Review article: moving towards common therapeutic goals in Crohn's disease and rheumatoid arthritis.

BACKGROUND: Crohn's disease (CD) and rheumatoid arthritis are chronic, progressive and disabling conditions that frequently lead to structural tissue damage. Based on strategies originally developed for rheumatoid arthritis, the treatment goal for CD has recently moved from exclusively controlling symptoms to both clinical remission and complete mucosal healing (deep remission), with the final aim of preventing bowel damage and disability. AIM: To review the similarities and differences in treatment goals between CD and rheumatoid arthritis. METHODS: This review examined manuscripts from 1982 to 2016 that discussed and/or proposed therapeutic goals with their supportive evidence in CD and rheumatoid arthritis. RESULTS: Proposed therapeutic strategies to improve outcomes in both rheumatoid arthritis and CD include: (i) evaluation of musculoskeletal or organ damage and disability, (ii) tight control, (iii) treat-to-target, (iv) early intervention and (v) disease modification. In contrast to rheumatoid arthritis, there is a paucity of disease-modification trials in CD. CONCLUSIONS: Novel therapeutic strategies in CD based on tight control of objective signs of inflammation are expected to change disease course and patients' lives by halting progression or, ideally, preventing the occurrence of bowel damage. Most of these strategies require validation in prospective studies, whereas several disease-modification trials have addressed these issues in rheumatoid arthritis over the last decade. The recent approval of new drugs in CD such as vedolizumab and ustekinumab should facilitate initiation of disease-modification trials in CD in the near future.

Fibroblast Growth Factor 23 drives MMP13 expression in human osteoarthritic chondrocytes in a Klotho-independent manner.

OBJECTIVE: Fibroblast Growth Factor 23 (FGF23) may represent an attractive candidate that could participate to the osteoarthritic (OA)-induced phenotype switch of chondrocytes. To address this hypothesis, we investigated the expression of FGF23, its receptors (FGFRs) and co-receptor (Klotho) in human cartilage and studied the effects of rhFGF23 on OA chondrocytes. METHOD: Gene expression or protein levels were analysed by RT-PCR and immunohistochemistry. Collagenase 3 (MMP13) activity was measured by a fluorescent assay. MAPK signalling pathways were investigated by phosphoprotein array, immunoblotting and the use of selective inhibitors. RNA silencing was performed to confirm the respective contribution of FGFR1 and Klotho. RESULTS: We showed that the expression of FGF23, FGFR1 and Klotho was up-regulated at both mRNA and protein levels in OA chondrocytes when compared to healthy ones. These overexpressions were markedly elevated in the damaged regions of OA cartilage. When stimulated with rhFGF23, OA chondrocytes displayed an extended expression of FGF23 and of markers of hypertrophy such as MMP13, COL10A1, and VEGF. We demonstrated that FGF23 auto-stimulation was both FGFR1-and Klotho-dependent, whereas the expression of markers of hypertrophy was mainly dependent on FGFR1 alone. Finally, we showed that FGF23-induced MMP13 expression was strongly regulated by the MEK/ERK cascade and to a lesser extent, by the PI-3K/AKT pathway. CONCLUSION: These results demonstrate that FGF23 sustains differentiation of OA chondrocytes in a Klotho-independent manner.

Oxidative stress-induced expression of HSP70 contributes to the inhibitory effect of 15d-PGJ2 on inducible prostaglandin pathway in chondrocytes.

The inhibitory effect of 15-deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) on proinflammatory gene expression has been extensively documented and frequently ascribed to its ability to prevent NF-κB pathway activation. We and others have previously demonstrated that it was frequently independent of the peroxisome proliferator activated receptor (PPAR)γ activation. Here, we provide evidence that induction of intracellular heat shock protein (HSP)70 by oxidative stress is an additional regulatory loop supporting the anti-inflammatory effect of 15d-PGJ2 in chondrocytes. Using real-time quantitative PCR and Western blotting, we showed that 15d-PGJ2 stimulated HSP70, but not HSP27 expression while increasing oxidative stress as measured by spectrofluorimetry and confocal spectral imaging. Using N-acetylcysteine (NAC) as an antioxidant, we demonstrated further that oxidative stress was thoroughly responsible for the increased expression of HSP70. Finally, using an HSP70 antisense strategy, we showed that the inhibitory effect of 15d-PGJ2 on IL-1-induced activation of the NF-κB pathway, COX-2 and mPGES-1 expression, and PGE2 synthesis was partly supported by HSP70. These data provide a new anti-inflammatory mechanism to support the PPARγ-independent effect of 15d-PGJ2 in chondrocyte and suggest a possible feedback regulatory loop between oxidative stress and inflammation via intracellular HSP70 up-regulation. This cross talk is consistent with 15d-PGJ2 as a putative negative regulator of the inflammatory reaction.

