No Correlation between Anti-drug Antibodies and Therapeutic Response in Tunisian Patients with Chronic Inflammatory Diseases Treated by TNF Blockers.

INTRODUCTION: Tumor necrosis factor alpha (TNF alpha) blockers such as infliximab (IFX) and adalimumab (ADA) had significantly changed the course of inflammatory diseases such as rheumatoid arthritis (RA), spondyloarthritis (SpA) and Crohn's disease (CD). However, about 30% of patients do not respond to these treatments. This lack of response may be due to the formation of antibodies against these drugs (anti-drug antibodies: ADAbs). The aim of this study was to determine the prevalence of ADAbs against IFX and ADA, and the trough serum concentration of IFX and ADA in RA, SpA or CD patients and to assess their impact on the therapeutic response. METHODS: A cross sectional, multi-centric study was conducted, including patients with RA, SpA or CD treated with IFX or ADA as a first biotherapy for at least 6 months. ADAbs and trough levels were measured by an Enzyme Linked Immunosorbent assay (ELISA). RESULTS: 197 patients were included (57 RA, 73 SpA and 67 CD). ADAbs were positive in 40% of cases for IFX and 25% for ADA. They were positive in 40% of SpA, 35% of RA, and 21% of CD. The presence of ADAbs was inversely correlated to the trough levels of IFX and ADA during RA (p = 0.01 and p < 0.0001), SpA (p < 0.01 and p < 0.0001) and CD (p = 0.001 and p = 0.04). For all pathologies, the presence of ADAbs was not correlated with disease activity. Concomitant methotrexate significantly reduced immunogenicity. CONCLUSION: In our study, the presence of ADAb and low trough levels seem to not affect the therapeutic response in patients on TNF alpha antagonists. Other tracks more than immunogenicity should be investigated to explain the loss of response to these biotherapies.

Factors influencing therapeutic adherence in Tunisian adults with asthma.

INTRODUCTION: Despite current recommendations, most asthmatics remain insufficiently controlled. This is largely due to non-adherence to medications. Looking for factors associated with lack of therapeutic adherence is mandatory in order to improve the management of these patients. AIM: To assess the degree of compliance in a population of Tunisian asthmatic patients and to identify the factors associated with poor compliance. METHODS: It was a cross-sectional study over a period of six months. Asthma control was assessed using the Asthma Control Test. Treatment compliance was specified using the Morisky questionnaire. Associations between adherence to treatment and certain patient characteristics were sought. RESULTS: During the study period, 165 adult patients were included (average age: 46.8 years±15.3 years; 114 women). The median duration of asthma evolution was 10.5 years [1-60 years]. Asthma was uncontrolled in 50% of the cases. Lack of treatment adherence was observed in 45% of patients. Compliance was better in women (p <0.05) and in patients with better socioeconomic status (p= 0.04). Patients with gastroesophageal reflux disease were also more observant (p=0.03); however, those with obesity were less (p> 0.05). In multivariate analysis, patients with good socioeconomic conditions (OR=4,516; IC95% [1.433-14.232]; p=0,01) and those with a previous a history of coronary artery disease (OR=15,37 ; IC95% [1.25-188.857] ; p=0.03) were more likely to have good adherence. CONCLUSION: Although it is a key element in the management of asthma, treatment compliance remains insufficient in Tunisian patients with asthma. Patient education is essential in order to correct the factors incriminated in uncontrolled asthma. The challenge remains to overcome the socioeconomic difficulties and the lack of access to treatment in our context.

