Overview of the molecular determinants contributing to the expression of Psoriasis and Psoriatic Arthritis phenotypes

Psoriasis and psoriatic arthritis are multifactorial chronic disorders whose etiopathogenesis essentially derives from the alteration of several signalling pathways and the co‐occurrence of genetic, epigenetic and non‐genetic susceptibility factors that altogether affect the functional and structural property of the skin. Although shared and differential susceptibility genes and molecular pathways are known to contribute to the onset of pathological phenotypes, further research is needed to dissect the molecular causes of psoriatic disease and its progression towards Psoriatic Arthritis. This review will therefore be addressed to explore differences and similarities in the etiopathogenesis and progression of both disorders, with a particular focus on genes involved in the maintenance of the skin structure and integrity (keratins and collagens), modulation of patterns of recognition (through Toll‐like receptors and dectin‐1) and immuno‐inflammatory response (by NLRP3‐dependent inflammasome) to microbial pathogens. In addition, special emphasis will be given to the contribution of epigenetic elements (methylation pattern, non‐coding RNAs, chromatin modifiers and 3D genome organization) to the etiopathogenesis and progression of psoriasis and psoriatic arthritis. The evidence discussed in this review highlights how the knowledge of patients'' clinical and (epi)genomic make‐up could be helpful for improving the available therapeutic strategies for psoriasis and psoriatic arthritis treatment.     

Discovery of {4-[4,9-bis(ethyloxy)-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-2-fluorophenyl}acetic acid (GSK726701A), a novel EP4 receptor partial agonist for the treatment of pain

A novel series of EP₄ agonists and antagonists have been identified, and then used to validate their potential in the treatment of inflammatory pain. This paper describes these novel ligands and their activity within a number of pre-clinical models of pain, ultimately leading to the identification of the EP₄ partial agonist GSK726701A.     

Expression of the VEGF receptor-3 in osteoarthritic chondrocytes: stimulation by interleukin-1β and association with β<Subscript>1</Subscript>-integrins

Recent studies have demonstrated enhanced expression of vascular endothelial growth factor and vascular endothelial growth factor receptor (VEGFR)-1 and -2 in chondrocytes of rheumatoid and osteoarthritic cartilage. Since expression of VEGFR-3 (Flt-4) in chondrocytes has not yet been investigated, we studied the distribution of VEGFR-3 in osteoarthritic cartilage samples by immunohistochemistry and immunoelectron microscopy. Furthermore, we looked for functional colocalization of VEGFR-3 with the signal transduction receptor ₁-integrin. Superficial osteoarthritic chondrocytes exhibited VEGFR-3 expression in the cytoplasm and on the cell membrane. Using western blotting we could demonstrate that interleukin-1 (IL-1) stimulates the expression of VEGFR-3 in chondrocytes in vitro in a dose-dependent manner. By coimmunoprecipitation assay we found a functional complex between the ₁-integrin and VEGFR-3 in IL-1-stimulated chondrocytes indicating that activated VEGFR-3 may interact with ₁-integrin and associated subcellular pathways in osteoarthritic chondrocytes. Taken together with results of previous studies showing that ₁-integrins were also associated with other surface receptors and proteins in chondrocytes that cause cartilage destruction in arthritis (for example, urokinase-type plasminogen activator receptor and matrix metalloproteinases), we can hypothesize that signal transduction by these receptor complexes via ₁-integrins may play a crucial role in pathogenesis of osteoarticular disorders. Further work needs to be done to elucidate downstream signaling events activated by these receptors.     

TIMP-3 inhibits aggrecanase-mediated glycosaminoglycan release from cartilage explants stimulated by catabolic factors

Aggrecanases are considered to play a key role in the destruction of articular cartilage during the progression of arthritis. Here we report that the N-terminal inhibitory domain of tissue inhibitor of metalloproteinases 3 (N-TIMP-3), but not TIMP-1 or TIMP-2, inhibits glycosaminoglycan release from bovine nasal and porcine articular cartilage explants stimulated with interleukin-1alpha or retinoic acid in a dose-dependent manner. This inhibition is due to the blocking of aggrecanase activity induced by the catabolic factors. Little apoptosis of primary porcine chondrocytes is observed at an effective concentration of N-TIMP-3. These results suggest that TIMP-3 may be a candidate agent for use against cartilage degradation.     

