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Infertility in couples is a common problem, with both female and male factors contributing to similar extents. Severe, congenital disorders affecting fertility are, however, rare. While folliculogenesis and spermatogenesis are generally orchestrated via different mechanisms, some genetic anomalies can impair both female and male gametogenesis. Minichromosome maintenance complex component 9 (MCM9) is involved in DNA repair and mutations of the MCM9 gene have been previously reported in females with premature ovarian insufficiency (POI). MCM9 is also an emerging cancer risk gene. We performed next-generation and Sanger sequencing of fertility and related genes and hormonal and imaging studies in a kindred whose members had POI and disordered spermatogenesis. We identified a homozygous pathogenic MCM9 variant, c.394C>T (p.Arg132*) in three sisters affected by POI due to ovarian dysgenesis and their brother who had normal pubertal development but suffered from non-obstructive azoospermia. Testicular biopsy revealed Sertoli cell-only testicular histopathology. No evidence of early onset cancer was found in the homozygotic family members, but they were all young (

Autophagy receptor p62/SQSTM1 signals a complex network that links autophagy-lysosomal system to proteasome. Phosphorylation of p62 on Serine 349 (P-Ser349 p62) is involved in a cell protective, antioxidant pathway. We have shown previously that P-Ser349 p62 occurs and is rapidly degraded during human synovial fibroblasts autophagy. In this work we observed that fingolimod (FTY720), used as a medication for multiple sclerosis, induced coordinated expression of p62, P-Ser349 p62 and inhibitory TFEB form, phosphorylated on Serine 211 (P-Ser211 TFEB), in human synovial fibroblasts. These effects were mimicked and potentiated by proteasome inhibitor MG132. In addition, FTY720 induced autophagic flux, LC3B-II up-regulation, Akt phosphorylation inhibition on Serine 473 but down-regulated TFEB, suggesting stalled autophagy. FTY720 decreased cytoplasmic fraction contained TFEB but induced TFEB in nuclear fraction. FTY720-induced P-Ser211 TFEB was mainly found in membrane fraction. Autophagy and VPS34 kinase inhibitor, autophinib, further increased FTY720-induced P-Ser349 p62 but inhibited concomitant expression of P-Ser211 TFEB. These results suggested that P-Ser211 TFEB expression depends on autophagy. Overexpression of GFP tagged TFEB in HEK293 cells showed concomitant expression of its phosphorylated form on Serine 211, that was down-regulated by autophinib. These results suggested that autophagy might be autoregulated through P-Ser211 TFEB as a negative feedback loop. Of interest, overexpression of p62, p62 phosphorylation mimetic (S349E) mutant and phosphorylation deficient mutant (S349A) in HEK293 cells markedly induced P-Ser211 TFEB. These results showed that p62 is involved in regulation of TFEB phosphorylation on Serine 211 but that this involvement does not depend on p62 phosphorylation on Serine 349.

Background Inflammation of patients joints with severe disease activity of rheumatoid arthritis (RA) has already been visualized and quantified by 2-[18F]fluoro-2-deoxy-D-glucose positron emission computed tomography ([18F] FDG PET/CT), but little is known about the metabolic status and its relationship with clinical and ultrasonography (US) metrology in patients with low/moderate activity or in remission. Methods Clinical assessments [based on 28-joint disease activity score (DAS28-CRP) and Clinical Disease Activity Index (CDAI)], [18F] FDG PET/CT, US and X-ray were performed on 63 RA patients classified into remission or low/moderate or severe disease activity groups. PET/CT was visually and then semi-quantitatively analysed by determining the standardized uptake value (SUV) of positive joints. Results Of the 1764 joints, 21.1% were tender only, 13.7% swollen only, 27.6% tender or swollen, 7.3% tender and swollen, 20.5% PET/CT-positive and 8.6% US-positive. PET and US measurements were correlated, albeit with poor concordance. The positive predictive value of PET/CT for clinical evaluation (tender and/or swollen) was low, whereas its negative predictive value was high. Highly significant differences were found with the number of PET/CT-positive joints and with cumulative SUV between “severe” and “non-severe” patients (including those in remission and those with low/moderate activity) and not between those classified as “remission” and “non-remission” or “remission” and “low/moderate activity”. Moreover, the correlation between PET/CT measurements and clinical activity was positive only in the CDAI severe disease group. In patients in remission or with low/moderate activity, only 20–30% of joints were PET/CT-negative. In remission, PET/CT and US were positive in different joints, and PET/CT-positive but US-negative joints mainly exhibited RA (38.1%) or normal (49.2%) and not osteoarthritic (12.7%) X-ray patterns. Conclusions [18F] FDG PET/CT was effective at distinguishing patients with severely active disease from other patients. In non-severe RA patients, including those in remission, PET/CT results are discordant from US and clinical observations. A longitudinal analysis is needed to explore the clinical relevance of such infra-clinical disease.

We previously reported 18FPRGD2 uptake by the coxofemoral lining, intervertebral discs and facet joint osteophytes in OA using PET/SCAN imaging. However, the molecular mechanism by which the PRGD2 tracer interacts with joint tissues and osteophytes in OA remains unclear. As PRGD2 ligands are expected to belong to the RGD-specific integrin family, the purpose of this study was (i) to determine which integrin complexes display the highest affinity for PRGD2-based ligands, (ii) to analyze integrin expression in relevant tissues, and (iii) to test integrin regulation in chondrocytes using OA-related stimuli to increase the levels of fibrosis and ossification markers. To this end, the affinity of PRGD2-based ligands for five heterodimeric integrins was measured by competition with 125I-echistatin. In situ analyses were performed in human normal vs. OA cartilage and spinal osteophytes. Osteophytes were characterized by (immuno-)histological staining. Integrin subunit expression was tested in chondrocytes undergoing dedifferentiation, osteogenic differentiation, and inflammatory stimulation. The integrins αVβ5, αVβ3, and αVβ6 presented the highest affinity for PRGD2-based ligands. In situ, the expression of these integrins was significantly increased in OA compared to normal cartilage. Within osteophytes, the mean integrin expression score was significantly higher in blood vessels, fibrous areas, and cells from the bone lining than in osteocytes and cartilaginous zones. In vitro, the levels of integrin subunits were significantly increased during chondrocyte dedifferentiation (except for β6), fibrosis, and osteogenic differentiation as well as under inflammatory stimuli. In conclusion, anatomical zones (such as OA cartilage, intervertebral discs, and facet joint osteophytes) previously reported to show PRGD2 ligand uptake in vivo expressed increased levels of αVβ5, αVβ3, and β6 integrins, whose subunits are modulated in vitro by OA-associated conditions that increase fibrosis, inflammation, and osteogenic differentiation. These results suggest that the increased levels of integrins in OA compared to normal tissues favor PRGD2 uptake and might explain the molecular mechanism of OA imaging using the PRGD2-based ligand PET/CT.

Sclerostin is sometimes presented as a promising biomarker in assessing bone health both in the general population and chronic kidney disease patients. However, it is still unclear whether it has any true added value compared to existing bone biomarkers in predicting bone turnover and/or bone density in chronic kidney disease patients. A wealth of papers has been published to evaluate the association between sclerostin and vascular calcifications development or even as prognostic biomarker for mortality, but often with conflicting results. Standardization and harmonization of analytical techniques is a prerequisite to advance clinical knowledge in sclerostin.