The synovial fluid fibroblast-like synoviocyte: A long-neglected piece in the puzzle of rheumatoid arthritis pathogenesis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease during which fibroblast-like synoviocytes (FLS) contribute to both joint inflammation and destruction. FLS represent the core component of the synovial membrane. Following inflammation of this membrane, an effusion of cell-rich synovial fluid (SF) fills the joint cavity. Unlikely, SF has been shown to contain fibroblasts with some shared phenotypic traits with the synovial membrane FLS. These cells are called SF-FLS and their origin is still unclear. They are either brought into the synovium via migration through blood vessels, or they could originate within the synovium and exist in projections of the synovial membrane. SF-FLS function and phenotype are poorly documented compared to recently well-characterized synovial membrane FLS subsets. Furthermore, no study has yet reported a SF-FLS single-cell profiling analysis. This review will discuss the origin and cellular characteristics of SF-FLS in patients with RA. In addition, recent advances on the involvement of SF-FLS in the pathogenesis of RA will be summarized. Current knowledge on possible relationships between SF-FLS and other types of fibroblasts, including synovial membrane FLS, circulating fibrocytes, and pre- inflammatory mesenchymal (PRIME) cells will also be addressed. Finally, recent therapeutic strategies employed to specifically target SF-FLS in RA will be discussed.

SFRP5 Enhances Wnt5a Induced-Inflammation in Rheumatoid Arthritis Fibroblast-Like Synoviocytes.

Background: Tissue derived fibroblast-like synoviocytes (td-FLS) are key actors in pannus formation and contribute to joint destruction and inflammation during rheumatoid arthritis (RA). Several members of the Wnt family, including Wnt5a, may contribute to RA td-FLS activation and can potentially serve as therapeutic targets. Objective: The present work aimed to investigate the expression of Wnt5a signaling elements in RA td-FLS and their potential precursors (fluid derived (fd) FLS and fibrocytes). We also studied the role of Wnt5a in RA td-FLS pro-inflammatory activity and whether the inhibitor SFRP5 could restore Wnt5a-induced synovial dysfunction in vitro. Materials and Methods: The levels of Wnt5a, SFRP5, Wnt5a receptors/coreceptors and Wnt5a pro-inflammatory targets were determined in cultured RA td-FLS, fd-FLS and fibrocytes using qPCR under basal conditions. The expression of pro-inflammatory molecules was assessed after RA td-FLS stimulation with Wnt5a and SFRP5 at different time points. Results: Our data showed that td-FLS, fd-FLS and fibrocytes from patients with RA expressed similar levels of Wnt5a and a set of Wnt5a receptors/coreceptors. We also demonstrated that Wnt5a stimulated the expression of the pro-inflammatory targets, especially IL1ß, IL8 and IL6 in RA td-FLS. Wnt5a-induced inflammation was enhanced in the presence of SFRP5. Furthermore, Wnt5a alone and in conjunction with SFRP5 inhibited the gene expression of TCF4 and the protein levels of the canonical coreceptor LRP5. Conclusion: Wnt5a pro-inflammatory effect is not inhibited but enhanced by SFRP5 in RA td-FLS. This research highlights the importance of carefully evaluating changes in Wnt5a response in the presence of SFRP5.

Expression of extracellular matrix components and cytokine receptors in human fibrocytes during rheumatoid arthritis.

Purpose: Fibroblast-like synoviocytes (FLS) represent one of the principal effectors of joint damage in rheumatoid arthritis (RA). Recent discovery of the circulating fibrocyte, a potential precursor of FLS, has raised issues regarding the characterization of fibrocytes with respect to their morphology and their biological role. In this study, we evaluated the morphology of fibrocytes in vitro and their ability to produce different extracellular matrix (ECM) components in comparison with two populations of RA FLS: synovial fluid FLS (fd-FLS) and intimal lining FLS (td-FLS). We also studied the expression of ECM regulators and a set of cytokine receptors involved in the pathogenesis of RA. Materials and Methods: Fibrocytes were cultured from peripheral blood of patients with RA. FLS were cultured from synovial fluids and tissues. ECM proteins (collagen I (col I) and fibronectin), Matrix metalloproteinases (MMP) (MMP3, and MMP9), ECM regulators (ß catenin, TCF4, and c-fos), and cytokine receptors (CXCR1, CXCR2, CXCR3, IL1RI, IL1RII, and IL6Rα) were analyzed using qRT-PCR and/or western blot. Results: Our results demonstrated that fibronectin and MMP3 levels were higher in FLS compared to fibrocytes. Although MMP9 was expressed in the three cell types, its level was greater in fibrocytes than in td/fd FLS. The three cell types expressed CXCR3, IL1RI, IL1RII, and IL6Rα, while the expression of CXCR1 and CXCR2 was restricted to fibrocytes. Conclusion: Our results demonstrated that fibrocytes express ECM molecules and cytokines receptors. The observed differences between fibrocytes and FLS may be due to their distinct functions or differentiation state during RA.Abbreviations: RA: Rheumatoid ArthritisFLS: fibroblast-like synoviocytestd: tissue derivedfd: fluid derivedSF: Synovial FluidWnt: WinglessMMP: Matrix MetalloproteinaseCIA: murine collagen induced arthritisECM: Extracellular matrixcol I: Collagen ITCF/LEF: T-cell factor/lymphoid enhancer-binding factorAP1: Activator Protein 1.

