation. With the exception of the cellular responses to measles virus nucleocapsid protein and the interferon-gamma signature, the exact role of the immune system in Paget’s disease of bone is not well understood. The cytokine profiles, such as the increased levels of IL-6 and the interferon-gamma signature observed in this disease, are also very similar to those observed in other osteoimmunological disorders. As a potential osteoimmunological disorder, the treatment of Paget’s disease of bone may also benefit from progress made in targeted therapies, in particular for receptor activator of nuclear factor Kappa-B ligand and IL-6 signaling inhibition.

Atypical femur fractures (AFF) arise in the subtrochanteric and diaphyseal regions. Because of this unique distribution, we hypothesized that patients with AFF demonstrate specific geometrical variations of their lower limb whereby baseline tensile forces applied to the lateral cortex are higher and might favor the appearance of these rare stress fractures, when exposed to bisphosphonates. Using the low irradiation 2D-3D X-ray scanner EOS™ imaging technology we aimed to characterize and compare femur geometric parameters between women who sustained bisphosphonate-associated AFF and those who had experienced similar duration of exposure to bisphosphonates but did not sustain fractures. Conditional logistic regression models were constructed to estimate the association between selected geometric parameters and the occurrence of AFF. We identified 16 Caucasian women with AFF and recruited 16 ethnicity-, sex-, age-, height- and cumulative bisphosphonate exposure-matched controls from local osteoporosis clinics. Compared to controls, those with AFF had more lateral femur bowing (-3.2° SD [3.4] versus -0.8° SD [1.9] p=0.02). In regression analysis, lateral femur bowing was associated with the risk of AFF (aOR 1.54; 95% CI 1.04-2.28, p=0.03). Women who sustained a subtrochanteric AFF demonstrated a lesser femoral neck shaft angle (varus geometry) than those with a fracture at a diaphyseal site (121.9 [3.6]° versus 127.6 [7.2]°, p=0.07), whereas femur bowing was more prominent in those with a diaphyseal fracture compared to those with a subtrochanteric fracture (-4.3 [3.2]° versus -0.9 [2.7]°, p=0.07). Our analyses support that subjects with AFF exhibit femoral geometry parameters that result in higher tensile mechanical load on the lateral femur. This may play a critical role in the pathogenesis of AFF and requires further evaluation in a larger size population.

Resume La maladie de Paget est une maladie osseuse chronique touchant 3 % de la population caucasienne apres 55 ans. La cause de cette pathologie reste inconnue, mais une contribution genetique est demontree dans certaines formes familiales. Ces formes suivent un mode de transmission autosomique dominant avec penetrance incomplete. Une heterogeneite genetique est demontree avec huit loci decrits. Un premier gene est connu, Sequestosome1 (SQSTM1), situe sur le bras long du chromosome 5 (5q35-qter). Neuf mutations de ce gene ont deja ete rapportees dans la maladie de Paget. Ces mutations siegent dans les exons 7 et 8 du gene, codant pour le domaine tres conserve de liaison a l'ubiquitine. Le test genetique des mutations de SQSTM1 est recommande chez les patients atteints de maladie de Paget. Vu la frequence des formes cliniquement asymptomatiques, la notion familiale fait souvent defaut chez les patients porteurs d'une mutation, si bien que le test est recommande y compris en l'absence d'antecedents familiaux de maladie de Paget. L'identification des patients porteurs d'une mutation de SQSTM1 (pres de 10 % en France) permet de proposer un conseil genetique chez les apparentes en vue d'un depistage precoce de la maladie chez les porteurs, dans le but de leur eviter la revelation de la maladie de Paget par une complication.

International audience; Vitamin D is a potent regulator of calcium homeostasis and may have immunomodulatory effects. The influence of vitamin D on human autoimmune disease is controversial. The aim of this study was to investigate the role of vitamin D receptor gene (VDR) in rheumatoid arthritis (RA). Three polymorphisms for VDR gene FokI T\backslashtextgreaterC (rs 10735810), BsmI A\backslashtextgreaterG (rs 1544410) and TaqI C\backslashtextgreaterT (rs 731236) were genotyped in 100 RA French nuclear families (set 1) and 100 additional French nuclear families for replication (set 2). The association analysis was performed using comparison of alleles frequencies (AFBAC), transmission disequilibrium test and genotype relative risk. Our results revealed a significant difference of F allele of FokI polymorphism between transmitted and nontransmitted frequencies (P = 0.01) in set 1. Furthermore, the F/F genotype was more frequent in RA patients compared to controls (P = 0.01) in set 1. The replication in set 2 showed similar patterns of transmission with a nonsignificant association. Association with FokI was found to be significant when the two sets were combined (P = 0.006). These data suggest that the F allele and F/F VDR genotype are associated with RA. The mechanisms by which distinct receptor variants might confer disease susceptibility remain to be elucidated. © 2005 Nature Publishing Group. All rights reserved.