BACKGROUND AND AIMS Bone loss and mineral abnormalities are frequent in kidney transplant recipients (KTRs) and associated with a high risk of fracture, cardiovascular mortality and an increase in health care costs. In daily clinics, the detection of bone abnormalities after transplantation includes bone biomarkers and imaging technique [Dual Energy X-ray (DEXA)] to assess respectively the bone turnover and the bone mineral density (BMD), but with limitations. The high-resolution peripheral quantitative computed tomography (HR-pQCT) provides additional noninvasive information on bone microarchitecture and BMD with a better distinction between cortical and trabecular areas. The goal of our study is to evaluate the evolution of bone structure using HR-pQCT compared to standard technique (DXA) in a prospective cohort of KTRs. METHOD All patients referred for a single kidney transplant at the university hospital of Liège with no history of exposure to antiresorptive agents were eligible for inclusion (NCT04713774). Participants underwent baseline and 3-month biomarkers analysis, BMD measurements by DEXA. HR-pQCT images were obtained of the distal radius and distal tibia (non-dominant, non-fractured limb) using the XtremeCT device with standard protocols. HR-pQCT assessed quantitative measurement of the volumetric density of trabecular and cortical bone as well as bone structure (trabecular number or thickness or cortical porosity for instance). RESULTS A total of 26 patients were prospectively included. The mean age was 57.3 ± 12.1 years. The mean dialysis vintage was 27.5 ± 16.4 months before transplantation. Bone biomarkers showed a significant decrease at 3 months after transplantation. PTH decreased from 221.72 ng/L to 59.6 ng/L (P CONCLUSION HR-pQCT is sensitive enough to show a significant decrease of BMD at the trabecular site, as soon as 3 months after transplantation compared to DEXA at the lumbar spine. However, no change in bone structure nor cortical bone volume has been observed. The sensibility of this technique might be higher than DEXA. The rapid assessment of bone structure (3 months post-transplantation) might be too soon to evaluate such abnormalities. Detecting properly rapid changes in bone density, as soon as 3 months after renal transplantation seems feasible. The impact on bone health management needs to be further studied.

Chronic obstructive pulmonary disease (COPD) is a risk factor for osteoporosis. Our objective is to determine if functional indices associated with emphysema on pulmonary function tests (DLCO—diffusion capacity of the lung for CO-; DLCO/AV—DLCO corrected for alveolar volume- and TLC—total lung capacity), considered alone or together, can identify COPD patients with osteoporosis. Methods: 90 COPD patients underwent dual-energy X-ray absorptiometry (DEXA) and pulmonary function tests. Results: 26% of the COPD patients were osteoporotic. In univariate analysis, each functional parameter associated with emphysema, analyzed separately, was not associated with osteoporosis. In contrast, patients with hyperinflation associated with impaired diffusion capacity and transfer coefficient, defined by the association of the three functional indices (DLCO < 70%, DLCO/AV < 80% and CPT > 115%), had significantly more osteoporosis at the total hip (OR: 5.9, CI: 1.5–23.8, p = 0.013). In multivariate analysis, this phenotype was confirmed as an independent factor associated with hip osteoporosis. In contrast, COPD airway obstruction severity, based on FEV1 (%), was not associated with osteoporosis. A lower BMI, female gender and age were also identified as osteoporosis risk factors. Conclusions: COPD patients with hyperinflation associated with impaired diffusion capacity and transfer coefficient are at higher risk for osteoporosis. Pulmonary function tests associated with emphysema detection can help to identify COPD patients with osteoporosis, in addition to the classical risk factors.

An inflamed synovial membrane plays a major role in joint destruction and is characterized by immune cells infiltration and fibroblast proliferation. This proteomic study considers the inflammatory process at the molecular level by analyzing synovial biopsies presenting a histological inflammatory continuum throughout different arthritis joint diseases. Knee synovial biopsies were obtained from osteoarthritis (OA; n = 9), chronic pyrophosphate arthropathy (CPPA; n = 7) or rheumatoid arthritis (RA; n = 8) patients. The histological inflammatory score was determined using a semi-quantitative scale based on synovial hyperplasia, lymphocytes, plasmocytes, neutrophils and macrophages infiltration. Proteomic analysis was performed by liquid chromatography-mass spectrometry (LC-MS/MS). Differentially expressed proteins were confirmed by immunohistochemistry. Out of the 1871 proteins identified and quantified by LC-MS/MS, 10 proteins (LAP3, MANF, LCP1, CTSZ, PTPRC, DNAJB11, EML4, SCARA5, EIF3K, C1orf123) were differentially expressed in the synovial membrane of at least one of the three disease groups (RA, OA and CPPA). Significant increased expression of the seven first proteins was detected in RA and correlated to the histological inflammatory score. Proteomics is therefore a powerful tool that provides a molecular pattern to the classical histology usually applied for synovitis characterization. Except for LCP1, CTSZ and PTPRC, all proteins have never been described in human synovitis.

Osteoarthritis (OA) is recognized as being a cellular senescence-linked disease. Intra-articular injections of glucocorticoids (GC) are frequently used in knee OA to treat synovial effusion but face controversies about toxicity. We investigated the influence of GC on cellular senescence hallmarks and senescence induction in fibroblast-like synoviocytes (FLS) from OA patients and mesenchymal stem cells (MSC). Methods: Cellular senescence was assessed via the proliferation rate, β-galactosidase staining, DNA damage and CKI expression (p21, p16INK4A). Experimental senescence was induced by irradiation. Results: The GC prednisolone did not induce an apparent senescence phenotype in FLS, with even higher proliferation, no accumulation of β-galactosidase-positive cells nor DNA damage and reduction in p21mRNA, only showing the enhancement of p16INK4A. Prednisolone did not modify experimental senescence induction in FLS, with no modulation of any senescence parameters. Moreover, prednisolone did not induce a senescence phenotype in MSC: despite high β-galactosidase-positive cells, no reduction in proliferation, no DNA damage and no CKI enhancement was observed. Conclusions: We provide reassuring in vitro data about the use of GC regarding cellular senescence involvement in OA: the GC prednisolone did not induce a senescent phenotype in OA FLS (the proliferation ratio was even higher) and in MSC and did not worsen cellular senescence establishment.

Osteoarthritis (OA) synovial membrane is mainly characterized by low-grade inflammation, hyperplasia with increased cell proliferation and fibrosis. We previously underscored a critical role for CEMIP in fibrosis of OA cartilage. However, its role in OA synovial membrane remains unknown. An in vitro model with fibroblast-like synoviocytes from OA patients and an in vivo model with collagenase-induced OA mice were used to evaluate CEMIP-silencing effects on inflammation, hyperplasia and fibrosis. Our results showed that i. CEMIP expression was increased in human and mouse inflamed synovial membrane; ii. CEMIP regulated the inflammatory response pathway and inflammatory cytokines production in vitro and in vivo; iii. CEMIP induced epithelial to mesenchymal transition pathway and fibrotic markers in vitro and in vivo; iv. CEMIP increased cell proliferation and synovial hyperplasia; v. CEMIP expression was increased by inflammatory cytokines and by TGF-β signaling; vi. anti-fibrotic drugs decreased CEMIP expression. All these findings highlighted the central role of CEMIP in OA synovial membrane development and underscored that targeting CEMIP could be a new therapeutic approach.

Background Osteoporosis is a highly prevalent disease identified by Dual Energy X-ray Absorptiometry (DEXA) that can be performed in an ambulatory (out-patient) or hospitalized population. We evaluated the use of baseline in-hospital DEXA screening to identify osteoporosis in ambulatory care and hospitalized patients; we also assessed specific risk factors for osteoporosis among these populations. Methods We included a baseline initial DEXA from 6406 consecutive patients at our tertiary referral University Hospital. Results Osteoporosis was diagnosed in 22.3% of the study population. In univariate analysis, osteoporosis risk factors were age, fracture history and low BMI (for all 3 sites), but also corticotherapy (lumbar spine and femoral neck) and male (lumbar spine). In multivariate analysis, age, fracture history, low BMI, and male increased osteoporosis risk. In-hospital screening yielded a higher percentage of osteoporosis positive scans than ambulatory care screening (31.8% vs 18.5%, p Conclusions In-hospital osteoporosis screening revealed more osteoporosis than screening in ambulatory practice and could be an additional tool to improve the identification and management of osteoporosis. In addition to typical risk factors, we identified male gender as associated with osteoporosis detection in our cohort.