New Markers of Bone Fragility in Hemodialysis Patients: A Monocentric Study.

INTRODUCTION: Mechanisms underlying bone fragility in patients under dialysis are various. The assessment of bone disorder is not yet codified in these patients. Our study aimed to determine the relationship between the serum fibroblast growth factor 23 (FGF23) level and bone fragility. We also aimed to assess the bone alkaline phosphatase (bAP) to the C-terminal telopeptide of type I (CTX) ratio and the FGF23*bAP product to CTX ratio in patients under hemodialysis. METHODOLOGY: We conducted a cross-sectional study, including 76 patients under hemodialysis. To assess bone fragility, we measured bAP, CTX, and FGF 23. We calculated the bAP to the CTX ratio (bAP/CTX) and the FGF23*bAP product to the CTX ratio (FGF23*bAP/CTX). We defined bone fragility as the existence of osteoporosis or fragility fractures. Receiver operating characteristic (ROC) curves were evaluated for each biological using the existence of osteoporosis or fragility fracture as the gold standard for bone fragility. RESULTS: There were 51 men. The mean age was 53.36 ± 14.27 years. Bone fragility was noted in 25 cases. Patients with osteoporosis had higher FGF*bAP/CTX and bAP/CTX ratios. The ability of the ratio (bAP/CTX) to distinguish patients with osteoporosis from those without osteoporosis was good, with a ROC AUC of 0.707. The optimal ratio cut-off value with the highest accuracy was 9.72. The ability of the ratio (FGF23*bAP/CTX) to distinguish patients with bone fragility was good, with a ROC AUC of 0.701. The optimal ratio cut-off value with the highest accuracy was 1621.89 (sensitivity 60%, specificity 78.4%). CONCLUSION: Our study showed FGF23, FGF23*bAP product to CTX ratio, and the bAP to CTX ratio can be used as markers of bone fragility in hemodialysis patients. Therefore, these noninvasive and relatively inexpensive methods may serve to diagnose bone fragility in patients under hemodialysis.

Mineral bone disorder and osteoporosis in hemodialysis patients.

BACKGROUND: Bone disease is common in patients undergoing hemodialysis. It is the result of bone turnover abnormalities and the decrease of bone mineral density (BMD). We aimed to determine the usefulness of serum bone turnover markers and BMD measurement by dual-energy x-ray absorptiometry (DXA) in hemodialysis patients. METHODS: We conducted a cross-sectional study including 90 hemodialysis for more than 12 months. Bone mineral density was assessed by DXA. Peripheral blood samples were obtained from each patient before dialysis in a fasting state within a week of the DXA. Biochemical variables of calcium and phosphate were measured. One bone formation marker (bone-specific alkaline phosphatase (bAP), one bone resorption marker (carboxy-terminal telopeptides of type 1 collagen (CTX)) were measured. Total alkaline phosphatase (TAP), intact parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) which is a bone-derived hormone were also measured. RESULTS: CTX values were 6.25 times higher than the normal limit of the assay. Bone alkaline phosphatase levels were less than 10 ng/mL in 28.8% of cases. 23% of patients have osteoporosis and 45% have osteopenia. Femoral BMD had negative correlations with age and PTH levels. FGF23 levels were significantly increased in patients with osteoporosis affecting the lumbar. The levels of bAP and CTX showed a positive correlation. Both circulating bAP and CTX levels showed also positive correlations with PTH levels. Fractures, observed in 12.2% of cases, were associated with low PTH values and the existence of osteoporosis. CONCLUSIONS: Our study showed that osteoporosis and fracture are common in dialysis patients. The reduced BMD was associated with advanced age and elevated levels of PTH. Markers of bone turnover and FGF23 may play a role in the diagnosis of bone disease in hemodialysis patients. DXA measurement is necessary for the monitoring for bone loss.