International audience; Objective. The shared epitope hypothesis was formulated to explain the involvement of HLA-DRB1 in rheumatoid arthritis (RA). However, several studies, which considered only the HLA-DRB1 alleles shown to be associated with RA risk, rejected this hypothesis. In this report, we propose that a different classification of HLA-DRB1 alleles be considered, based on the amino acid sequence at position 70-74. Methods. The fit of both HLA-DRB1 classifications was tested in 2 groups of RA patients. All subjects were recruited through the European Consortium on Rheumatoid Arthritis Families, and included 100 patients with isolated RA and 132 patients with at least 1 affected sibling. Results. The new classification produced risk estimates that fit all of the observed data, i.e., the distribution of the HLA-DRB1 genotype in the 2 patient groups, and the distribution of parental alleles shared by affected sibpairs. The risk of developing RA under this new classification depends on whether the RAA sequence occupies position 72-74 but is modulated by the amino acid at position 71 (K confers the highest risk, R an intermediate risk, A and E a lower risk) and by the amino acid at position 70 (Q or R confers a higher risk than D). Conclusion. A new classification based on amino acid sequence allows us to show that the shared epitope RAA sequence at position 72-74 explains the data, with the risk of developing RA modulated by the amino acids at positions 70 and 71. © 2005, American College of Rheumatology.

Objective Rheumatoid arthritis (RA) is a heterogeneous disease that exhibits a complex genetic component. Previous RA genome scans confirmed the involvement of the HLA region and generated data on suggestive signals at non-HLA regions, albeit with few overlaps in findings between studies. The present study was undertaken to detect potential RA gene regions and to estimate the number of true RA gene regions, taking into account the heterogeneity of RA, through performance of a dense genome scan. Methods In a study of 88 French Caucasian families (105 RA sibpairs), 1,088 microsatellite markers were genotyped (3.3-cM genome scan), and a multipoint model-free linkage analysis was performed. The statistical assessment of the results relied on 10,000 computer simulations. A covariate-based multipoint model-free linkage analysis was performed on the locations of regions with suggestive evidence for linkage. Results Involvement of the HLA region was strongly confirmed (P = 6 × 10−5), and 19 non-HLA regions showed suggestive evidence for linkage (P < 0.05); 9 of these overlapped with regions suggested in other published RA genome scans. A routine 12-cM genome scan with the same families would have detected only 7 of the 19 regions, including only 4 of the 9 overlapping regions. From the 10,000 computer simulations, we estimated that 8 ± 4 regions (mean ± SD) were true-positives. RA covariate–based analysis provided additional linkage evidence for 3 regions, with age at disease onset, erosions, and HLA–DRB1 shared epitope as covariates. Conclusion The results of this study provide evidence of 19 non-HLA RA gene regions, with an estimate of 8 ± 4 as true-positives, and provide additional evidence for 3 regions from covariate-based analysis.

Paget's disease of bone is characterized by an anarchic bone remodelling, associated with morphological and functional abnormalities of osteoclasts. Its prevalence and incidence rates decreased gradually over the past two decades; the reason for this remains unclear. The aetiology of the disease is still obscure, the paramyxoviral theory being very controversial. Recent advances in understanding of the disease come from genetic studies, with the identification of specific mutations in the p62-sequestosome gene, which could be involved in pathogenetic mechanisms leading to increased osteoclast activity. The disease affects one or several bone pieces, leading to bone pain, deformities, characteristic imaging features, and increased markers of bone remodelling. The long-lasting disease activity leads to complications, including arthropathies, neurological compressions, fissures or fractures and, rarely, osteosarcomatous transformation of a pagetic lesion. Potent bisphosphonates have proven their efficacy in reducing symptoms and disease activity. They are currently used as the first-line treatment with the goal of normalizing bone remodelling and, hopefully, preventing late complications.