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive cartilage degradation but also synovial membrane inflammation, osteophyte formation and subchondral bone sclerosis. Medical care is mainly based on alleviating pain symptoms, but to date, no effective drug can stop the disease progression. Cartilage is a tissue composed of only one cell type, chondrocytes, wrapped in a collagen rich extracellular matrix they synthesize. Chondrocytes can adopt different phenotypes in vivo and in vitro, defined by the collagen type they produce. Isolated from their matrix, chondrocytes present the particularity to dedifferentiate, producing fibroblastic type I and III collagens. With OA onset, chondrocytes undergo multiple changes, in terms of proliferation, viability, but also secretory profile. The acquisition of a hypertrophic phenotype (producing aberrant type X collagen and catabolic MMP-13 protease) by chondrocytes is well documented and contributes to OA development. However, it is increasingly believed that chondrocytes rather acquire a variety of degenerated phenotypes at the onset of OA, including a "dedifferentiated-like" phenotype that might also contribute to OA progression. In this review, we will (i) present molecular knowledge underlying dedifferentiation process, (ii) emphasize connections between dedifferentiation and OA and (iii) consider OA therapeutic strategies aiming at the maintenance of chondrogenic phenotype.

Introduction Le HandScan (Hemics, Pays-Bas) est un appareil d’imagerie optique qui traduit l’absorption par le sang d’un faisceau de lumiere en une echelle colorimetrique et permet une evaluation non-invasive et indolore de l’inflammation articulaire. Ses avantages sont un cout et une duree d’acquisition faible, sans necessiter une presence medicale. Nos objectifs sont d’etudier l’efficacite du HandScan pour predire la remission (ou l’activite) clinique et echographique dans la polyarthrite rhumatoide (PR). Patients et methodes Soixante et un patients avec un diagnostic de PR ont ete recrutees avec evaluation clinique, biologique, echographique et par imagerie optique (HandScan : score Optical Spectral Transmission [OST] pour chaque articulation ; OST total et DAS-OST pour l’ensemble des articulations). Resultats (1) Le HandScan (score OST total et DAS-OST) correle significativement avec les scores d’evaluation clinicobiologiques (articulations douloureuses/gonflees, VAS medecin, HAQ, DAS28-CRP, CDAI, SDAI), en analyse multivariee apres ajustement pour les variables demographiques ou influencant l’absorption du faisceau du HandScan. (2) Deux seuils de remission sont proposes dans la litterature, bases sur le score OST total et le score DAS-OST. En fixant la remission DAS28-CRP comme reference ils presentent des valeurs predictives negatives (VPN) elevees (90,7 pour le DAS-OST), c’est-a-dire que si le patient n’est pas en remission HandScan, il a 90,7 % de risque de ne pas etre en remission DAS28-CRP. Ces bonnes VPN se retrouvent aussi pour les remissions DAS28-VS, SDAI, CDAI et booleenne (90,7, 95,4 et 97,7 et 95,4). Les performances diagnostiques sont significativement meilleures pour le score DAS-OST que pour l’OST total. Avec des courbes ROC, nous avons recherche un seuil DAS-OST adapte a notre population permettant de mieux predire la remission : les performances sont numeriquement meilleures, mais ne different pas significativement du seuil de la litterature. (3) Concernant l’echographie, les score OST total et DAS-OST fournis par le HandScan a l’echelle des 61 patient, mais aussi le score OST unitaire au niveau des 1342 (61 × 22 – MCP, IPP, poignets –) articulations, correlent significativement (analyse multivariee) a la synovite, son grade et son epaisseur, ainsi qu’a la presence d’un index de vascularisation positif et a son grade. (4) Nous avons recherche un seuil DAS-OST pour predire la remission echographique : les performances de ce seuil sont peu performantes a l’echelle du patient (valeurs predictives positives (VPP) de 66,7 a 58,7 et VPN de 65,2 a 84,6 en fonction de la definition de la remission echographique). Par contre, si l’on recherche un seuil OST pour predire la remission echographique au niveau d’une articulation prise isolement, les VPP sont elevees (95,9 ou 93,7 selon la definition de la remission) : si une articulation presente un score OST inferieur au seuil, il y a 95,9 ou 93,7 % de chances que cette articulation soit en remission echographique. Discussion Le HandScan est correle aux differents scores d’activite de la PR et a l’inflammation de la membrane synoviale en echographie. Le HandScan est capable de discriminer la remission selon les differents scores d’activite clinicobiologiques avec une bonne VPN : si la valeur fournie pour le patient par le HandScan est au-dessus du seuil, il est tres probable qu’il ne sera pas en remission clinique. Le HandScan est moins performant pour predire la remission echographique a l’echelle du patient, mais il fournit, a l’echelle de l’articulation, une excellente VPP quant a la remission echographique. Conclusion Le HandScan est un outil prometteur dans la metrologie de la PR.

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types., Graphical abstract, D’Antonio et al. characterize associations between GWAS signals for COVID-19 disease and eQTLs in 69 human tissues to identify causal variants and their underlying molecular mechanisms. They show that diverse symptoms and disease severity of COVID-19 are associated with variants affecting gene expression in a wide variety of tissues.

Osteoarthritis is characterized by structural alteration of joints. Fibrosis of the synovial tissue is often detected and considered one of the main causes of joint stiffness and pain. In our earlier proteomic study, increased levels of vitronectin (VTN) fragment (amino acids 381–397) were observed in the serum of osteoarthritis patients. In this work, the affinity of this fragment for integrins and its putative role in TGF-β1 activation were investigated. A competition study determined the interaction of VTN(381–397 a.a.) with αVβ6 integrin. Subsequently, the presence of αVβ6 integrin was substantiated on primary human fibroblast-like synoviocytes (FLSs) by western blot and flow cytometry. By immunohistochemistry, β6 was detected in synovial membranes, and its expression showed a correlation with tissue fibrosis. Moreover, β6 expression was increased under TGF-β1 stimulation; hence, a TGF-β bioassay was applied. We observed that αVβ6 could mediate TGF-β1 bioavailability and that VTN(381–397 a.a.) could prevent TGF-β1 activation by interacting with αVβ6 in human FLSs and increased α-SMA. Finally, we analyzed serum samples from healthy controls and patients with osteoarthritis and other rheumatic diseases by nano-LC/Chip MS–MS, confirming the increased expression of VTN(381–397 a.a.) in osteoarthritis as well as in lupus erythematosus and systemic sclerosis. These findings corroborate our previous observations concerning the overexpression of VTN(381–397 a.a.) in osteoarthritis but also in other rheumatic diseases. This fragment interacts with αVβ6 integrin, a receptor whose expression is increased in FLSs from the osteoarthritic synovial membrane and that can mediate the activation of the TGF-β1 precursor in human FLSs., Rheumatology: A starting point for joint disease Insights into a mechanism underlying the formation of fibrotic tissue within joints in osteoarthritis may also prove relevant to other rheumatological disorders. The general mechanisms underlying fibrosis are reasonably well understood, but it remains unclear what triggers these processes in osteoarthitis. Researchers of the University of Liège in Belgium have uncovered a possible explanation based on experiments with cultured primary synovial fibroblasts from patients. Osteoarthitis is characterized by increased levels of a fragment of the protein vitronectin, and the researchers demonstrated that this in turn binds to a protein called αVβ6, potentially promoting initiation of fibrosis. They also observed elevated levels of the same vitronectin fragment in two other rheumatoid disorders, lupus and systemic sclerosis, and concluded that further research is needed to characterize this protein’s role in inflammation and fibrosis.