Mineral bone disorder and osteoporosis in hemodialysis patients

Abstract Background: Bone disease is common in patients undergoing hemodialysis. It is the result of bone turnover abnormalities and the decrease of bone mineral density (BMD). We aimed to determine the usefulness of serum bone turnover markers and BMD measurement by dual-energy x-ray absorptiometry (DXA) in hemodialysis patients. Methods: We conducted a cross-sectional study including 90 hemodialysis for more than 12 months. Bone mineral density was assessed by DXA. Peripheral blood samples were obtained from each patient before dialysis in a fasting state within a week of the DXA. Biochemical variables of calcium and phosphate were measured. One bone formation marker (bone-specific alkaline phosphatase (bAP), one bone resorption marker (carboxy-terminal telopeptides of type 1 collagen (CTX)) were measured. Total alkaline phosphatase (TAP), intact parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) which is a bone-derived hormone were also measured. Results: CTX values were 6.25 times higher than the normal limit of the assay. Bone alkaline phosphatase levels were less than 10 ng/mL in 28.8% of cases. 23% of patients have osteoporosis and 45% have osteopenia. Femoral BMD had negative correlations with age and PTH levels. FGF23 levels were significantly increased in patients with osteoporosis affecting the lumbar. The levels of bAP and CTX showed a positive correlation. Both circulating bAP and CTX levels showed also positive correlations with PTH levels. Fractures, observed in 12.2% of cases, were associated with low PTH values and the existence of osteoporosis. Conclusions: Our study showed that osteoporosis and fracture are common in dialysis patients. The reduced BMD was associated with advanced age and elevated levels of PTH. Markers of bone turnover and FGF23 may play a role in the diagnosis of bone disease in hemodialysis patients. DXA measurement is necessary for the monitoring for bone loss.(AU)

Molecular basis of complement factor I deficiency in Tunisian atypical haemolytic and uraemic syndrome patients.

AIM: The aim of the present study was to characterize the molecular basis of complement factor I deficiency in Tunisian atypical haemolytic and uremic syndrome patients with low factor I levels. METHODS: Six adults and seven children were enrolled in this study. Complement factor I levels were assessed by a homemade sandwich ELISA and ranged between 12.5% and 60%. Genomic DNA was amplified by way of a polymerase chain reaction using intronic primers flanking the 13 coding exons. Sequencing of amplified products was carried out by the dye terminator sequencing method. Molecular study was performed on parental samples for three dead paediatric patients. The control group consisted of 100 healthy Tunisian donors. RESULTS: We identified a total of 13 substitutions and one insertion: seven in introns, four in exons and three in UTR. The new mutations were c.-132G > C, c.71 + 181 T > A in 5'UTR and intron 1, respectively. Three intronic polymorphisms were predicted to have impact on splicing events: c.482 + 6C > T, c.884-42_884-41insTTAAA (rs34422850) and c.1429 + 33 A > G (rs9998151). They were three missense mutations leading to a p.Ile 357Met, p.Ile416Leu and p.GLu548Gln. p.Ile 357Met was found in two patients and one relative. Half of the patients had associated mutation and/or polymorphisms. CONCLUSION: This is the first genetic study in Tunisian and Maghrebin atypical haemolytic and uraemic syndrome patients. The high occurrence of Ile357Met mutation may reflect a founding effect. Functional impact of the two new mutations c.-132G > C and c.71 + 181A > T have to be studied. Association of simultaneous genetic abnormalities may explain the variability of atypical haemolytic and uraemic syndrome, penetrance and disease phenotype.

