NLRP3 inflammasome plays an important role in the pathogenesis of rheumatoid arthritis (RA). However, the post-transcriptional regulation of NLRP3 expression by miRNA in synovial macrophages is still not well understood. The aim of the study is to elucidate the mechanisms of RA with the focus on miRNAs mediated post-transcriptional regulation of the NLRP3 inflammasome. Here, we used NLRP3-deficient mice (NLRP3KO) to cross with TNFα-transgenic mice (TNFTG) to generate NLRP3KO/TNFTG mice, and compared their joint phenotypes with those of their TNFTG and wild-type (WT) littermates at 5 months of age. In comparison to WT mice, articular bone volume and cartilage area are decreased, whereas inflammed area, eroded surface, ALP+ osteoblast number, TRAP+ osteoclast number, and the areas of RelA+F4/80+, Caspase-1+F4/80+, IL-1β+F4/80+ synoviocytes are increased in the TNFTG mice. Knockout of NLRP3 ameliorates joint inflammation and bone damage in TNFTG mice. Further, in TNFα-primed BMDMs, RelA positively regulates NLRP3 expression, but negatively regulates miR-30a. Additionally, miR-30a negatively mediates NLRP3 expression by directly binding to its 3' UTR, suggesting a miR-30a-mediated feedforward loop acting on NLRP3. Finally, intra-articular injection of AAV-miR-30a inhibits NLRP3 inflammasome activation, reduces joint inflammation, and attenuates bone damage in TNFTG mice. Thus, RelA/miR-30a/NLRP3 signal axis is involved in RA through regulating NLRP3 Inflammasome in macrophages.

RelA/MicroRNA-30a/NLRP3 signal axis is involved in rheumatoid arthritis via regulating NLRP3 inflammasome in macrophages.

Acid sensor ASIC1a induces synovial fibroblast proliferation via Wnt/β-catenin/c-Myc pathway in rheumatoid arthritis.

Synovial Fibroblasts (SFs) are key pathogenic drivers in arthritis and their in vivo activation by TNF is sufficient to orchestrate full arthritic pathogenesis in animal models. TNF blockade has been efficacious for a large percentage of Rheumatoid Arthritis (RA) patients, although characterized by a plethora of side effects. Novel therapeutic discoveries remain however challenging, especially in optimizing drug safety, side effects, longer-term responses, costs and administration routes. Aiming to find new potent therapeutics, we applied the L1000CDS2 search engine, in order to identify compounds that could potentially reverse the pathogenic expression signature of arthritogenic SFs, derived from the human TNF transgenic mouse model (hTNFtg). We identified a neuroleptic drug, namely Amisulpride, which was validated to reduce SFs’ inflammatory potential while decreasing the clinical score of hTNFtg polyarthritis. Notably, we found that Amisulpride did not exert its biological activities through its known targets Dopamine receptors 2 and 3 and Serotonin Receptor 7, nor through TNF-TNFRI binding inhibition. By applying a click chemistry approach, novel potential targets of Amisulpride were identified, which were further validated to repress hTNFtg SFs’ inflammatory potential in vitro (Ascc3 and Sec62), while phosphoproteomics analysis revealed important fibroblast activation pathways, such as adhesion, to be altered upon treatment. Our data support that Amisulpride could provide an additive beneficial effect to patients suffering from RA and comorbid dysthymia, as it may reduce SFs pathogenicity in parallel with its anti-depressive activity. Importantly, Amisulpride may also serve as a “lead” compound for the development of novel, more potent therapeutics against chronic inflammatory diseases.

Repurposing of Amisulpride, a known antipsychotic drug, to target synovial fibroblasts activation in arthritis

WNT9A and WNT9B in Development and Disease

Background: There is no definitive conclusion on relationship between insulin and pain threshold through opioid mechanism in experimental animal model. The present study investigated the role of endogenous insulin in the modulation of pain using opioid drugs through opioid mechanism and their relationship in experimental animal model. Methods: Eight animal groups were used, each group consisting of six mice (Swiss albino). Group 1-treated saline ip; Group 2- administered pentazocine ip; Group 3- treated naloxone in low dose (0.005 mg/kg, ip) 15 min prior to pentazocine treatment; Group 4- administered naloxone in high dose (5 mg/kg, ip)15 min prior to pentazocine treatment. Another four groups of animals (Group 5, 6, 7 and 8) treated saline, pentazocine, low dose and high dose naloxone both administered 15 min prior to pentazocine treatment respectively. Group 1,2,3 and 4 subjected to acetic acid challenge and Group 5,6, 7 and 8 subjected to formalin test. Blood samples were collected and serum insulin was estimated by ELISA and blood glucose was measured by using Ames glucometer. Results: Pentazocine significantly increased both serum insulin and antinociceptive response to nociceptive stimuli to acetic acid as well as formalin challenge without significantly affecting plasma glucose in both pain models as compared to saline control. Conclusion: The study concluded that possible association between endogenous insulin and pain threshold which is independent of the glycemic status in both the chemically induced nociceptive tests. The relationship between endogenous insulin and pain threshold involves an interaction with opioid system possibly by binding with kappa receptor. Key words: Endogenous insulin, Plasma glucose, Pentazocine, Pain thresholds, Mice.

Endogenous Insulin: Study on Pain Threshold Through Opioid Mechanism in Swiss Albino Mice

Agonists and antagonists of the canonical Wnt signaling pathway are modulators of pathological aspects of rheumatoid arthritis (RA). Their activity is primarily modifying bone loss and bone formation, as shown in animal models of RA. More recently, modulation of Wnt signaling by the antagonist Sclerostin has also been shown to influence soft-tissue-associated inflammatory aspects of the disease pointing towards a role of Wnt signaling in soft-tissue inflammation as well. Yet, nothing is known experimentally about the role of Wnt ligands in RA. Here we provide evidence that altering Wnt signaling at the level of a ligand affects all aspects of the rheumatoid arthritic disease. WNT9a levels are increased in the pannus tissue of RA patients, and stimulation of synovial fibroblasts (SFB) with tumor necrosis factor (TNF) leads to increased transcription of Wnt9a. Loss of Wnt9a in a chronic TNF-dependent RA mouse model results in an aggravation of disease progression with enhanced pannus formation and joint destruction. Yet, loss of its activity in the acute K/BxN serum-transfer induced arthritis (STIA) mouse model, which is independent of TNF signaling, has no effect on disease severity or progression. Thus, suggesting a specific role for WNT9a in TNF-triggered RA. In synovial fibroblasts, WNT9a can activate the canonical Wnt/β-catenin pathway, but it can also activate P38- and downregulate NFκB signaling. Based on in vitro data, we propose that loss of Wnt9a creates a slight proinflammatory and procatabolic environment that boosts the TNF-mediated inflammatory response.

/pdf/loss-of-the-wnt9a-ligand-aggravates-the-rheumatoid-arthritis-3rlwcmn05a.pdf

Loss of the WNT9a ligand aggravates the rheumatoid arthritis-like symptoms in hTNF transgenic mice.

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Loss of the WNT9a ligand aggravates the rheumatoid arthritis-like symptoms in hTNF transgenic mice.