We read with interest the article of Bozzalla Cassione et al about COVID-19 incidence in their systemic lupus erythematosus (SLE) cohort.1 Their study adds useful epidemiological information about COVID-19 risk in SLE.1 They suggest that hydroxycholoroquine was not protective, but could not draw definite conclusion and open the question to immunosuppressive drugs’ influence. We would like to share analysis of our SLE cohort (n=225) that can help to answer these questions and determine COVID-19 infection risk factors. Determining COVID-19 incidence is challenging: PCR lacks sensitivity, was usually realised only in severely ill patients and patients with suggestive benign symptoms could stay at home without medical contact. We studied the incidence of COVID-19 infection, either asserted or suspected, by analysing positive nasopharyngeal PCR, hospitalisation or contact with emergency department, but also suspected diagnosis in ambulatory medicine. Each patient was called by phone to determine COVID-19 suggestive symptoms since 4 February 2020, date of the first case in our country. Among our patients, 92.9% were female, with a mean (±SD) age of 51.7 (±14.9) years. Most recent biological evaluation showed positivity for ds-DNA in 24% (median (min–max) levels: 139 (12–758) IU/mL). Mean (±SD) number of 1997 American College of Rheumatology (ACR), 2019 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) and Systemic Lupus International Collaborating Clinics (SLICC) classification criteria were 4.5 (±1.5), …

CEMIP (for “Cell migration-inducing protein” also called KIAA1199 and Hybid for “Hyaluronan-binding protein”) expression is increased in cancers and described as a regulator of cell survival, growth and invasion. In rheumatoid arthritis, CEMIP is referred to as an angiogenic marker and participates in hyaluronic acid degradation. In this study, CEMIP expression is investigated in healthy and osteoarthritis (OA) cartilage from human and mouse. Its role in OA physiopathology is deciphered, specifically in chondrocytes proliferation and dedifferentiation and in the extracellular matrix remodeling. To this end, CEMIP, αSMA and types I and III collagen expressions were assessed in human OA and non-OA cartilage. CEMIP expression was also investigated in a mouse OA model. CEMIP expression was studied in vitro using a chondrocyte dedifferentiation model. High-throughput RNA sequencing was performed on chondrocytes after CEMIP silencing. Results showed that CEMIP was overexpressed in human and murine OA cartilage and along chondrocytes dedifferentiation. Most of genes deregulated in CEMIP-depleted cells were involved in cartilage turnover (e.g., collagens), mesenchymal transition and fibrosis. CEMIP regulated β-catenin protein level. Moreover, CEMIP was essential for chondrocytes proliferation and promoted αSMA expression, a fibrosis marker, and TGFβ signaling towards the p-Smad2/3 (Alk5/PAI-1) pathway. Interestingly, CEMIP was induced by the pSmad1/5 (Alk1) pathway. αSMA and type III collagen expressions were overexpressed in human OA cartilage and along chondrocytes dedifferentiation. Finally, CEMIP was co-expressed in situ with αSMA in all OA cartilage layers. In conclusion, CEMIP was sharply overexpressed in human and mouse OA cartilage and along chondrocytes dedifferentiation. CEMIP-regulated transdifferentiation of chondrocytes into “chondro-myo-fibroblasts” expressing α-SMA and type III collagen, two fibrosis markers. Moreover, these “chondro-myo-fibroblasts” were found in OA cartilage but not in healthy cartilage.

Phosphorylation of p62/SQSTM1 (p62) on Serine 349 (P-Ser349 p62) as well as proteasome dysfunction have been shown to activate the cell protective Keap1/Nrf2 pathway. We showed previously that BAY 11-7085-induced human synovial fibroblast cell death includes autophagy and p62 downregulation. In this work, we have studied expression of P-Ser349 p62 in human synovial fibroblasts. Results showed that P-Ser349 p62 was not detected in synovial cell extracts unless cells were cultured in the presence of proteasome inhibitor (MG132). MG132 revealed P-Ser349 p62 turnover, that was further increased by concomitant autophagy inhibition and markedly enhanced in serum starved cells. Starvation sensitized synovial fibroblasts to BAY 11-7085 while MG132 protected both non-starved and starved cells from BAY 11-7085-induced cell death. Lentivirus mediated overexpression of phosphorylation-mimetic p62 mutant S349E markedly protected synovial fibroblasts from BAY 11-7085. Inhibitor of Keap1-P-S349 p62 interaction, K67, had synergistic effect with MG132. Starvation increased p62 molecular weight, that was reversed by serum and bovine serum albumin re-feeding. Furthermore, starvation markedly induced RAD23B. Increased endo-β-N-acetylglucosaminidase (ENGase) turnover was detected in starved synovial fibroblasts. PNGase F treatment produced faster migration p62 form in human synovial tissue extracts but starvation-like p62 form of higher molecular weight in synovial cell extracts. Co-transfection of NGLY1, with p62 or p62 mutants S349A and S349E markedly stabilized p62 expressions in HEK293 cells. Tunicamycin upregulated p62 and protected synovial fibroblasts from BAY 11-7085-induced cell death. These results showed that P-Ser349 p62 has pro-survival role in human synovial fibroblasts and that de-glycosylation events are involved in p62 turnover.

Introduction L’arthrose est maintenant reconnue comme une pathologie associee a la senescence cellulaire, caracterisee par un arret robuste de la proliferation cellulaire, l’apparition de degâts a l’ADN, l’expression d’une activite enzymatique metabolique comme la β-galactosidase acide ou encore l’expression d’inhibiteurs des proteines-kinases dependantes des cyclines (CKI) p16INK4A et p21, induisant un secretome catabolique et pro-inflammatoire. A ce jour, il n’y a pas de traitement curatif de l’arthrose et les infiltrations intra-articulaires de glucocorticoides restent toujours largement utilisees dans la gonarthrose pour lutter contre l’inflammation de la membrane synoviale. Toutefois, ces infiltrations restent debattues compte tenu d’une toxicite potentielle sur l’articulation et d’une possible augmentation des marqueurs de senescence par les glucocorticoides dans des etudes in vitro. L’objectif de ce travail est d’etudier l’influence des glucocorticoides sur les marqueurs de senescence et sur l’induction de la senescence dans des fibroblastes synoviaux (FS) issus de patients arthrosiques et dans des cellules souches mesenchymateuses (CSM). Materiels et methodes In vitro, les FS et les CSM sont stimules pendant 7 jours avec le glucocorticoide prednisolone a trois doses differentes (1,5 et 10 μM), puis etudies aux 8e et au 15e jours. Les marqueurs de senescence cellulaire sont etudies par les techniques suivantes : proliferation et viabilite cellulaire (BrdU et MTS), coloration β-galactosidase acide, lesions a l’ADN (immunofluorescence pour ɣH2AX) et expression (Western-Blot et RT-qPCR) des CKI p16INK4A et p21. La senescence est induite experimentalement par irradiation. p16INK4A est egalement etudie dans des biopsies de membrane synoviale par immunohistochimie (CINtec, Roche). Resultats (1) Nous confirmons la presence de cellules senescentes positives pour p16INK4A dans les membranes synoviales de patients arthrosiques. Ces cellules sont significativement plus presentes dans les stades avances (Kellgren & Lawrence grade 2-4 versus grade 0–1). (2) La prednisolone n’induit pas de phenotype senescent dans les FS, quelle que soit la dose utilisee : nous n’observons pas de reduction de la proliferation cellulaire (au contraire, le taux de proliferation est plus eleve dans les FS stimules par la prednisolone), sans accumulation significative de cellules positives pour la β-galactosidase acide ni apparition de lesions a l’ADN. Les taux d’ARNm codant pour p21 sont diminues, alors que seule une augmentation de p16INK4A est retrouvee. (3) La prednisolone n’aggrave pas l’induction experimentale de la senescence dans les FS apres irradiation : aucune modulation des parametres de senescence n’est observee. (4) La prednisolone n’induit pas de phenotype senescent dans les CSM : malgre l’augmentation du pourcentage de cellules positives pour la β-galactosidase apres stimulation par la prednisolone, nous n’observons aucune reduction de la proliferation cellulaire, aucune accumulation de degâts a l’ADN et pas d’augmentation d’expression des CKI p16INK4A et p21. Discussion La prednisolone n’induit pas de phenotype senescent dans les FS de patients arthrosiques et les CSM, avec au contraire un taux de proliferation plus eleve dans les FS apres stimulation par la prednisolone. Il n’y a pas d’effet deletere (mais pas non plus d’effet positif) sur l’etablissement de la senescence cellulaire apres induction experimentale dans les cellules arthrosiques. Conclusion Les cellules senescentes sont presentes dans la membrane synoviale arthrosique, mais nos donnees in vitro sont rassurantes quant a l’absence d’induction ou d’aggravation de la senescence cellulaire apres stimulation par un derive cortisone.