A cross sectional study of bone and cartilage biomarkers: correlation with structural damage in rheumatoid arthritis.

The aim of our study was to assess the relationship between bone and cartilage remodeling biomarkers and joint damage in Rheumatoid Arthritis (RA), and to detect whether they have the capacity to predict the progression of joint disease assessment by computed tomography (CT) erosion score. We analyzed 65 female patients with established RA in our Rheumatology Department. Serum levels of bone and cartilage markers were measured: osteocalcin (OC), N-propeptide of type I collagen (PINP), collagen type I and II, C-telopeptide (CTX I, CTX-II) and cartilage oligomeric matrix protein (COMP). Radiography of both wrist and MCP joints were available. Two expert-readers independently scored articular damage and progression using the High-resolution low dose CT scan in a blinded fashion. 65 female patients with established RA with a median age of 44 years were included. The median disease-duration was two years and the median (Disease activity score) DAS 28 score at 4.46 [2.65-7.36]. The percentage of patient with low disease activity was 13.8%, while 55.4 and 30.8% for those with moderate and high disease activity respectively. The resorption bone markers were high in active versus non-active RA. Wrist and MCP erosion scores were also associated with RA activity. Our study shows that biomarkers of bone and cartilage collagen breakdown were related to specific joint erosion in RA and could predict subsequent radiographic damage in RA. Further larger scale longitudinal studies maybe needed to confirm our data.

Detection of Shigella spp. nucleic acids in the synovial tissue of Tunisian rheumatoid arthritis patients and other forms of arthritis by quantitative real-time polymerase chain reaction.

Enterobacterial components in the joints of patients are believed to contribute to a perpetuating inflammation leading to a reactive arthritis (ReA), a condition in which microbial agents cannot be recovered from the joint. At present, it is unclear whether nucleic acids from Shigella spp. are playing a pathogenic role in causing not only ReA but also other forms of arthritis. Quantitative real-time polymerase chain reaction assay (qPCR) is the method of choice for the identification of bacteria within the synovium. The aim of our study was to detect the presence of Shigella spp. nucleic acids in the synovial tissue (ST) of Tunisian arthritis patients. We investigated 57 ST samples from rheumatoid arthritis (RA) n = 38, undifferentiated oligoarthritis (UOA) n = 12, and spondyloarthritis (SpA) n = 7 patients; 5 ST samples from healthy individuals were used as controls. Shigella spp. DNA and mRNA transcripts encoding the virulence gene A (VirA) were examined using an optimized qPCR with newly designed primers and probes. Using qPCR, Shigella spp. DNA was found in 37/57 (65%) ST samples (24/38, i.e., 63.2% of RA, 8/12, i.e., 67% of UOA, and 5/7, i.e., 71.4% of SpA patients). Paired DNA and mRNA were extracted from 39 ST samples, whose VirA cDNA was found in 29/39 (74.4%) patients. qPCR did not yield any nucleic acids in the five healthy control ST samples. The qPCR assay was sensitive and showed a good intra- and inter-run reproducibility. These preliminary findings generated by an optimized, highly sensitive PCR assay underline a potential role of past gastrointestinal infections. In Tunisian patients, a bacterial etiology involving Shigella spp. in the manifestation of arthritic disorders including RA might be more common than expected.

sFRP3 and DKK1 Regulate Fibroblast-Like Synoviocytes Markers and Wnt Elements Expression Depending on Cellular Context.

