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Context Vertebral fracture (VF) prevalence up to 24% has been reported among young people with type 1 diabetes (T1D). If this high prevalence is confirmed, individuals with T1D could benefit from preventative VF screening. Objective We compared the prevalence of VFs between adults with T1D and nondiabetic controls. Methods This cross-sectional study included 127 adults with T1D, and 65 controls with a similar age, sex, and BMI distribution, from outpatient clinics of 2 tertiary care centers. Vertebral fracture assessment (VFA) by dual-energy x-ray absorptiometry (DXA) was used for prevalent VFs. The modified algorithm-based qualitative (mABQ) method was applied. Bone mineral density (BMD) and trabecular bone score (TBS) were assessed by DXA. Serum bone turnover markers and sclerostin were measured in a subgroup of participants. Results Participants with T1D (70 women, 57 men) had a mean age of 42.8 ± 14.8 years, median diabetes duration of 25.8 (15.8-34.4) years, mean BMI of 26.6 ± 5.4 kg/m2 and mean HbA1c over the past 3 years of 7.5 ± 0.9%. Controls (35 women, 30 men) had mean age of 42.2 ± 15.9 years and mean BMI of 26.1 ± 5.1 kg/m2. VF prevalence was comparable between groups (2.4% vs 3.1%, P = 0.99). TBS, BMD at the total hip and femoral neck, and bone formation and resorption markers were lower while sclerostin levels were similar in participants with T1D vs controls. Conclusion Our VFA results using the mABQ method do not confirm increased prevalence of VFs in men and women with relatively well-controlled T1D.

In Canadian medicine faculties, an average of 2.3% of the medical curriculum is dedicated to musculoskeletal problems with a focus on orthopedic conditions. The goal of this descriptive study was to assess the educational preferences in rheumatology of family medicine residents and to identify their preferred methods of learning.From September 2017 to December 2017, two hundred and thirty-six first- and second-year family medicine residents from Université Laval were asked to complete an electronic anonymous survey assessing their confidence in doing different rheumatology tasks. They were also consulted on their favorite methods of learning and their preferred periods throughout their medical cursus to learn the different skills related to rheumatology.Eighty-five family medicine residents completed the survey. The residents were rather confident when evaluating mono-arthritis but less confident for oligo/polyarthritis and even less confident with connective tissue diseases. The family medicine residents mentioned preferring traditional lecture classes and clinical cases. They wanted to learn the majority of rheumatology education during medical school training. As residents, they wanted only small capsules, seminars, or memory aids. Interestingly, men preferred learning rheumatology skills during the residency, whereas women preferred learning it in medical school.The lack of confidence of family medicine residents when evaluating systemic inflammatory diseases compared to mechanical musculoskeletal problems highlights the importance of rheumatology teaching through general medical training and through family medicine residency. Key Points • Family medicine residents are less confident when evaluating systemic inflammatory diseases than musculoskeletal disorders. • Family medicine residents prefer traditional lecture classes and clinical cases. • Family medicine residents prefer learning rheumatology during medical school training.

The myeloid inhibitory receptor CLEC12A negatively regulates inflammation. Reduced CLEC12A expression enhances inflammation in CLEC12A knock-out mice with collagen antibody-induced arthritis. Moreover, CLEC12A internalisation augments human neutrophil activation. We thus postulated that CLEC12A expression on circulating myeloid cells of rheumatoid arthritis patients is associated with disease manifestations. Cell-surface, CLEC12A receptor expression was determined on circulating neutrophils and monocytes of eRA patients and of healthy donors. Generalized estimating equations model, Student’s t-test and Spearman’s correlations were performed to compare CLEC12A expression between groups and test its association with disease activity and clinical parameters. Plasma cytokines were measured by multiplex immunoassay. Patients with reduced neutrophil or monocyte CLEC12A expression at baseline and at 3 months have an increased simple disease activity index. Low baseline CLEC12A expression also correlates with a higher SDAI at 6 months. In contrast, positive correlations were observed between baseline CLEC12A expression and several cytokines. Moreover, neutrophil and monocyte CLEC12A expression is significantly higher in early rheumatoid arthritis patients at baseline than healthy controls. Circulating neutrophil and monocyte CLEC12A expression correlates with disease activity at baseline and is predictive of SDAI at later stages of the disease indicative of a regulatory role for CLEC12A in RA.