Introduction Les biphosphonates previennent les fractures osteoporotiques en inhibant la resorption osseuse. Leur utilisation a long terme a, cependant, ete associee a des fractures femorales dites « atypique ». Chez les patients ayant subi des arthroplasties de hanche ou de genou, la prevalence de ces fractures et les facteurs de risque associes sont inconnus. L’objectif de cette etude est de determiner la proportion des fractures femorales periprothetiques atypiques chez les patients avec arthroplasties de hanche et de genou et d’etablir les facteurs de risque cliniques et radiologiques associes a ce type de fracture. Materiel et methodes Les dossiers des patients ayant subi une fracture periprothetiques femorale entre le 1 er janvier 2006 et le 31 mars 2015 dans notre CHU ont ete revises. L’analyse radiologique a permis de confirmer les fractures atypiques periprothetiques selon les criteres majeurs de l’ASBMR et d’etablir leur prevalence. Des mesures biometriques radiologiques ainsi que les donnees cliniques pertinentes au dossier medical ont ete comparees par des analyses statistiques bivariees. Resultats La prevalence des fractures periprothetiques femorales atypiques est de 8,3 % (11/122). On observe une association entre les fractures periprothetiques atypiques et la prise de bisphosphonates ( p = 0,0072), un prodrome douloureux ( p = 0,0329), la presence d’une reaction periostee ( p p p = 0,0003) augmentees au site de fracture ainsi qu’une augmentation de l’epaisseur corticale laterale diaphysaire ( p = 0,0461). Le type d’implant, son positionnement et la geometrie femorale semblent pas etre des facteurs de risque de fractures femorales periprothetiques atypiques. Discussion Les fractures atypiques periprothetiques femorales s’averent une problematique considerable quoique leur potentiel de guerison demeure meconnu. On retrouve une association tres forte avec l’utilisation des biphosphonates. Leur exclusion des criteres de l’ASBMR serait a reconsiderer etant donne qu’elles presentent des signes cliniques et radiologiques similaires a celles des fractures atypiques femorales sans arthroplastie adjacente.

International audience; 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 to 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.

In genome-wide association studies, single nucleotide polymorphisms located in five novel loci were associated with PDB. We aimed at identifying rare genetic variants of candidate genes located in these loci and search for genetic association with PDB in the French-Canadian population. Exons, promoter and exon–intron junctions from patients with familial PDB and healthy individuals were sequenced in candidate genes, located within novel loci associated with PDB in our population. Rare variant was defined by a minor allele frequency

Intraarticular hyaluronan injections are used to treat osteoarthritis of the knee. Acute painful swelling with a joint effusion develops locally after the injection in about 10% of cases but resolves spontaneously. Crystals are identifiable in some patients, but the mechanism in crystal-negative cases remains unknown. We report knee arthritis with inflammatory joint fluid free of organisms and crystals in two patients after Hylan GF-20 treatment for femorotibial osteoarthritis. Synovial membrane histology disclosed granulomatous synovitis with epithelioid histiocytic and multinucleate giant cells but no visible foreign bodies. These two cases suggest that crystal-negative arthritis after Hylan GF-20 injection may be ascribable to granulomatous synovitis of the foreign-body giant-cell type.

Objective To investigate whether bariatric surgery increases the risk of fracture. Design Retrospective nested case-control study. Setting Patients who underwent bariatric surgery in the province of Quebec, Canada, between 2001 and 2014, selected using healthcare administrative databases. Participants 12 676 patients who underwent bariatric surgery, age and sex matched with 38 028 obese and 126 760 non-obese controls. Main outcome measures Incidence and sites of fracture in patients who had undergone bariatric surgery compared with obese and non-obese controls. Fracture risk was also compared before and after surgery (index date) within each group and by type of surgery from 2006 to 2014. Multivariate conditional Poisson regression models were adjusted for fracture history, number of comorbidities, sociomaterial deprivation, and area of residence. Results Before surgery, patients undergoing bariatric surgery (9169 (72.3%) women; mean age 42 (SD 11) years) were more likely to fracture (1326; 10.5%) than were obese (3065; 8.1%) or non-obese (8329; 6.6%) controls. A mean of 4.4 years after surgery, bariatric patients were more susceptible to fracture (514; 4.1%) than were obese (1013; 2.7%) and non-obese (3008; 2.4%) controls. Postoperative adjusted fracture risk was higher in the bariatric group than in the obese (relative risk 1.38, 95% confidence interval 1.23 to 1.55) and non-obese (1.44, 1.29 to 1.59) groups. Before surgery, the risk of distal lower limb fracture was higher, upper limb fracture risk was lower, and risk of clinical spine, hip, femur, or pelvic fractures was similar in the bariatric and obese groups compared with the non-obese group. After surgery, risk of distal lower limb fracture decreased (relative risk 0.66, 0.56 to 0.78), whereas risk of upper limb (1.64, 1.40 to 1.93), clinical spine (1.78, 1.08 to 2.93), pelvic, hip, or femur (2.52, 1.78 to 3.59) fractures increased. The increase in risk of fracture reached significance only for biliopancreatic diversion. Conclusions Patients undergoing bariatric surgery were more likely to have fractures than were obese or non-obese controls, and this risk remained higher after surgery. Fracture risk was site specific, changing from a pattern associated with obesity to a pattern typical of osteoporosis after surgery. Only biliopancreatic diversion was clearly associated with fracture risk; however, results for Roux-en-Y gastric bypass and sleeve gastrectomy remain inconclusive. Fracture risk assessment and management should be part of bariatric care.