Reduced sensitivity to emotional facial expressions in borderline personality disorder: effects of emotional valence and intensity.

A heightened sensitivity towards negative emotional stimuli has been described for Borderline Personality Disorder (BPD). We investigated whether a faster and more accurate detection of negatively valent information in BPD can be confirmed by means of a visual search task which required subjects to detect a face with an incongruent emotional expression within a crowd of neutral faces. Twenty eight BPD patients and 28 nonpatients were asked to indicate whether a set of schematic neutral faces (3 × 3, 4 × 4 matrices) contained a happy or an angry face. Besides valence, the intensity of the target's emotion was varied in two steps. BPD patients and nonpatients both demonstrated an anger-superiority effect. However, no higher sensitivity towards negative stimuli was observed in BPD compared to nonpatients. BPD patients seem to rely to a stronger extent on controlled, i.e., serial, attention demanding processes when searching more subtle social-emotional information with positive valence.

Bone formation induced by growth factors embedded into the nanostructured particles.

Tissue engineering has merged with stem cell biotechnology with development of new sources of transplantable biomaterials for the treatment of bone tissue diseases. Bone defects are expected to benefit from this new biotechnology because of the low self-regenerating capacity of bone matrix secreting cells. The differentiation of stem cells to bone cells using bi-functionalized multilayered particles is presented. The functionalized particles are composed of poly-glutamic acid (PGA) and poly-L-lysine (PLL) with two bone growth factors (BMP-2 and TGFbeta1) embedded into the multilayered film. The induction of bone from these bioactive particles incubated with embryonic stem cells was demonstrated in vitro. We report the demonstration of a multilayered particle-based delivery system for inducing bone formation in vivo. This new strategy is an alternative approach for in vivo bone formation.

Depressive and aggressive responses to frustration: development of a questionnaire and its validation in a sample of male alcoholics.

Since clinical and biochemical observations point to much overlap between depression and aggression, both characterised by intolerance to frustration, a questionnaire was developed to test if different patterns of depressive and aggressive reactions elicited by exposure to negative events and deprivation from expected positive ones in human and nonhuman conditions, respectively, would result in specific response patterns in depressive and aggressive persons. The questionnaire was tested for internal consistency in a pilot healthy sample and for correlations of responses with the personality factors of Aggression and Depression in 60 abstinent male alcoholics. Aggressive and depressive responses were highly correlated across all stimulus conditions, and not specifically but rather equally associated with the personality factors of Aggression and Depression, confirming the close association between these dimensions.

Magnetic resonance imaging in osteoarthritis: which method best reflects synovial membrane inflammation? Correlations with clinical, macroscopic and microscopic features.

OBJECTIVES: : To study synovial membrane (SM) inflammation near the patella with different magnetic resonance imaging (MRI) approaches performed using a T1-injected sequence in knee osteoarthritis (OA), and to compare MRI results with macroscopic, microscopic and clinical findings. METHODS: Fifteen patients fulfilling American College of Rheumatology (ACR) criteria for knee OA and requiring joint lavage completed a functional index (Lequesne's functional index) and a pain visual analog scale (VAS). SM inflammation near the patella was assessed on axial fat saturation post-injected T1 MRI images using three different methods: (1) semi-quantitative score=MRI synovitis score; (2) synovial membrane volume (SMV) analysis; (3) SMV with low (SMVL) (<0.3%/s(-1)), intermediate (SMVI) (0.3%/s(-1) to 1%/s(-1)) and high (SMVH) (> or =1%/s(-1)) speed of enhancement. Chondral lesions and SM inflammation were macroscopically graded and SM biopsies performed for microscopic scoring. RESULTS: All MRI approaches exhibited excellent intra- and inter-observer reproducibility. MRI synovitis score correlated well with macroscopic (r=0.61, P=0.003) and total microscopic scores (r=0.55, P=0.03). Correlations between SMV and macroscopic (r=0.60, P=0.02) and microscopic congestion (r=0.63, P=0.01) were good. SMVH was correlated only with microscopic congestion (r=0.79, P=0.01). Low SMV was associated with neither macroscopic nor microscopic scores. However, it did correlate well with pain-VAS score (r=0.61, P=0.03) and moderately with a functional index (r=0.46, P=0.10). CONCLUSION: The three MRI approaches used here provided highly reproducible information on SM inflammation near the patella in knee OA. Compared to SMV, MRI synovitis score seems sufficient to assess synovial inflammation but high SMV is an appropriate indicator of vascular congestion, and low SMV reflects pain in knee OA.

Three-dimensional sprayed active biological gels and cells for tissue engineering application.