This study evaluated early and medium-term changes in bone turnover markers, and their associations with weight loss, total bone mineral density (BMD), and hormonal changes after biliopancreatic diversion (BPD). Ancillary study from a one-year prospective cohort of 16 individuals assessed before, 3 days, 3 and 12 months after BPD. Bone turnover markers (C-terminal telopeptide (CTX), intact osteocalcin (OC), sclerostin, and osteoprotegerin (OPG)) and several hormones were measured at each visit. Total BMD by DXA was assessed at baseline, 3 and 12 months after BPD. Three participants were lost to follow-up. CTX increased significantly at 3 days (+ 66%), 3 months (+ 219%), and 12 months (+ 295%). OC decreased at 3 days (− 19%) then increased at 3 months (+ 69%) and 12 months (+ 164%). Change in sclerostin was only significant between 3 days and 3 months (+ 13%), while change in OPG was significant between baseline and 3 days (+ 48%) and baseline and 12 months (+ 45%). CTX increase correlated negatively with weight loss at 3 (r = − 0.63, p = 0.009) and 12 months (r = − 0.58, p = 0.039), and total BMD decrease (r = − 0.67, p = 0.033) at 12 months. Change in insulin and adiponectin correlated with changes in bone turnover markers independently of weight loss. BPD causes an earlier and greater increase in bone resorption over bone formation markers and a decrease in total BMD. Sclerostin did not increase as expected following extensive weight loss. Changes in insulin and adiponectin seem to play a role in the activation of bone remodeling after BPD.

Bisphosphonate use has been associated with atypical femoral fractures (AFFs), defined by the American Society of Bone and Mineral Research (ASBMR) Task Force criteria, which currently exclude periprosthetic fractures. The objectives of this study were to establish the prevalence of atypical periprosthetic femoral fractures (APFFs) in patients with hip and knee arthroplasties and to determine the clinical and radiological risk factors associated with these fractures. We performed a retrospective radiological review of all femoral fractures between January 1, 2006, and March 31, 2015, in Quebec City, Canada. Patients who sustained a periprosthetic femoral fracture (PFF) were identified and included in this study. We used the ASBMR Task Force criteria to identify atypical fractures and establish their prevalence. Data from medical records and radiological assessments of the femoral anatomy, the characteristics of the fracture, and the positioning of the prosthesis were collected. The prevalence of APFFs among PFFs was 8.3% (11/133). A strong association with bisphosphonates (p = 0.007) was observed, as well as an increased risk of APFFs among alendronate users compared to risedronate users (p = 0.04). A transverse fracture (p < 0.0001), a periosteal thickening of the lateral cortex at the fracture (p < 0.0001), a unicortical fracture (p = 0.02), and prodromal symptoms (p = 0.03) were associated with APFFs. The type of implant, its positioning, and the femoral geometry did not appear to be risk factors for APFFs compared to PFFs. © 2018 American Society for Bone and Mineral Research.

The most frequent mutation linked to Paget's disease of bone (PDB), p.Pro392Leu within SQSTM1 gene, leads to phenotypic characteristics of PDB, but this mutation is seemingly insufficient to result in complete pagetic osteoclast phenotype, suggesting that possible environmental factors play a role in PDB pathogenesis. We performed an exploratory study to identify environmental factors potentially associated with familial or non-familial form of PDB in the French-Canadian population.We investigated environmental factors through a questionnaire in 176 pagetic patients, including 86 patients with a familial form, and 147 healthy controls. All participants lived in the same geographic area, within a 120km radius of Quebec City. Associations between environmental factors and familial and non-familial forms of PDB were searched.In the multivariate model adjusted for intra-familial correlation, PDB was associated with wood fired heating in childhood and/or adolescence (OR=2.10; 95% CI 1.13-3.90, P=0.02). In the multivariate model without considering correlation for family relatedness, familial form of PDB was associated with residency near a mine (OR=11.70; 95% CI 2.92-46.80, P0.01) and hunting (OR=2.92; 95% CI 1.14-7.47, P=0.03). Wood fired heating during childhood and/or adolescence (P=0.02) was associated with both familial and non-familial forms.In conclusion, PDB was significantly associated with wood fired heating in childhood and/or adolescence, regardless of the form of PDB, familial or not.