We performed a genetic association study of rare variants and single nucleotide polymorphisms (SNPs) of UCMA/GRP and OPTN genes, in French-Canadian patients with Paget's disease of bone (PDB) and in healthy controls from the same population. We reproduced the variant found in the UCMA/GRP basal promoter and tested its functionality using in vitro transient transfection assays. Interestingly, this SNP rs17152980 appears to affect the transcription level of UCMA/GRP. In addition, we have identified five rare genetic variants in UCMA/GRP gene, four of them being population-specific, although none were found to be associated with PDB. Six Tag SNPs of UCMA/GRP gene were associated with PDB, particularly the SNP rs17152980 (uncorrected P = 3.8 x 10(-3)), although not significant after Bonferroni's correction. More importantly, we replicated the strong and statistically significant genetic association of two SNPs of the OPTN gene, the rs1561570 (uncorrected P = 5.7 x 10(-7)) and the rs2095388 (uncorrected P = 4.9 x 10(-3)), With PDB. In addition, we identified a very rare variant found to be located close to the basal promoter of the OPTN gene, at -232 bp from its distal transcription start site. Furthermore, depending on the type of allele present (G or A), the binding of several important nuclear factors such as the vitamin D or the retinoic acid receptors is predicted to be altered at this position, suggesting a significant effect in the regulation of transcription of the OPTN gene. In conclusion, we identified a functional SNP located in the basal promoter of the UCMA/GRP gene which provided a weak genetic association with PDB. In addition, we replicated the strong genetic association of two already known SNPs of the OPTN gene, with PDB in a founder effect population. We also identified a very rare variant in the promoter of OPTN, and through bioinformatic analysis, identified putative transcription factor binding sites likely to affect OPTN gene transcription. (C) 2012 Elsevier Inc. All rights reserved. Fonds de la Recherche du Quebec - Sante (FRQS), Canada; Portuguese Science and Technology Foundation, Portugal [SFRH/BPD/48206/2008]; Catalyst Grant (Bone Health) from the Canadian Institutes of Health Research (Canada); CHUQ Foundation (Canada); Groupe de Recherche en Maladies Osseuses (Canada); Canadian Foundation for Innovation (Canada); FRSQ (Canada); Laval University (Canada); CHUQ (CHUL) Research Centre (Canada); Centre of Marine Sciences (CCMAR) (Portugal) info:eu-repo/semantics/publishedVersion

Osteoclast (OCL) precursors from many Paget's disease (PD) patients express measles virus nucleocapsid protein (MVNP) and are hypersensitive to 1,25-dihydroxyvitamin D₂ (1,25-(OH)₂D₃; also know as calcitriol). The increased 1,25-(OH)₂D₃ sensitivity is mediated by transcription initiation factor TFIID subunit 12 (TAF12), a coactivator of the vitamin D receptor (VDR), which is present at much higher levels in MVNP-expressing OCL precursors than normals. These results suggest that TAF12 plays an important role in the abnormal OCL activity in PD. However, the molecular mechanisms underlying both 1,25-(OH)₂D₃'s effects on OCL formation and the contribution of TAF12 to these effects in both normals and PD patients are unclear. Inhibition of TAF12 with a specific TAF12 antisense construct decreased OCL formation and OCL precursors' sensitivity to 1,25-(OH)₂D₃ in PD patient bone marrow samples. Further, OCL precursors from transgenic mice in which TAF12 expression was targeted to the OCL lineage (tartrate-resistant acid phosphatase [TRAP]-TAF12 mice), formed OCLs at very low levels of 1,25-(OH)₂D₃, although the OCLs failed to exhibit other hallmarks of PD OCLs, including receptor activator of NF-κB ligand (RANKL) hypersensitivity and hypermultinucleation. Chromatin immunoprecipitation (ChIP) analysis of OCL precursors using an anti-TAF12 antibody demonstrated that TAF12 binds the 24-hydroxylase (CYP24A1) promoter, which contains two functional vitamin D response elements (VDREs), in the presence of 1,25-(OH)₂D₃. Because TAF12 directly interacts with the cyclic adenosine monophosphate-dependent activating transcription factor 7 (ATF7) and potentiates ATF7-induced transcriptional activation of ATF7-driven genes in other cell types, we determined whether TAF12 is a functional partner of ATF7 in OCL precursors. Immunoprecipitation of lysates from either wild-type (WT) or MVNP-expressing OCL with an anti-TAF12 antibody, followed by blotting with an anti-ATF7 antibody, or vice versa, showed that TAF12 and ATF7 physically interact in OCLs. Knockdown of ATF7 in MVNP-expressing cells decreased cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1) induction by1,25-(OH)₂D₃, as well as TAF12 binding to the CYP24A1 promoter. These results show that ATF7 interacts with TAF12 and contributes to the hypersensitivity of OCL precursors to 1,25-(OH)₂D₃ in PD.