To perform a systematic review to establish whether blind injections of the gleno-humeral (GHJ) joint may be an accurate alternative to injections performed imaging guidance, considering multiple anatomical approaches. Our search strategy yielded 478 articles for Scopus, 815 articles for MEDLINE, 128 articles for Cochrane Central Register of Controlled Trials and 555 articles for Embase until May 2016. One hundred and sixty-seven abstracts were retrieved after duplicates removal. Two readers independently reviewed all the 1067 abstracts. They selected for the full-text analysis only the abstracts in which the accuracy of intra-articular position of the needle was confirmed on imaging (humans) or by a surgical dissection (cadavers). Thirty-eight studies were eventually selected for the full-text reading and data extraction. The selected studies included a total of 2309 patients (2690 shoulders) and 195 cadavers (299 shoulders). To objectively assess the methodological quality of the present systematic review, “Assessment of Multiple Systematic Review” (AMSTAR) tool was used. The overall accuracy of the intra-articular injection in GHJ varied from 42 to 100% in the 38 selected studies. Imaging guidance was used in 65% of articles and the overall accuracy of guided GHJ injections was higher than blind injection. However, five articles in which blind injection the GHJ was used (159 shoulders) reported accuracy as high as 100%. A comprehensive review of the literature confirms that guided injections of the GHJ have overall accuracy higher compared to blind injection. Nevertheless, in some studies, including a relatively large number of shoulders, blind injections have been proven to be 100% accurate. Hence, blind injections of GHJ could be proposed a cost-effective alternative to imaging-guided injection. A large prospective randomized study is needed to gauge this hypothesis and compare the cost-effectiveness of these two techniques for the most common anatomical approaches.

Introduction La dermatomyosite (DM) est une maladie auto-immune rare caracterisee par une faiblesse musculaire et une eruption cutanee. Son association avec le cancer est bien connue mais le terme « paraneoplasique » reste debattu. Nous rapportons ici le premier cas d’une patiente atteinte d’une DM ayant recu du pembrolizumab, un inhibiteur des points de controle immunitaire (IPCI) dirige contre le recepteur « Programmed cell Death protein 1 » (PD-1). Observation Une patiente de 71 ans est vue en consultation avec une clinique de DM, des creatines kinases (CK) augmentees (1800 UI/L, n Trois semaines plus tard, la patiente presente une poussee de dermatomyosite avec perte de force severe des 4 membres et nette majoration des CK (9359 UI/L). L’administration de hautes doses de corticoides (methylprednisolone 125, puis 1000 mg) et une perfusion d’infliximab (4 mg/kg) ont ete inefficaces, tant sur les symptomes que sur le taux de CK, avec apparition de troubles de deglutition. Des immunoglobulines intraveineuses (IgIV) ont alors ete administrees pendant 4 jours (0,5 g/kg/j), suivies de methotrexate sous-cutane (20 mg/semaine). L’evolution clinique et biologique a alors ete progressivement positive, avec un suivi clinique a un an rassurant : amelioration significative de la force musculaire, recuperation complete des troubles de deglutition et normalisation des CK. Discussion Les patients avec maladie auto-immune preexistante qui recoivent une immunotherapie par IPCI presentent un taux plus eleve d’effets secondaires immuno-induits que la population generale, avec significativement plus de poussees de la maladie. En general, ces poussees sont peu graves et une maladie immunitaire preexistante n’est pas une contre-indication absolue a l’utilisation d’un IPCI. Toutefois, notre patiente a presente un effet secondaire immuno-induit grave resistant a une corticotherapie intraveineuse. Une analyse de la litterature a identifie 3 autres patients avec une DM preexistante traites par d’autres IPCI, avec une poussee chez 2 d’entre eux. Ce cas illustre l’effet benefique des IgIV pour le traitement des poussees de dermatomyosite induites par un IPCI. En effet, notre patiente n’a pas repondu a l’infliximab alors que les anti-TNF alpha sont habituellement consideres comme la deuxieme ligne de traitement pour la plupart des effets secondaires immuno-induits. Pour les myosites, les IgIV devraient donc etre preferees [1] . Les maladies auto-immunes « paraneoplasiques » ou « associees au cancer » ont une evolution particuliere sous IPCI. Une etude recente a montre une aggravation de la maladie auto-immune dans la moitie des cas, meme lorsque l’evolution du cancer sous-jacent est positive [2] . Cela doit donc nous inciter a etre prudent lorsque nous introduisons un IPCI chez des patients atteints d’une maladie auto-immune preexistante. Conclusion Vu l’utilisation grandissante des IPCI, leur administration chez des patients avec une maladie auto-immune preexistante va etre de plus en plus frequente. Ce cas clinique rappelle que, bien que les IPCI ne soient pas contre-indiques formellement dans cette situation, leur utilisation peut mener a une poussee parfois grave de la maladie sous-jacente. Le cas d’une myosite preexistante doit mener a une attention particuliere vu la gravite potentielle des poussees.

We previously reported 18FPRGD2 uptake by the coxofemoral lining, intervertebral discs and facet joint osteophytes in OA using PET/SCAN imaging. However, the molecular mechanism by which the PRGD2 tracer interacts with joint tissues and osteophytes in OA remains unclear. As PRGD2 ligands are expected to belong to the RGD-specific integrin family, the purpose of this study was (i) to determine which integrin complexes display the highest affinity for PRGD2-based ligands, (ii) to analyze integrin expression in relevant tissues, and (iii) to test integrin regulation in chondrocytes using OA-related stimuli to increase the levels of fibrosis and ossification markers. To this end, the affinity of PRGD2-based ligands for five heterodimeric integrins was measured by competition with 125I-echistatin. In situ analyses were performed in human normal vs. OA cartilage and spinal osteophytes. Osteophytes were characterized by (immuno-)histological staining. Integrin subunit expression was tested in chondrocytes undergoing dedifferentiation, osteogenic differentiation, and inflammatory stimulation. The integrins αVβ5, αVβ3, and αVβ6 presented the highest affinity for PRGD2-based ligands. In situ, the expression of these integrins was significantly increased in OA compared to normal cartilage. Within osteophytes, the mean integrin expression score was significantly higher in blood vessels, fibrous areas, and cells from the bone lining than in osteocytes and cartilaginous zones. In vitro, the levels of integrin subunits were significantly increased during chondrocyte dedifferentiation (except for β6), fibrosis, and osteogenic differentiation as well as under inflammatory stimuli. In conclusion, anatomical zones (such as OA cartilage, intervertebral discs, and facet joint osteophytes) previously reported to show PRGD2 ligand uptake in vivo expressed increased levels of αVβ5, αVβ3, and β6 integrins, whose subunits are modulated in vitro by OA-associated conditions that increase fibrosis, inflammation, and osteogenic differentiation. These results suggest that the increased levels of integrins in OA compared to normal tissues favor PRGD2 uptake and might explain the molecular mechanism of OA imaging using the PRGD2-based ligand PET/CT.