Complex three-dimensional structures can "a priori" be built layer-by-layer with a large number of different components, including various cell types, polyelectrolytes, drugs, proteins, peptides or DNA. Our approach is based on the spraying of such elements in order to form a highly functionalized and structured biomaterial. The proposed route will allow the control at the surface and in depth the distribution of the different included elements (matrix and cells).The main objective of this work concerns the buildup of biomaterials aimed to reconstruct biological tissue. The proposed ways are highly innovative and consist in a simple and progressive spraying of all the elements constituting finally the biomaterial.We report here that it is possible (i) to build an alginate gel by alternate spraying of alginate and Ca(2+); (ii) to spray active alginate gel and cells; (iii) to build layer-by-layer an active reservoir under and on the top of this sprayed gel and cells; (iv) to follow the activity of these sprayed cells with time; (v) to propose a three-dimensional sprayed structure for tissue engineering application.

Evidence for species differences in the regulation of MMPs by all-trans retinoic acid in cytokine-stimulated chondrocytes.

In inflammatory conditions, chondrocytes produce large amounts of matrix metalloproteases (MMP) and nitric oxide (NO) thought to contribute to joint degradation. We tested the ability of all-trans retinoic acid (ATRA, a retinoic acid receptor (RAR) agonist) to modulate these inflammatory genes in chondrocytes from humans or rats, chosen as representative of animal models of arthritis. All RAR subtypes and RXR-alpha or -beta were expressed at the mRNA level in both species, although IL-1beta (10 ng/ml) inhibited RAR subtypes more markedly in rat than in human cells. ATRA (300 or 1000 nM) inhibited IL-1-induced expression of iNOS and nitrites level in both species, although the NO pathway was induced maximally in rat cells. ATRA displayed controversial effects on MMPs between rat and human chondrocytes, especially for MMP-9 expression. The effects of ATRA were irrelevant to the nuclear translocation of AP-1. The present data underlines that retinoids have a species-dependent impact on IL-1-induced responses in chondrocytes, suggesting that extrapolation of their pharmacological properties from animal cells has a poor relevance to clinical situation.

Modulatory effect of rhein on IL-1alpha-induced responses in human chondrocytes: a comparative study between antibody microarrays and specific ELISAs.

The present work aimed to take advantage of the screening capacity of protein arrays to search for additional targets of rhein in interleukin (IL)-1-stimulated chondrocytes. Primary cultures of chondrocytes from osteoarthritic (OA) patients were stimulated for 24 and 48 h with 1 ng/ml of IL-1alpha, in the presence or absence of 10(-5) M of rhein. Culture supernatants were analyzed with arrays membranes consisting of 120 antibodies directed against cytokines, chemokines, and angiogenic or growth factors and were controlled for 8 proteins by specific immuno-enzymatic assays (ELISA). Protein arrays showed that several CC or CXC chemokines, the growth factor GM-CSF, the cytokines IL-6, IL-7 and IL-10 (but unexpectedly not IL-1beta or TNFalpha) and the adhesion molecule ICAM-1 were induced maximally by IL-1alpha. In IL-1-stimulated chondrocytes, rhein reduced slightly the production of MCP-1 and increased those of IL-1Ra, of the cytokine receptors sgp130, IL-6R, sTNFR I and R II, but also of some chemokines or ICAM-1. Specific ELISAs confirmed the effect of rhein on MCP-1, IL-1Ra, sgp130, IL-6R and sTNFR II but was discrepant for GROalpha and were always more sensitive than protein arrays to detect IL-1 effects such as IL-1Ra and TNFalpha release. The present data show that rhein modulated some IL-1-induced responses contributing possibly to its chondroprotective (IL-1Ra, MCP-1) or cytokine modifying (sTNFR II, sgp130) properties, but that protein arrays were poorly sensitive to check for IL-1- and/or rhein-induced changes.

Influences of construct properties on the proliferation and matrix synthesis of dedifferentiated chondrocytes cultured in alginate gel.

To investigate whether the chondrocytes-alginate construct properties, such as cell seeding density and alginate concentration might affect the redifferentiation, dedifferentiated rat articular chondrocytes were encapsulated at low density (LD: 3 x 10(6) cells/ml) or high density (HD: 10 x 10(6) cells/ml) in two different concentrations of alginate gel (1.2% or 2%, w/v) to induce redifferentiation. Cell viability and cell proliferation of LD culture was higher than those of HD culture. The increase in alginate gel concentration did not make an obvious difference in cell viability, but reduced cell proliferation rate accompanied with the decrease of cell population in S phase and G2/M phase. Scan electron microscopy observation revealed that chondrocytes maintained round in shape and several direct cell-cell contacts were noted in HD culture. In addition, more extracellular matrix was observed in the pericellular region of chondrocytes in 2% alginate culture than those in 1.2% alginate culture. The same tendency was found for the synthesis of collagen type II. No noticeable expression of collagen type I was detected in all constructs at the end of 28-day cultures. These results suggested that construct properties play an important role in the process of chondrocytes' redifferentiation and should be considered for creating of an appropriate engineered articular cartilage.