Contains fulltext : 110641.pdf (Publisher’s version ) (Closed access) OBJECTIVE: The CLEC12A gene codes for an immune inhibitory receptor that maps to 12p13.2. Since an increase in CLEC12A mRNA correlates with rheumatoid factor values greater than 40 IU/ml in rheumatoid fibroblast-like synovial cells, this study assessed the potential of an association between CLEC12A and rheumatoid arthritis (RA) using a phenotype-based approach. METHODS: A discovery cohort of Western European ethnicity was genotyped for eight tag single nucleotide polymorphisms. Statistical analyses relied on the transmission disequilibrium test, relative risk and 95% confidence interval (CI) calculations. Observed haplotype frequencies were compared to expected frequencies using a family-based association test. Statistically significant associations were further tested in a second cohort of unrelated West-European RA patients. RESULTS: An overtransmission of the C allele of the rs1323461 tag single nucleotide polymorphism was observed (56.6% of allele C transmission, P = 0.046) in the discovery cohort. The relative risk of the AC and CC genotypes when compared to the AA genotype was high (relative risk = 4.08; 95% CI: 1.52-10.95, uncorrected P = 2.1 x 10(-3)), particularly in the subgroup of erosive RA (relative risk = 5.27; 95% CI: 1.53-18.19, uncorrected P = 2.1 x 10(-3)), both remaining statistically significant after conservative Bonferroni's correction. The CGAGCCGA haplotype was observed more frequently than expected (P = 0.013). In the second cohort, the C allele had a tendency to be more frequent in RA patients (82.4%) than controls (79.2%) (P = 0.069). CONCLUSION: We report a potential genetic association of CLEC12A with RA. Since CLEC12A encodes for the myeloid inhibitory C-type lectin-like receptor that modulates cytokine synthesis, this receptor may contribute to the pathogenesis of RA.

ObjectivesIn cystic fibrosis, mutations of the CFTR gene lead to diffuse bronchiectasis (DB). DB is also associated with other diseases including rheumatoid arthritis (RA) in which the role of genetic factors in the predisposition to DB remains unclear.MethodsA family-based association study was carried out to determine whether the frequency of CFTR mutations was higher in patients with RA-associated DB and to determine whether a causal relationship could be established between the variant and the disease by evaluating its cosegregation with DB within families. Families of probands with RA-DB were included if one first-degree relative had RA and/or DB. The controls comprised healthy subjects requesting genetic counselling because their partner had cystic fibrosis.ResultsThe frequency of CFTR mutations was higher in family members with RA-DB or DB only than in unaffected relatives (pCFTR mutations were more frequent in family members with RA-DB than in those with RA only (OR 5.30, 95% CI 2.48 to 11.33; p−5). They cosegregated with RA-DB in the families (sib-TDT=10.82, p=0.005).ConclusionsRA-DB should be added to the list of phenotypes in which CFTR mutations are pathogenic. CFTR mutation is the first genetic defect linked to an extra-articular feature of RA to be described. CFTR mutations in patients with RA appear to be an important marker of the risk of associated DB, which has been linked to a less favourable prognosis.

More than 20 mutations of the Sequestosome 1 (SQSTM1) gene have been reported in patients of European descent affected by Paget's disease of bone (PDB). In this investigation, a systematic screening for SQSTM1 mutations was conducted in consecutively evaluated unrelated patients with phenotypical PDB living in the New York City area (NY, United States). Seventy unrelated PDB patients with a multiethnic background, mostly of Jewish, Italian American, and Western European ancestries, were recruited. Sequencing of exons 7 and 8 was performed on DNA samples isolated from peripheral blood. Seven patients (10%) had SQSTM1 mutations, of which three had a family history of PDB. Four patients carried the C1215T (P392L) mutation, and three patients carried novel SQSTM1 missense mutations: T1085A (S349T), C1209T (A390V), and T1290A (L417Q) mutations. All PDB patients with SQSTM1 mutations had polyostotic involvement, and the mean number of affected bones was significantly higher in pagetic patient carriers of a SQSTM1 mutation when compared to non-mutated PDB patients (4.0 vs. 2.0, respectively; P = 0.003). Haplotype analysis in patient carriers of the P392L mutation revealed that all P392L mutations were carried by haplotype 2. The SQSTM1 mutation rate in unrelated American patients described in the present study was similar to that reported in European populations.