CONTEXT: Fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) display pathogenic behavior. Various members of the Wnt pathway, especially the canonical Wnt/ß-catenin cascade, may contribute to autonomous RA FLS activation. It has been shown that the two Wnt inhibitors: sFRP3 and DKK1 contribute to several critical aspects of joint biology. However, their effects on RA FLS are poorly characterized. The aim of our study was to investigate the effects of sFRP3 and DKK1 on FLS markers, Wnt components, and target oncogenes expression by RA FLS and compare the findings to osteoarthritic (OA) FLS. MATERIALS AND METHODS: RA and OA FLS were treated with sFRP3 and DKK1 for 6 days. Wnt signaling components (Wnt5a, LRP5 and ß-catenin), Wnt target oncogenes (cyclin E1 and WISP1), and FLS markers (fibronectin and MMP3) were analyzed using western blotting and/or qRT-PCR. RESULTS: Our data indicated that sFRP3 down-regulated the key gene ß-catenin in RA FLS. sFRP3 decreased fibronectin, a well-known downstream effectors gene of Wnt/ß-catenin pathway, and LRP5 expression in both RA and OA FLS. In OA FLS, sFRP3 induced increased expression of Wnt5a and MMP3 but did not affect their levels in RA FLS. On the other hand, DKK1 increased fibronectin expression in RA FLS and decreased its expression in OA FLS. CONCLUSION: Our results confirm the involvement of Wnt signaling in FLS transformation and show that two inhibitors of the same cascade can regulate differently the same elements and that a single inhibitor can initiate signaling depending on cellular context. ABBREVIATIONS: FLS: fibroblast-like synoviocytes; RA: rheumatoid arthritis; Wnt: Wingless; Fz: frizzled; LRP: Fz/low-density lipoprotein receptor protein; WISP1: Wnt1 inducible signaling pathway protein 1; sFRP: secreted Fz-related proteins; DKK: Dickkopf; OA: osteoarthritis; DMEM: Dulbecco's modified Eagle's medium; FBS: fetal bovine serum; PBS: phosphate buffered saline; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; ECL: enhanced chemiluminescence detection solution; MMP3: metaloproteinase 3; qRT-PCR: quantitative real-time polymerase chain reaction; S.D: standard deviation; CRD: cysteine-rich domain; MeCP2: methyl-CpG-binding protein; RANKL: nuclear factor-kappa B ligand.

High prevalence of antineuronal antibodies in Tunisian psychiatric inpatients.

The authors aimed to determine the prevalence of antineuronal antibodies in 103 psychiatric inpatients and 41 control subjects with no history of malignancies or neurological disorders. All sera were tested by indirect immunofluorescence and positive sera by immunoblot. Using immunofluorescence, antineuronal nuclear autoantibodies were detected in 20 patients and none of the control subjects, and antibodies reacted with the cytoplasm of Purkinje cells in six patients and two control subjects. The immunoblot confirmed well-characterized antineuronal antibodies only in five patients: two had anti-Ri and three had anti-Yo antibodies. After a follow-up of 5 years, none of these patients developed neurological disorder or malignancy.

[The role of type II collagen fragments and X-ray progression of knee osteoarthritis]. / Rôle des marqueurs de dégradation du collagène de type II au cours de la progression de l'arthrose du genou.

AIMS: To investigate the association between type II collagen fragments and the presence of knee osteoarthritis (OA) in the Tunisian population and to determine whether this biomarker can predict X-ray progression of this disease. METHODS: Type II collagen C-telopeptide (uCTX-II) and helical peptide (sHelix-II) were assessed in 125 female patients with knee osteoarthritis aged 54 ± 8 years over 2 years and 57 female age-matched controls. The markers were measured at baseline, 1 and 2 yrs' follow-up corresponding to x-ray time points. RESULTS: Only urinary CTX-II values were significantly 48% higher in knee OA patients compared with controls (p=0.001). The longitudinal changes over 2 yrs in Helix-II were also significantly associated with Joint Space Narrowing: JSN (p=0.03). Over the 2-yr study period average CTX-II levels were not significantly higher in progressor compared with non-progressor (339.96 vs 256.00; NS). CONCLUSION: The data presented here suggest that CTX-II may be useful to identify patients with knee OA. These results demonstrate significantly association between progression of this disease and alterations levels of Helix-II.

Notch signaling is involved in human articular chondrocytes de-differentiation during osteoarthritis.