Tissue accumulation of p16INK4a-positive senescent cells is associated with age-related disorders, such as osteoarthritis (OA). These cell-cycle arrested cells affect tissue function through a specific secretory phenotype. The links between OA onset and senescence remain poorly described. Using experimental OA protocol and transgenic Cdkn2a+/luc and Cdkn2aluc/luc mice, we found that the senescence-driving p16INK4a is a marker of the disease, expressed by the synovial tissue, but is also an actor: its somatic deletion partially protects against cartilage degeneration. We test whether by becoming senescent, the mesenchymal stromal/stem cells (MSCs), found in the synovial tissue and sub-chondral bone marrow, can contribute to OA development. We established an in vitro p16INK4a-positive senescence model on human MSCs. Upon senescence induction, their intrinsic stem cell properties are altered. When co-cultured with OA chondrocytes, senescent MSC show also a seno-suppressive properties impairment favoring tissue degeneration. To evaluate in vivo the effects of p16INK4a-senescent MSC on healthy cartilage, we rely on the SAMP8 mouse model of accelerated senescence that develops spontaneous OA. MSCs isolated from these mice expressed p16INK4a. Intra-articular injection in 2-month-old C57BL/6JRj male mice of SAMP8-derived MSCs was sufficient to induce articular cartilage breakdown. Our findings reveal that senescent p16INK4a-positive MSCs contribute to joint alteration.

Background Tissue accumulation of p16INK4A-positive senescent cells is associated with age-related disorders such as osteoarthritis (OA). These senescent cells induce a tissue loss of function through a particular secretory phenotype called SASP (senescence-associated secretory phenotype). Objectives Links between OA onset and cellular senescence remain poorly detailed. We wanted to determine the localization of articular senescent cells in in vivo OA mouse models and study the involvement of mesenchymal stem cells (MSC) senescence in OA pathogenesis. Methods Wild-type mice C57BL/6, SAMP8/R1 (senescence accelerated mouse-prone and resistant), transgenic p16INK4A+/Luc and p16INK4A Luc/Luc were used. Experimental OA was induced by intraarticular injections of collagenase (CIOA). Cartilage, synovial tissue and subchondral bone were analyzed by histology, RT-qPCR and micro-tomography. MSCs come from healthy human donors and primary chondrocytes from OA patients. Results (1) CIOA was induced in senescence-driven luciferase transgenic mice. Under CCD camera, a peak in luminescence was detected at day 24 post-injection revealing the presence of senescent cells in the joint. Remarkably, articular senescence is not only a marker of the pathology but contributes to OA onset: mice deficient in p16INK4a, a main senescence-driving known cell cycle inhibitor, were partially protected against CIOA. These results were confirmed in C57Bl/6 mice after CIOA by showing an increase in gene expression for senescence, catabolic and inflammatory markers in the synovial tissue preceding cartilage degradation. (2) MSCs found in synovial, cartilage, fat pad and bone marrow participate in joint homeostasis. Because MSC are proposed to be at the root of OA development, we hypothesize that cellular senescence onset in these progenitor cells would be a possible etiological factor for OA. We have established an in vitro p16INK4A-induced senescence model on human primary MSC: their intrinsic properties such as self-renewing are altered during senescence onset. Furthermore, in co-culture conditions with chondrocytes from OA patients, senescent MSC lost their extrinsic chondroprotective properties. (3) To in vivo challenge these findings, we rely on the mouse model of accelerated senescence SAMP8, which develop spontaneous OA at the age of 6 months with cartilage degradation, synovial hypertrophy, osteophytosis and subchondral bone remodeling associated to meniscal calcification. Isolated MSC from these mice express senescence but non-inflammatory markers (p16INK4a, p21waf1, MMP13, TGF-β1). Remarkably, intra-articular injection of these isolated SAMP8-derived MSC compared to SAMR1-derived control MSC, in young wid-type C57Bl/6 mice, was suffisant by its own, to induce significant articular cartilage degradation (OA score of 12.2 ± 1.5 vs 6.1 ± 3.5 for SAMP8 and SAMR1 MSC respectively. p Conclusion p16INK4A-induced cellular senescence in MSC played a causative role in cartilage loss of function and OA pathogeny. In vitro, senescent MSC show altered intrinsic and extrinsic supportive tissue functions. In vivo, intra-articular injection of senescent MSC was sufficient to induce cartilage degradation. Specific targeting of such deleterious senescent cells could be an innovating and promising treatment in OA. Acknowledgement We acknowledge FOREUM and AGEMED as supporters of our projects. Disclosure of Interests Olivier Malaise Speakers bureau: Amgen, Yassin Tachikart: None declared, Michael Constantinides: None declared, Marcus Mumme: None declared, Daniele Noel: None declared, Jing Wang: None declared, Christian Jorgensen: None declared, Jean-Marc Brondello: None declared

Background Osteoporosis (OP) is a serious and prevalent disease identified by Dual Energy X-ray Absorptiometry (DEXA) that can be performed in an ambulatory or an hospitalized population. Objectives Aims are: (1) to characterize patients who had DEXA in a university department of rheumatology to study its diagnostic efficacy; (2) to look after risk factors specific to our population; (3) to evaluate the efficiency of a non-systematic and opportunistic intra-hospital OP screening by comparing results for ambulatory and hospitalized patients in the different departments of the hospital. Methods From 2007 to 2012, 6406 initial DEXA from consecutive patients were prospectively encoded (1494 in 2007, 1158 in 2008, 1079 in 2009, 945 in 2010, 868 in 2011 and 862 in 2012) (identical DEXA). Results Cohort characteristics are the following: women 74.4%, mean age (± 1 standard deviation) 60.5 years (± 14.3), mean BMI 25.1 (± 5.1), history of corticotherapy in 30.5%, previous fracture in 29% and current hospitalization in 28.8% of cases. OP (at one of the 3 sites) was diagnosed in 22.3%, a stable value over the years, with, as a repartition, lumbar spine, femoral neck and total hip OP in 13.7%, 13.6% and 9.2% respectively. In 3.9%, OP was diagnosed at all the 3 sites. In univariate analysis, OP risk factors were age, history of fracture and low BMI (for all 3 sites), corticotherapy (lumbar spine and femoral neck) and male gender (lumbar spine). In multivariate analysis, regardless of site, age, fracture history, low BMI, and male gender increased the OP risk. Intra-hospital screening identified OP (at any of the 3 sites) in 31.8% (vs 18.5%, p Conclusion (1) One in five DEXA identified OP at one of the three sites in the ambulatory population but only one in three in the hospitalized patients. Hospital screening is therefore essential and more efficient than the ambulatory one. Hospital time seems to be an opportunity to fill the gaps in ambulatory screening. (2) Intra–hospital screening targeted an older and more masculine population with more fracture history, which may explain its better performance, which does not decline over the years. Z–score differences revealed that the efficiency difference was not only due to an older age of the hospitalized population but could be secondary to more internistical co–morbidities or treatment deleterious for bones. (3) In addition to conventional ones, the male gender is a risk factor for OP, recalling the importance of screening for all and not only in the female population (which represents ¾ of the cohort). Disclosure of Interests Olivier Malaise Speakers bureau: Amgen, Marie Detroz: None declared, Mathieu Leroy: None declared, Lorenzo Leonori: None declared, Laurence Seidel: None declared, Michel Malaise: None declared

Objectives: To contribute to a precise and thorough knowledge of immune-related adverse events (irAE) induced by immune checkpoint inhibitors (ICI) and to emphasize the importance of this specific form of toxicity in terms of potential predictive value and long-term effects. Materials and Methods: We report the first case of granulomatosis with polyangiitis (GPA) in a patient treated with an anti-Programmed Death protein-1 (PD-1) antibody for advanced non-small-cell lung cancer (NSCLC). Results: After a single dose of this drug the patient showed severe myositis associated with a high anti-PR3 anti-neutrophil cytoplasmic antibody titer. Discontinuation of the anti-PD-1 and introduction of corticoids led to a remission of the irAE. Regarding tumor a partial response was noted. A year later a neutrophilic, sterile pleural exudate and cutaneous lesions appeared with the pathological findings of neutrophilic vasculitis. Retreatment with corticoids induced a new remission of symptoms. It remains unclear whether GPA was preexisting and clinically silent but revealed by the use of ICI or primarily induced by this treatment. Conclusions: irAE are rare when anti-PD-1 antibodies are used in monotherapy. They present with a distinct clinical picture and temporal course and require specific treatment. Patients with irAE usually have a favorable oncological outcome.