Over the last few years, research into the genetics of bone diseases has produced new insights into the pathophysiology of bone remodeling. The identification of SQSTM1 mutations in Paget's disease of bone established that osteoclast activation involved both binding to ubiquitin and the proteasome pathway. However, murine models fail to replicate the full phenotype, and somatic SQSTM1 mutations have been identified, suggesting a role for complex mechanisms. In patients with fibrous dysplasia of bone, postzygotic somatic mutations in the GNAS gene are now well documented. Technological advances have improved the detection of somatic mutations in peripheral blood cells. Osteopetrosis is characterized by increased bone density due to deficient osteoclastic bone resorption. Most of the genes involved in the various clinical patterns of osteopetrosis have been identified. The identification of LRP5 gain-of-function mutations in autosomal dominant osteopetrosis type I prompted a revision of the classification scheme, and this form is now being included among the high-bone-mass diseases. Osteogenesis imperfecta is characterized by an inherited abnormality in bone formation that manifests as osteopenia with increased bone fragility. Mutations in the COL1A1 and COL1A2 genes are found in over 90% of patients. The recent identification of mutations in the CRTAP, LEPRE1, and PPIB genes in recessive forms has radically changed the classification of osteogenesis imperfecta and generated new pathophysiological hypotheses.

Objectives:The objective of this study was to investigate the association between genes (HLA-DRB1 and PTPN22) and tobacco smoking, separately as well as combined, and serological markers of rheumatoid arthritis (RA) in a French population with RA.Methods:274 patients with RA with half of them belonging to RA multicase families, were genotyped for HLA-DRB1 allele and for PTPN22-1858 polymorphism. IgM rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibodies were determined by ELISA method. The search for association relied on χ2 test and odds ratio with 95% confidence interval calculation. The interaction study relied on the departure-from-additivity-based method.Results:The presence of at least one shared epitope (SE) allele was associated with anti-CCP antibodies presence (82.5% vs. 68.4%, p = 0.02), particularly with HLA-DRB1*0401 allele (28.0% vs. 16.4%, p = 0.01). Tobacco exposure was associated with anti-CCP antibodies, but only in presence of SE. A tendency toward an interaction was found between tobacco, the presence of at least one HLA-DRB1*0401 allele and anti-CCP antibodies (attributable proportion due to interaction = +0.24 (−0.21+0.76)). The cumulative dose of cigarette smoking was correlated with anti-CCP antibody titres (r = 0.19, p = 0.04). The presence of both SE and 1858T alleles was associated with a higher, but not significantly different, risk for anti-CCP antibodies presence than for each separately. No association was found between PTPN22-1858T allele and tobacco smoking for autoantibody positivity.Conclusions:Our findings suggest an association between SE alleles and tobacco smoking for anti-CCP positivity and a tendency toward an interaction between the HLA-DRB1*0401 allele and smoking for anti-CCP positivity in this sample of RA.

Mutation screening of the SQSTM1 gene in 94 French patients with PDB revealed two novel point-mutations (A381V and L413F) and two new compound heterozygous genotypes (P392L/A381V and P392L/A390X). Functional analysis showed an increased level of SQSTM1/p62 protein in PDB patients and truncated forms of the protein encoded by the A390X allele. Clinical data indicate that PDB patients with SQSTM1 mutation are younger at PDB diagnosis and have more extensive bone lesions. Introduction: Paget's disease of bone (PDB) is a common chronic disease of the skeleton, with a strong genetic component. A recurrent mutation (P392L) was first identified on chromosome 5, in the Sequestosome 1 (SQSTM1) gene. Several other mutations of the SQSTM1 gene have been described in PDB patients, affecting the ubiquitin-associated domain (UBA) of the SQSTM1/p62 protein. The objectives of this study were to evaluate the frequency of the SQSTM1 mutations in French PBD patients, to study the expression of the SQSTM1/p62 protein, and to search for genotype–phenotype correlations. Materials and Methods: Blood was obtained from 94 unrelated French PDB patients and 100 controls for mutation screening of exons 7 and 8, encoding for the UBA domain of SQSTM1. Epstein-Barr virus (EBV)-immortalized B-cell lymphocytes were established from 13 patients, giving access to functional analysis of the gene and the SQSTM1/p62 expressions using real-time PCR and Western blot. Results: Mutations of the SQSTM1 gene were identified in 12 of the 94 PDB patients (13%). Eight patients carried P392L. Two novel missense mutations were identified: L413F and A381V. This A381V mutation and A390X were found in distinct patients already carriers of P392L. The SQSTM1/p62 protein expression in PDB patients increased when zero, one, or two mutations were present, and SQSTM1 truncated forms were associated with the A390X mutation. The mean age of PDB diagnosis was younger in patients with the SQSTM1 mutation. PDB was more extensive in patients who carried a SQSTM1 mutation. Conclusions: Mutations of SQSTM1 are present in the French population. PDB patients with and without the SQSTM1 mutation have an increased level of SQSTM1/p62, caused by overproduction of the protein, probably involved in the pathophysiology of PDB. The presence of the SQSTM1 mutation may be a worsening factor for PDB.