The presence of microcalcifications in the breast microenvironment, combined with the growing evidences of the possible presence of osteoblast-like or osteoclast-like cells in the breast, suggest the existence of active processes of calcification in the breast tissue during a woman’s life. Furthermore, much evidence that osteoimmunological disorders, such as osteoarthritis, rheumatoid arthritis, or periodontitis influence the risk of developing breast cancer in women exists and vice versa. Antiresorptive drugs benefits on breast cancer incidence and progression have been reported in the past decades. More recently, biological agents targeting pro-inflammatory cytokines used against rheumatoid arthritis also demonstrated benefits against breast cancer cell lines proliferation, viability, and migratory abilities, both in vitro and in vivo in xenografted mice. Hence, it is tempting to hypothesize that breast carcinogenesis should be considered as a potential osteoimmunological disorder. In this review, we compare microenvironments and molecular characteristics in the most frequent osteoimmunological disorders with major events occurring in a woman’s breast during her lifetime. We also highlight what the use of bone anabolic drugs, antiresorptive, and biological agents targeting pro-inflammatory cytokines against breast cancer can teach us.

Objectives This study explored the role of outdoor and indoor air pollutants in Paget's disease of bone (PDB). Methods We performed a survey in 140 French-Canadian patients with PDB, including 39 carriers of p.Pro392Leu mutation (SQSTM1 gene) and 113 healthy not mutated controls. The survey covered outdoor air pollution near the residence and indoor air pollutants by focusing on heating fuels and exposure to tobacco smoke. In a subgroup of patients, urinary concentrations of 17 heavy metals and 11 polycyclic aromatic hydrocarbons were measured by mass spectrometry. In light of what we learned from the survey and urinary assays, we explored the in vitro effects of certain toxics on osteoclasts in PDB. We conducted in vitro monocytes differentiation from peripheral blood of more than 40 participants, whose osteoclasts were treated with or without the toxic. The morphology of osteoclasts, their bone resorption abilities, gene and protein expression levels, and cellular oxidative stress levels were assayed. Results An inhibitory effect of cigarette smoke condensate and heavy metals was observed on morphology and bone resorption activity of patients' osteoclasts. SQSTM1 gene expression was upregulated in osteoclasts from patients with PDB versus healthy controls in presence of cadmium, and SQSTM1 protein expression was upregulated in presence of bismuth and tobacco smoke condensates, in particular in osteoclasts from carriers of the SQSTM1 mutation. Furthermore, high levels of oxidative stress in patients' osteoclasts were observed. Conclusions Our in vitro experiments suggest an interaction between SQSTM1 gene and exposure to cadmium and tobacco smoke condensates.

We report the case of a 53-year-old female, treated by bisphosphonate for 12 years, who presented atraumatic fractures of both fibulas. Her X-rays showed bilateral distal fibula fractures with radiological features similar to atypical femur fractures. The distal fibula should be considered as a potential site for stress fractures in bisphosphonate users. Bisphosphonates are the most widely used drugs in the treatment of osteoporosis. During the last decade, the occurrence of atypical fractures, mostly subtrochanteric and diaphyseal femoral fractures, has been acknowledged in patients with long-term use of bisphosphonates. We report the case of a 53-year-old female on alendronate therapy for the past 12 years who presented with a few months history of atraumatic right, and subsequently left, lateral ankle pain. Her X-rays showed bilateral distal fibula fractures with radiological features similar to atypical femur fractures. She had been treated conservatively with walking boots and her treatment with bisphosphonate had been stopped 5 months prior to the fractures. Callus was progressively seen on serial follow-up X-rays, and both fractures healed completely within a reasonable period of 1 year. Investigations did not reveal any secondary causes of osteoporosis or metabolic bone disorders. To our knowledge, this is the first reported case of bilateral distal fibula fractures in a patient on long-term bisphosphonate therapy.