Inhibition of proapoptotic pathways in synovial fibroblasts is one of the major causes of synovial proliferation and hyperplasia in rheumatic diseases. We have shown previously that NF-κB inhibitor BAY 11-7085, through inactivation of PPAR-γ, induces apoptosis in human synovial fibroblasts. In this work we showed that BAY 11-7085 induced autophagy that preceded BAY 11-7085-induced apoptosis. Of interest, BAY 11-7085 induced Serine 211 phosphorylation and degradation of glucocorticoid receptor (GR). Glucocorticoid prednisolone induced both activation and degradation of GR, as well as autophagy in synovial fibroblasts. BAY 11-7085-induced cell death was significantly decreased with glucocorticoid inhibitor mifepristone and with inhibitors of autophagy. Both BAY 11-7085-induced autophagy and GR activation were down regulated with PPAR-γ agonist, 15d-PGJ2 and MEK/ERK inhibitor UO126. Inhibition of autophagy markedly decreased endogenous and BAY 11-7085-induced ERK phosphorylation, suggesting a positive feed back loop between ERK activation and autophagy in synovial fibroblasts. Co-transfection of MEK1 with PPAR-γ1 in HEK293 cells caused known inhibitory phosphorylation of PPAR-γ1 (Serine 112) and enhanced GR degradation, in the absence or presence of prednisolone. Furthermore, GR was both phosphorylated on Serine 211 and down regulated in synovial fibroblasts during serum starvation induced autophagy. These results showed that GR activation and PPAR-γ inactivation mediated BAY 11-7085-induced autophagy.

Introduction Le depistage de l’osteoporose (OP) dans la polyarthrite rhumatoide (PR) reste insuffisant. Nos objectifs sont de determiner : – si les patients redevables d’un traitement anti-OP selon les recommandations SFR 2018 presentent des caracteristiques de la PR permettant de les identifier, de determiner ; – si ces recommandations sont discriminantes en termes de micro-architecture osseuse ; – de correler l’activite de la PR avec la structure osseuse. Patients et methodes Quarante-deux PR ont passe une evaluation clinique avec biologique, echographique, PET-scan articulaire, osteodensitometrie osseuse (DEXA) et micro-scanner osseux peripherique (Hr-pQCT). Resultats Dix-huit pour cent des patients presentent une OP densitometrique, avec un tassement (VFA) chez 8 % et un FRAX moyen de 10,6 ± 7,2 %. Quinze pour cent des patients ont recu un traitement contre l’OP. Si l’on applique les recommandations SFR 2018 du traitement de l’OP, 38 % des patients auraient du etre traites (absence d’accord entre le traitement donne et recommande). Les patients redevables d’un traitement selon les recommandations SFR 2018 ont des DMO plus basses, un FRAX plus eleve, un TBS plus bas et plus de fractures. L’etude de la micro-architecture (Hr-pQCT, tibia et radius) montre que ces patients ont des densites volumiques totales et trabeculaires (Tt. et Tb.vBMD), un rapport volume trabeculaire/volume total (BV/TV), un nombre (Tb.N) et une epaisseur des travees (Tb.Th) inferieurs, avec un espacement entre les travees (Tb.sp) plus eleve. L’epaisseur corticale (CT.Th) est plus faible. Ces patients ont une activite plus elevee de la maladie (duree de la maladie, nombre d’articulations douloureuses, VAS patient, scores DAS28CRP, DAS28VS, CDAI et SDAI plus eleves), sans difference d’âge, d’IMC, de traitement, de parametres biologiques ou echographiques. En analyse multivariee (considerant egalement l’âge, le sexe, l’IMC et les traitements), plusieurs caracteristiques de la PR influencent negativement les parametres osseux : – la densite osseuse (DEXA) est plus basse si la duree de la maladie est plus longue et le DAS28CRP eleve (correlation duree de la maladie et demineralisation au col femoral ; DAS28CRP et DMO L1L4/demineralisation a la hanche/demineralisation globale) ; – la densite trabeculaire, la structure des travees et epaisseur corticale sont moins bonnes si la maladie est active (articulations gonflees et Tb.vBMD ; DAS28CRP et Tb.Th ; HAQ et Tb.Th/Ct.Th/BV/TV ; ankylose matinale et Ct.vBMD) ; – la structure des travees est moins bonne si la VS est haute (VS et Tb.Sp/Tb.1/N.SD) ; – la porosite corticale est plus importante et la densite osseuse trabeculaire inferieure si l’activite echographique est elevee (PDI poignet et Ct.Po/Ct.Po.dm ; positivite en echographie et Tb.vBMD) ; l’architecture des travees et les densites trabeculaires sont moins bonnes si l’activite articulaire par PET-scan est elevee (∑SUV et Tt.vBMD/Tb.vBMD/Tb.N/Tb.Sp). Discussion Le pourcentage de patient traites est inferieur a ce que proposent les recommandations, montrant l’importance de definir une population a risque sur qui centrer le depistage. L’activite de la PR est associee a des densites osseuses inferieures (DEXA) et a des parametres micro-architecturaux de densite (trabeculaire et corticale) et de structure (organisation des travees et porosite corticale) moins bons (Hr-pQCT), independamment du sexe, du BMI et de l’âge. Les patients avec une maladie active sont egalement plus susceptibles de devoir recevoir un traitement contre l’osteoporose selon les recommandations SFR 2018. L’application de ces criteres identifie une population avec une micro-architecture (Hr-pQCT) moins bonne. Conclusion L’activite de la PR est un facteur de risque de mauvaise macro- et micro-architecture osseuse.

International audience; Over the past years, through in vitro studies and unique animal models, biologists and clinicians have demonstrated that cellular senescence is at the root of numerous age-related chronic diseases including osteoarthritis and osteoporosis. This non-proliferative cellular syndrome can modify other surrounding tissue-resident cells through the establishment of a deleterious catabolic and inflammatory microenvironment. Targeting these deleterious cells through local or systemic seno-therapeutic agent delivery in pre-clinical models improves dramatically clinical signs and extends health span. In this review, we will summarize the current knowledge on cellular senescence, list the different strategies for identifying seno-suppressive therapeutic agents and their translations to rheumatic diseases.

[Abstract] Abstract Background/aims: Synovial fibrosis is a pathological process that is observed in several musculoskeletal disorders and characterized by the excessive deposition of extracellular matrix, as well as cell migration and proliferation. Despite the fact that glucocorticoids are widely employed in the treatment of rheumatic pathologies such as osteoarthritis (OA) and rheumatoid arthritis, the mechanisms by which glucocorticoids act in the joint and their impacts on pro-fibrotic pathways are still unclear. Materials: Human OA synovial fibroblasts were obtained from knee and hip joints. Cells were treated with prednisolone (1 mM) or transforming growth factor-beta 1 (TGF-β1) (10 ng/ml) for 1 and 7 days for quantification of RNA and protein expression (by real-time quantitative reverse transcription-PCR and western blot, respectively), 72 h for immunocytochemistry analysis, and 48 h for proliferation (by BrdU assay) and migration (by wound assay) studies. In addition, cells were preincubated with prednisolone and/or the peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist 15-deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2) for 6 h before adding TGF-β1. pSmad1/5, pSmad2 and β-catenin levels were analyzed by Western blot. The activin receptor-like kinase-5 (ALK-5) inhibitor (SB-431542) was employed for the mechanistic assays. Results: Prednisolone showed a predominant anti-fibrotic impact on fibroblast-like synoviocytes as it attenuated the spontaneous and TGF-β-induced gene expression of pro-fibrotic markers. Prednisolone also reduced α-sma protein and type III collagen levels, as well as cell proliferation and migration after TGF-β stimulation. However, prednisolone did not downregulate the gene expression of all the pro-fibrotic markers tested and did not restore the reduced PPAR-γ levels after TGF-β stimulation. Interestingly, anti-fibrotic actions of the glucocorticoid were reinforced in the presence of the PPAR-γ agonist 15d-PGJ2. Combined pretreatment modulated Smad2/3 levels and, similar to the ALK-5 inhibitor, blocked β-catenin accumulation elicited by TGF-β. Conclusions: Prednisolone, along with 15d-PGJ2, modulates pro-fibrotic pathways activated by TGF-β in synovial fibroblasts at least partially through the inhibition of ALK5/Smad2 signaling and subsequent β-catenin accumulation. These findings shed light on the potential therapeutic effects of glucocorticoids treatment combined with a PPAR-γ agonist against synovial fibrosis, although future studies are warranted to further evaluate this concern.