Objective: TNFRSF1A mutations cause TRAPS (MIM#142680). A recent study suggested that the R92Q mutation was associated with polyarthritis. We aimed at searching for this and other TNFRSF1A mutations in RA, to be tested for linkage. Material and methods: the 386 DNA of 100 trio families and 86 index cases of RA affected sib-pair (ASP) families from the French Caucasian population were investigated by dHPLC (denatured high-performance liquid chromatography) for TNFRSF1A mutations in exons 2 to 4. The test for association compared cases and controls (derived from un-transmitted parental chromosomes). The test for linkage relied on the transmission disequilibrium test (TDT) in trio families and cosegregation in ASP families. Results: Only the R92Q mutation was detected, in 2 of the 100 index cases of trio families and 5 (5.8%) of the index cases of ASP families, but also 5% of the controls, showing no association with the disease. No RA linkage evidence was found in TDT and ASP RA families. Conclusion: This TNFRSF1A investigation in RA from the French Caucasian population showed only the R92Q mutation, with a frequency of 4.5%, but no evidence for RA association nor linkage to the disease. The R92Q mutation could be considered as a low-penetrance variant.

Background: 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.

International audience; The heat shock 60-kDa protein 1 (HSP60) is involved in immune and inflammatory reactions, which are hallmarks of rheumatoid arthritis (RA). HSP60 is encoded by the HSPD1 gene located on 2q33, one of the suggested RA susceptibility loci in the French Caucasian population. Our aim was to test whether HSPD1 is a major susceptibility gene by studing families from the French Caucasian population. Three single nucleotide polymorphisms (SNPs) were studied in 100 RA trio families, and 100 other families were used for replication. Genetic analyses were performed by comparing allelic frequencies, by applying the transmission disequilibrium test, and by assessing the genotype relative risk. We observed a significant RA association for the C/C genotype of rs2340690 in the first sample. However, this association was not confirmed when the second sample was added. The two other SNPs and the haplotype analysis did not give any significant results. We conclude that HSPD1 is not a major RA susceptibility gene in the French Caucasian population.

Background Several publications have demonstrated that the most frequent mutation in Paget9s disease of bone (PDB), SQSTM1/P392L, leads to some of the phenotypic characteristics of PDB, but this single mutation is seemingly unable to result in the complete pagetic phenotype, suggesting that other mechanisms such as environmental factors may play a role. Objectives Identify environmental factors associated with PDB or with the SQSTM1/P392L mutation carriage in the French-Canadian population. Methods We investigated environmental factors through a questionnaire in 176 French-Canadian patients with PDB and 147 healthy controls not carrier of the SQSTM1/P392L mutation. The questionnaire contained the following sections: socio-demographic and physical characteristics, tobacco exposure, diet, residency, work, leisure, and contact with animals, during childhood/adolescence and adulthood. Associations between environmental factors and PDB, or SQSTM1/P392L mutation (86 individuals carried the mutation, including 48 patients with PDB), were searched relying on Chi-squared, Fisher and t tests. Odds ratio (OR) and 95% confidence interval were calculated. Univariate followed by multivariate analysis were done for association with PDB. Correlation between members of same family was considered when possible. Analysis adjusted for age and gender were done for the association study with SQSTM1/P392L mutation. Results We administered the questionnaire to 361 participants: 176 patients with PDB and 147 healthy controls. 86 individuals were carriers of the SQSTM1/P392L mutation, among whom 48 were patients with PDB and 38 were healthy carriers of the mutation. In univariate model, we found an association of PDB with, wood-fire heating in childhood (OR=2.48 (1.37-4.49), p SQSTM1/P392L mutation was associated with rural residency (OR=2.66 [1.42-4.99], p SQSTM1/P392L mutation (p Conclusions PDB and the carriage of the SQSTM1/P392L mutation were significantly associated with rural residency. Carriage of the SQSTM1/P392L mutation was also strongly associated to work on a farm or in a mine and exposition to some animals during childhood. Acknowledgements CHU de Quebec foundation Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4393