Paget's disease of bone (PDB) is the second most frequent metabolic bone disease after osteoporosis. Genetic factors play an important role in PDB, but to date PDB causing mutations were identified only in the Sequestosome 1 gene at the PDB3 locus. OPTN has been recently associated with PDB, however little is known about the effect of genetic variants in this gene in PDB pathophysiology. By sequencing OPTN in SQSTM1 non-carriers PDB patients we found 16 SNPs in regulatory, coding and non-coding regions. One of those was found to be associated with PDB in our cohort - rs2234968. Our results show that rs2238968 effect may be explained by a change in OPTN splicing that give rise to a predicted truncated protein. We also performed functional studies on the variants located in OPTN promoter - rs3829923 and the rare variant -9906 - to investigate putative regulators of OPTN. Our results show that OPTN expression seems to be regulated by SP1, RXR, E47, and the E2F family. In conclusion, our work suggests a potential pathophysiological role of SNPs in OPTN, giving a new perspective about the regulatory mechanisms of this gene. Ultimately we discovered a new variant associated with PDB in OPTN, reinforcing the relevance of this gene for the development of this bone disease. info:eu-repo/semantics/publishedVersion

Objective.In our region in Quebec, Canada, access to rheumatologists is very limited. Sharing followup of stable patients with their primary care physicians (PCP) could increase access to rheumatologists. In our study, we assessed the feasibility and potential benefits of sharing followup of inflammatory arthritis (IA) patients with their PCP.Methods.We reviewed the clinical records of 300 patients with peripheral arthritis who presented at our rheumatology outpatient clinic between July and October 2015. We distributed questionnaires to their treating rheumatologist, asking whether a PCP could participate in the followup of the patient and whether there were any factors that would prevent shared followup. We also distributed questionnaires to PCP to assess their level of comfort in participating in the followup care of patients with arthritis.Results.Chart review was completed on 300 patients. There was no treatment modification in 49% of the cases, and 38% of the visits were deemed unnecessary by the attending rheumatologist. We found that 74% of PCP were very interested in sharing the arthritis followup care of their patients. According to PCP, the main barriers to shared followup were treatment with biological agents, active disease, and need for infiltrations. Main organizational barriers were the lack of rheumatologist availability to see patients urgently (46%) and the lack of clear guidelines for the management of IA (58%).Conclusion.Up to 38% of peripheral IA visits to a rheumatologist could have been prevented and done by a PCP. In our department, this represented up to 19 followup visits per week that could have been avoided by involving a PCP.

Joint Bone Spine - In Press.Proof corrected by the author Available online since vendredi 23 janvier 2015

Increased expression of DKK1 gene was reported in pagetic osteoblasts and stromal cells, and increased serum levels of DKK1 and SOST proteins were reported in patients with Paget disease of bone (PDB). This study aimed at identifying rare genetic variants of the DKK1 and SOST genes and at testing for genetic association with PDB in the French-Canadian population. Exons, promoters, and exon-intron junctions of these genes were sequenced in patients with PDB and healthy controls. An association study of Tag SNPs of both genes was also performed in 239 pagetic patients and 297 healthy individuals. Three rare variants were identified in this study, all located in the DKK1 gene: one variant in the second exon leading to alteration in a highly conserved amino acid (p.R120L), one in the 5'-untranslated region (-50 C/A), and one in a splice site of intron 1 (IVS1 184 T/C), although none of these rare variants were associated with PDB. A genetic association of a Tag SNP of the DKK1 gene was found: the G allele of rs1569198 was significantly decreased in patients in comparison to controls (42 vs. 49 %, uncorrected P = 0.03, OR = 0.77, 95 % CI 0.61-0.98). In conclusion, this study identified three rare genetic variants in DKK1 in the French-Canadian population. In addition, a weak genetic association of a common variant of DKK1, rs1569198, which is located on a predicted new acceptor site for splicing of this gene, was observed in PDB, whereas no rare variant or genetic association was found in the SOST gene.