CONTEXT: During osteoarthritis (OA), chondrocytes undergo de-differentiation, resulting in the acquisition of a fibroblast-like morphology, decreased expression of collagen type II (colII) and aggrecan, and increased expression of collagen type I (colI), metalloproteinase 13 (MMP13) and nitric oxide synthase (eNOS). Notch signaling plays a crucial role during embryogenesis. Several studies showed that Notch is expressed in adulthood. OBJECTIVE: The aim of our study was to confirm the involvement of Notch signaling in human OA at in vitro and ex vivo levels. MATERIALS AND METHODS: Normal human articular chondrocytes were cultured during four passages either treated or not with a Notch inhibitor: DAPT. Human OA cartilage was cultured with DAPT for five days. Chondrocytes secreted markers and some Notch pathway components were analyzed using Western blotting and qPCR. RESULTS: Passaging chondrocytes induced a decrease in the cartilage markers: colII and aggrecan. DAPT-treated chondrocytes and OA cartilage showed a significant increase in healthy cartilage markers. De-differentiation markers, colI, MMP13 and eNOS, were significantly reduced in DAPT-treated chondrocytes and OA cartilage. Notch1 expression was proportional to colI, MMP13 and eNOS expression and inversely proportional to colII and aggrecan expression in nontreated cultured chondrocytes. Notch ligand: Jagged1 increased in chondrocytes culture. DAPT treatment resulted in reduced Jagged1 expression. Notch target gene HES1 increased during chondrocyte culture and was reduced when treated with DAPT. CONCLUSION: Targeting Notch signaling during OA might lead to the restitution of the typical chondrocyte phenotype and even to chondrocyte redifferentiation during the pathology.

New C1q mutation in a Tunisian family.

Hereditary C1q deficiency (C1qD) is the most penetrant genetic factor predisposing to the development of lupus pathology with more than 93% of C1q deficient patients developing this autoimmune pathology throughout their life. It is a rare autosomal recessive deficiency, with only 67 cases reported so far including one Tunisian girl who died at the age of three from complications resulting from severe systemic lupus erythematosus. Although C1qD was confirmed in the serum of this patient using C1q ELISA and classical pathway specific functional assays, no DNA sample had been obtained from this patient. Here we report the analysis of sera and DNA of members of this patient's closer family. Our analysis identified a homozygous mutation within the gene encoding the C-chain of C1q leading to a deficiency of C1q in an older sister of our original patient. This mutation, termed g.5580G4C, represents a single basepair substitution in exon 1 of the C1q C chain gene which changes the codon of Gly61 to Arg 61. Amongst the other 14 mutations leading to C1qD, g.5580G4C represents the first reported transversion leading to human C1qD.

WNT signaling and chondrocytes: from cell fate determination to osteoarthritis physiopathology.

CONTEXT: Osteoarthritis (OA) is an articular disorder leading to the degradation of articular cartilage phenotypical chondrocytes modifications, including the acquisition of a fibroblast-like morphology, decreased expression of collagen type II, and increased expression of fetal collagen type I, metalloproteinase 13 and nitric oxide synthase. This promotes matrix degradation and unsuccessful cartilage repair. WNT signaling constitutes one of the most critical biological processes during cell fate assignment and homeostasis. OBJECTIVES: This review aims to give an insight on results from the studies that were interested in the involvement of WNT in OA. METHODS: Studies were selected through a pubmed search. RESULTS: Recent genetic data showed that aberration in WNT signaling may be involved in OA. WNT signals are transduced through at least three cascades: the canonical WNT/ß-catenin pathway, the WNT/Ca(2+) pathway and the WNT/planar cell polarity pathway. Most of the studies used in-vitro models to elucidate the involvement of WNT in the physiopathology of OA. These studies analyzed the expression pattern of WNT pathway components during OA such as WNT5, WNT7, co-receptor LRP, ß-catenin, WNT target genes (c-jun, cyclins) and/or the interaction of these components with the secretion of OA most important markers such as IL-1, collagens, MMPs. Results from these studies are in favor of a deep involvement of the WNT signaling in the physiopathology of OA either by having a protective or a destructive role. CONCLUSION: Deeper researches may eventually allow scientists to target WNT pathway in order to help develop efficient therapeutic approaches to treat OA.