Corrigendum to “Gene expression profile in osteoclasts from patients with Paget's disease of bone” [Bone 46 (2010) 598–603] Laetitia Michou , Estelle Chamoux , Julie Couture , Jean Morissette , Jacques P. Brown , Sophie Roux b,⁎ a Department of Medicine, Laval University, Centre de recherche du CHUQ (CHUL) and Division of Rheumatology, CHUQ (CHUL), Quebec City (Quebec), Canada G1V 4G2 b Department of Medicine, Division of Rheumatology, University of Sherbrooke, 3001, 12th avenue N, Sherbrooke, PQ, Canada J1H 5N4

Rheumatoid arthritis (RA) linkage has been observed on the 18q chromosome in the white population.1 The 18q locus has also shown evidence of linkage with type I insulin-dependent diabetes mellitus, systemic lupus erythematosus and Grave’s disease.2 A candidate gene on chromosome 18q, the TNFRSF11A ( RANK ) gene, which encodes the receptor activator of nuclear factor kappa B, has been shown to be involved in the osteoclast differentiation playing a pivotal role in bone resorption.3 A single RANK haplotype was reported to be associated with RA in a case–control association study.4 Furthermore, activating mutations in the RANK gene cause bone disorders such as early-onset Paget’s disease,5 expansile skeletal hyperphosphatasia6 and familial expansile osteolysis.7 The aim of this …

Paget’s disease of bone (PDB) is a progressive monostotic or polyostotic metabolic bone disease characterized by focal abnormal bone remodeling, with increased bone resorption and excessive, disorganized, new bone formation. PDB rarely occurs before middle age, and it is the second most frequent metabolic bone disorder after osteoporosis, affecting up to 3% of adults over 55 years of age. One of the most striking and intriguing clinical features is the focal nature of the disorder, in that once the disease is established within a bone, there is only local spread within that bone and no systemic dissemination. Despite many years of intense research, the etiology of PDB has still to be conclusively determined. Based on a detailed review of genetic and viral factors incriminated in PDB, we propose a unifying hypothesis from which we can suggest emerging strategies and therapies. PDB results in weakened bone strength and abnormal bone architecture, leading to pain, deformity or, depending on the bone involved, fracture in the affected bone. The diagnostic assessment includes serum total alkaline phosphatase, total body bone scintigraphy, skull and enlarged view pelvis x-rays, and if needed, additional x-rays. The ideal therapeutic option would eliminate bone pain, normalize serum total alkaline phosphatase with prolonged remission, heal radiographic osteolytic lesions, restore normal lamellar bone, and prevent recurrence and complications. With the development of increasingly potent bisphosphonates, culminating in the introduction of a single intravenous infusion of zoledronic acid 5 mg, these goals of treatment are close to being achieved, together with long-term remission in almost all patients. Based on the recent pathophysiological findings, emerging strategies and therapies are reviewed: ie, pulse treatment with zoledronic acid; denosumab, a fully human monoclonal antibody directed against RANK ligand; tocilizumab, an interleukin-6 receptor inhibitor; odanacatib, a cathepsin K inhibitor; and proteasome and Dickkopf-1 inhibitors.

Recently, we proposed a classification of HLA-DRB1 alleles that reshapes the shared epitope hypothesis in rheumatoid arthritis (RA); according to this model, RA is associated with the RAA shared epitope sequence (72–74 positions) and the association is modulated by the amino acids at positions 70 and 71, resulting in six genotypes with different RA risks. This was the first model to take into account the association between the HLA-DRB1 gene and RA, and linkage data for that gene. In the present study we tested this classification for validity in an independent sample. A new sample of the same size and population (100 RA French Caucasian families) was genotyped for the HLA-DRB1 gene. The alleles were grouped as proposed in the new classification: S1 alleles for the sequences A-RAA or E-RAA; S2 for Q or D-K-RAA; S3D for D-R-RAA; S3P for Q or R-R-RAA; and X alleles for no RAA sequence. Transmission of the alleles was investigated. Genotype odds ratio (OR) calculations were performed through conditional logistic regression, and we tested the homogeneity of these ORs with those of the 100 first trio families (one case and both parents) previously reported. As previously observed, the S2 and S3P alleles were significantly over-transmitted and the S1, S3D and X alleles were under-transmitted. The latter were grouped as L alleles, resulting in the same three-allele classification. The risk hierarchy of the six derived genotypes was the same: (by decreasing OR and with L/L being the reference genotype) S2/S3P, S2/S2, S3P/S3P, S2/L and S3P/L. The homogeneity test between the ORs of the initial and the replication samples revealed no significant differences. The new classification was therefore considered validated, and both samples were pooled to provide improved estimates of RA risk genotypes from the highest (S2/S3P [OR 22.2, 95% confidence interval 9.9–49.7]) to the lowest (S3P/L [OR 4.4, 95% confidence interval 2.3–8.4]).