Objective To search for association with environmental factors and to determine SQSTM1/p62 mutations prevalence in French families with Paget's disease of bone (PDB). Methods Unrelated patients with a confirmed diagnosis of PDB were recruited in three Rheumatology departments and informed consent obtained. First- and second-degree relatives of each index case had a physical examination, blood taken for DNA extraction and biochemical measurements, and a whole-body bone scan. Exons 7 and 8 and exon-intron boundaries of SQSTM1/p62 (p62) gene were PCR-amplified before sequencing. Haplotype carriers of the p62 P392L mutation were determined. Comparisons between PDB patients and healthy relatives were performed. Results We investigated 18 families consisting of 83 individuals: 20 patients with known PDB, three relatives with newly-diagnosed PDB and 60 healthy relatives. Index cases and/or relatives with Dupuytren's disease were found in eight (44.4%) out of the 18 families. Forty-three percent of PDB patients were former or current tobacco users versus 18% of healthy relatives ( P = 0.02; OR = 3.37 (1.04–11.09)). Five index cases (27.8%) were carriers of SQSTM1/p62 mutations: three p62 P392L mutations, one p62 P392L / A390X double mutation and one p62 A390X mutation. The p62 P392L mutation was carried by haplotype 2 in all four index cases. Conclusion Accurate phenotypic assessment of PDB patients’ relatives allowed for diagnosing PDB in three asymptomatic relatives. There was evidence for an aggregation of Dupuytren's disease in PDB families (not associated with SQSTM1/p62 mutation), and for an association between PDB and tobacco use. Half of PDB familial forms carried a SQSTM1/p62 mutation, p62 P392L mutation being the most frequent.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Paget’s disease of bone (PDB) is transmitted, in one-third of cases, in an autosomal dominant mode of inheritance with incomplete penetrance. The SQSTM1/P392L germinal mutation is the most common mutation associated with PDB. Given the focal nature of PDB, one team of investigators showed that SQSTM1/P392L somatic mutations could occur in pagetic bone lesions in the absence of germinal mutations detectable in the peripheral blood. The objectives of this study were to develop a reliable method to detect SQSTM1/P392L post-zygotic mutations, by optimizing a polymerase chain reaction (PCR)-clamping method reported to be effective in detecting post-zygotic mutations in peripheral blood from patients with fibrous dysplasia; and to evaluate the frequency of this post-zygotic mutation in PDB patients. We used a locked nucleic acid (LNA) specifically designed for the SQSTM1/P392L mutation, which blocks the wild-type allele amplification during the PCR. DNA from 376 pagetic patients and 297 controls, all without any SQSTM1/P392L germinal mutation, was analyzed. We found that 4.8 % of PDB patients and 1.4 % of controls were carriers of this post-zygotic mutation [p = 0.013, OR 3.68 (1.23; 11.00)]. PDB patient carriers of a post-zygotic mutation had a lower number of affected bones and Renier’s index than patients carrying a germinal mutation, suggesting a lower disease extension. We also demonstrated that this post-zygotic mutation was restricted to the monocytic lineage. These results confirmed that LNA PCR clamping is effective for the detection of SQSTM1/P392L post-zygotic mutations, which may occur in patients with PDB. Electronic supplementary material The online version of this article (doi:10.1007/s00439-014-1488-3) contains supplementary material, which is available to authorized users.

Background Mutations in the SQSTM1/p62 gene have been reported in Paget’s disease of bone (PDB), but they are not sufficient to induce the pagetic osteoclast (OC) phenotype. We hypothesized that specific RNA isoforms of OC-related genes may contribute to the overactivity of pagetic OCs, along with other genetic predisposing factors. Methods Alternative splicing (AS) events were studied using a PCR-based screening strategy in OC cultures from 29 patients with PDB and 26 healthy donors (HD), all genotyped for the p62P392L mutation. Primer pairs targeting 5223 characterized AS events were used to analyze relative isoform ratios on pooled cDNA from samples of the four groups (PDB, PDBP392L, HD, HDP392L). Of the 1056 active AS events detected in the screening analysis, 192 were re-analyzed on non-amplified cDNA from each subject of the whole cohort. Results This analysis led to the identification of six AS events significantly associated with PDB, but none with p62P392L. The corresponding genes included LGALS8, RHOT1, CASC4, USP4, TBC1D25, and PIDD. In addition, RHOT1 and LGALS8 genes were upregulated in pagetic OCs, as were CASC4 and RHOT1 genes in the presence of p62P392L. Finally, we showed that the proteins encoded by LGALS8, RHOT1, USP4, TBC1D25, and PIDD were expressed in human OCs. Conclusion This study allowed the identification of hitherto unknown players in OC biology, and our findings of a differential AS in pagetic OCs may generate new concepts in the pathogenesis of PDB.