This work reports on musculoskeletal uptake of 18F-FPRGD2, targeting the integrin αvβ3, in patients who had undergone 18F-FPRGD2 positron emission tomography combined with computed tomography (PET/CT) for oncologic purposes. Whole-body 18F-FPRGD2 PET/CT images of 62 cancer patients were retrospectively reviewed to detect foci of musculoskeletal 18F-FPRGD2 uptake. For 37 patients, a FDG PET/CT performed in clinical settings was available. In each joint with an abnormal uptake, the maximum standardized uptake value (SUVmax) was estimated. A total of 260 musculoskeletal foci of 18F-FPRGD2 uptake were detected. Most common sites of uptake were joints and discs (n = 160; 61.5 %), entheses (osteotendinous and osteoligamentous junctions; n = 55; 21.2 %) and recent fractures (n = 18; 6.9 %). In addition, 27 (10.4 %) miscellaneous foci were detected. Out of the 146 lesions for which a FDG PET was available, 63 % showed both 18F-FPRGD2 and FDG uptake, 33.6 % did not show FDG avidity and 3.4 % showed only FDG uptake. The uptake intensity of the 92 lesions positive with 18F-FPRGD2 and FDG was similar with both radiopharmaceuticals, but the target-to-background (blood pool or muscle) ratios were significantly higher with 18F-FPRGD2 than with FDG (p

International audience; Our societies are facing with the emergence of an exponential number of patients with age-related degenerative chronic diseases such as osteoarthritis or osteoporosis. The "better" aging will thus be at the center of the next medical challenges in order to delay the loss of independence of the elderly and reduce costs of our health services. Over the last 5 years, based on innovative mouse models or in vitro studies, several research teams have demonstrated that many age-related degenerative diseases have in common a deleterious accumulation of so-called senescent cells in their respective deficient tissues. Thus, under the concept of senolysis, it has been proposed to target pharmacologically in vivo these cells to eliminate them and thus delay the emergence of these chronic diseases of the elderly subject. We propose here to summarize the recent strategies applied for the identification of novel senolytics and their uses in osteoarthritis and osteoporosis therapies.; Avec le vieillissement des populations, nos sociétés doivent faire face à l’émergence d’un nombre exponentiel de patients atteints de maladies chroniques dégénératives liées à l’âge, telles que l’arthrose ou l’ostéoporose. Le « mieux » vieillir sera ainsi au centre des prochains défis médicaux par un maintien de l’autonomie des sujets âgés et une réduction des coûts des services de santé. Au cours des 5 dernières années, en se fondant sur des modèles murins innovants ou des études in vitro, de nombreuses équipes ont démontré que plusieurs pathologies dégénératives liées à l’âge avaient en commun une accumulation délétère de cellules dites sénescentes. Sous le concept de sénolyse, il a ainsi été proposé d’éliminer pharmacologiquement ces cellules afin de retarder l’émergence de ces pathologies chroniques du sujet âgé. Nous nous proposons ici de faire le point sur les stratégies récemment mises en place, permettant l’identification de composés sénolytiques, ainsi que de définir leurs utilisations thérapeutiques comme traitement de l’arthrose et de l’ostéoporose.

The aim of the study was to compare the learning curves of three beginner operators using two different techniques of intra-articular injection of the knee under fluoroscopic guidance with a superolateral approach. In total, 177 consecutive patients (72 females (40.7%) and 105 males (59.3%), mean age 42.2 ± 15.0 years) scheduled for a computed tomography (CT) arthrography and without joint effusion on the lateral X-rays were enrolled. They underwent an intra-articular injection of the knee under fluoroscopic guidance with a superolateral approach. Patients were randomly assigned to three different operators, including a junior supervisor and two first-year residents in radiology who never performed an intra-articular injection of the knee before the present study. Procedures in lateral or supine position were randomly assigned to three operators. There was a higher rate of successful injections with the lateral position (92.1%) than with supine position (80.2%) (odds ratio (OR) 4.52, 95% confidence interval (CI) 1.46–14.0). A significant learning effect was observed for the supine position, while none was observed for the lateral position. Pain and time of fluoroscopy did not differ between the two procedures (p = 0.85 and p = 0.10, respectively). Junior supervisor had a higher rate of successful intra-articular injection compared with the other two operators (p = 0.0072). There was a statistically significant higher rate of extravasation with the supine position (66.3%) than with lateral position (19.7%) (p

Objective Glucocorticoids are powerful anti-inflammatory compounds that also induce the expression of leptin and leptin receptor (Ob-R) in synovial fibroblasts through TGF-βsignalling and Smad1/5 phosphorylation. Compound A (CpdA), a selective glucocorticoid receptor agonist, reduces inflammation in murine arthritis models and does not induce diabetes or osteoporosis, thus offering an improved risk:benefit ratio in comparison with glucocorticoids. Due to the detrimental role of leptin in OA pathogenesis, we sought to determine whether CpdA also induced leptin and Ob-R protein expression as observed with prednisolone. Methods Human synovial fibroblasts and chondrocytes were isolated from the synovium and cartilage of OA patients after joint surgery. The cells were treated with prednisolone, TGF-β1, TNF-α and/or CpdA. Levels of leptin, IL-6, IL-8, MMP-1 and MMP-3 were measured by ELISA and expression levels of Ob-R phospho-Smad1/5, phospho-Smad2, α-tubulin and glyceraldehyde 3-phosphate dehydrogenase were analysed by western blotting. Results CpdA, unlike prednisolone, did not induce leptin secretion or Ob-R protein expression in OA synovial fibroblasts. Moreover, CpdA decreased endogenous Ob-R expression and down-regulated prednisolone-induced leptin secretion and Ob-R expression. Mechanistically, CpdA, unlike prednisolone, did not induce Smad1/5 phosphorylation. CpdA, similarly to prednisolone, down-regulated endogenous and TNF-α-induced IL-6, IL-8, MMP-1 and MMP-3 protein secretion. The dissociative effect of CpdA was confirmed using chondrocytes with no induction of leptin secretion, but with a significant decrease in IL-6, IL-8, MMP-1 and MMP-3 protein secretion. Conclusion CpdA, unlike prednisolone, did not induce leptin or Ob-R in human OA synovial fibroblasts, thereby demonstrating an improved risk:benefit ratio.

Osteoarthritis (OA) is a joint pathology characterized by progressive cartilage degradation. Medical care is mainly based on alleviating pain symptoms. Compelling studies report the presence of empty lacunae and hypocellularity in cartilage with aging and OA progression, suggesting that chondrocyte cell death occurs and participates to OA development. However, the relative contribution of apoptosis per se in OA pathogenesis appears complex to evaluate. Indeed, depending on technical approaches, OA stages, cartilage layers, animal models, as well as in vivo or in vitro experiments, the percentage of apoptosis and cell death types can vary. Apoptosis, chondroptosis, necrosis, and autophagic cell death are described in this review. The question of cell death causality in OA progression is also addressed, as well as the molecular pathways leading to cell death in response to the following inducers: Fas, Interleukin-1β (IL-1β), Tumor Necrosis factor-α (TNF-α), leptin, nitric oxide (NO) donors, and mechanical stresses. Furthermore, the protective role of autophagy in chondrocytes is highlighted, as well as its decline during OA progression, enhancing chondrocyte cell death; the transition being mainly controlled by HIF-1α/HIF-2α imbalance. Finally, we have considered whether interfering in chondrocyte apoptosis or promoting autophagy could constitute therapeutic strategies to impede OA progression.