Promotion of neutrophil adherence to human osteoblasts by microcrystals and f-Met-Leu-Phe

Human osteoblast-like cells (hOB) stimulated by monosodium urate monohydrate (MSUM) or calcium pyrophosphate dihydrate (CPPD) microcrystals produce the neutrophil chemoattractant IL-8. We investigated whether human neutrophils can adhere to hOB and respond to hOB preactivated by MSUM, CPPD, or by f-Met-Leu-Phe (fMLP). Confluent hOB were coincubated with human blood neutrophils in the presence of MSUM, CPPD or fMLP. MSUM, CPPD, and fMLP stimulated a significant adherence of neutrophils to hOB after a 1h incubation. This effect was not abrogated by pretreating the cells with an anti-CD18 mAb. MSUM stimulated more efficiently the adherence of neutrophils to non-preactivated hOB while CPPD were more efficient when hOB were preactivated. Crystal-free conditioned media from MSUM- or CPPD-stimulated hOB mobilized intracellular free calcium in human neutrophils. Thus, microcrystals were powerful promoters of neutrophil adherence to hOB via a CD18-independent mechanism. The bacterial peptide fMLP also stimulated the adherence of neutrophils to hOB. Functional neutrophil-hOB interactions could be important in bone pathophysiology of crystal- or infection-associated arthritis.     

Two-loci interaction confirms arthritis-regulating quantitative trait locus on rat chromosome 6

A form of genetic interaction, or epistasis, occurs when one gene interferes with the phenotypic effect of another nonallelic gene. In pristane-induced arthritis (PIA) in rats we have previously identified Pia3, on chromosome 6, to be a locus that regulates onset of disease. In a single congenic strain containing Pia3 on the arthritis-susceptible DA background, DA.Pia3, no difference in onset of disease or early disease severity could be detected. After a two-loci interaction analysis of (E3 x DA)F2 intercross data, Pia3 was found to interact with Pia4 (chromosome 12). Subsequently, the DA.Pia3 congenic strain was combined with the DA.Pia4 congenic strain so that an effect of Pia3 could be observed. The effect of heterozygosity in Pia4 results in lower severity and thus in combination with Pia3 made it possible to observe that Pia3 alleles from the arthritis-resistant E3 strain rendered more severe arthritis into the otherwise 100% susceptible DA strain. As the introduction of Pia4 heterozygosity results in a lower level of arthritis severity we regard this as an additive interaction with a severity threshold-lowering effect.     

尿酸钠结晶诱导痛风性关节炎动物模型研究进展

痛风性关节炎是由于机体嘌呤代谢紊乱,导致血内尿酸增高而引起尿酸盐在组织沉积的疾病,本文简要介绍大鼠尿酸钠结晶急性足跖肿胀模型、大鼠尿酸钠结晶急性痛风性踝关节炎模型、小鼠与大鼠尿酸钠结晶皮下气囊法急性痛风性滑膜炎模型和家兔尿酸钠结晶急性膝关节炎模型的制作方法进展。将有益于抗痛风性关节炎药物研究时的更多选择应用。     

MiR-125a-3p inhibits cell proliferation and inflammation responses in fibroblast-like synovial cells in rheumatoid arthritis by mediating the Wnt/β-catenin and NF-κB pathways via targeting MAST3

Objectives:To explore the role and mechanism of miR-125a-3p in rheumatoid arthritis (RA) progression.Methods:The RA-tissues and fibroblast-like synovial cells in rheumatoid arthritis (RA-FLS) were used in this study. qRT-PCR, western blot and ELISA assay were performed to detect the expression levels of IL-6, IL-β and ΤΝF-α. Dual-luciferase reporter gene assay was used to observe the binding effect of miR-125a-3p and MAST3, and CCK-8 was used to observe the effect of miR-125a-3p on the proliferation of RA-FLS.Results:miR-125a-3p was significantly downregulated in the RA-tissues and RA-FLS, and miR-125a-3p could inhibit the proliferation and reduce the inflammation response of RA-FLS. Besides, MAST3 was found as a target of miR-125a-3p, and increased MAST3 could reverse the effects of miR-125a-3p on RA-FLS including decreased proliferation, reduced inflammation level and the inactivation of Wnt/β-catenin and NF-κB pathways.Conclusions:This study suggests that miR-125a-3p could inactivate the Wnt/β-catenin and NF-κB pathways to reduce the proliferation and inflammation response of RA-FLS via targeting MAST3.