Exosomal MicroRNA-23-5p Derived from Bone Marrow Mesenchymal Stem Cells Relieves Inflammatory Response in Rheumatoid Arthritis

We aimed to explore the mechanism underlying microRNA-23-5p from exosomes (exo-miR-23-5p) of BMSCs in rheumatoid arthritis (RA). The candidate related genes of miR-23-5p were screened in RA by bioinformatics analysis through gain- and loss-function method along with analysis of histopathological changes in mice and RAC2 expression as well as the level of pro-inflammatory factors. In vivo RA model was established to detect miR-23-5p’s effect on RA. miR-23-5p level was significantly reduced in RA cells and RAC2 was highly expressed. Expression of RAC2 was inhibited and targeted by miR-23-5p in RA. Exo-miR-23-5p treatment effectively alleviated joint destruction, reduced inflammatory factor secretion in tissues and serum, as well as decreased RAC2 expression in RA model. In conclusion, the miR-23-5p in the BMSC-exo delays the inflammatory response in RA, indicating that it might be a new target for treating RA.

TNF-α Activating Osteoclasts in Patients with Psoriatic Arthritis Enhances the Recruitment of Osteoclast Precursors: A Plausible Role of WNT5A-MCP-1 in Osteoclast Engagement in Psoriatic Arthritis

Psoriatic arthritis (PsA) results from joint destruction by osteoclasts. The promising efficacy of TNF-α blockage indicates its important role in osteoclastogenesis of PsA. WNT ligands actively regulate osteoclastogenesis. We investigated how WNT ligands activate osteoclasts amid the TNF-α milieu in PsA. We first profiled the expression of WNT ligands in CD14+ monocyte-derived osteoclasts (MDOC) from five PsA patients and five healthy controls (HC) and then validated the candidate WNT ligands in 32 PsA patients and 16 HC. Through RNA interference against WNT ligands in MDOC, we determined the mechanisms by which TNF-α exerts its effects on osteclastogenesis or chemotaxis. WNT5A was selectively upregulated by TNF-α in MDOC from PsA patients. The number of CD68+WNT5A+ osteoclasts increased in PsA joints. CXCL1, CXCL16, and MCP-1 was selectively increased in supernatants of MDOC from PsA patients. RNA interference against WNT5A abolished the increased MCP-1 from MDOC and THP-1-cell-derived osteoclasts. The increased migration of osteoclast precursors (OCP) induced by supernatant from PsA MDOC was abolished by the MCP-1 neutralizing antibody. WNT5A and MCP-1 expressions were decreased in MDOC from PsA patients treated by biologics against TNF-α but not IL-17. We conclude that TNF-α recruits OCP by increased MCP-1 production but does not directly activate osteoclastogenesis in PsA.

Collagen-binding integrin alpha11beta1 contributes to joint destruction in arthritic hTNFtg mice

Background: In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) undergo a tumor-like transformation, wherein they develop an aggressive phenotype that is characterized by increased adhesion to components of cartilage extracellular matrix (ECM) and that contributes extensively to joint destruction. The collagen-binding integrin alpha11beta1 was previously shown to be involved in similar processes in cancer-associated fibroblasts mediating tumorigenicity and metastasis in certain tumors. Therefore, this study aimed to study the role of integrin alpha11beta1 in RA and to characterize the effects of alpha11beta1 deficiency on the disease course and severity in arthritic hTNFtg mice. Methods: The expression levels of integrin alpha11beta1 were analyzed by immunohistochemistry, immunofluorescence, and western blot analysis in synovial samples and FLS of patients with RA and osteoarthritis (OA) as well as in samples from wild type (wt) and arthritic hTNFtg mice. Furthermore, the subcellular expression of integrin alpha11beta1 was investigated in co-culture experiments with cartilage explants and analyzed by transmission electron microscopy. To investigate the effects of integrin alpha11beta1 deficiency, itga11-/- mice were interbred with hTNFtg mice and disease severity was assessed by clinical scoring of grip strength and paw swelling over the disease course. Hind paws of 12-weeks-old mice of all genotypes were analyzed by uCT imaging followed by stainings of paraffin-embedded tissue sections with Toluidine-blue and tartrate-resistant acid phosphatase (TRAP) to evaluate established parameters of joint destruction such as inflammation area, cartilage destaining, FLS attachment to the cartilage surface, and bone damage. Results: Expression levels of integrin alpha11beta1 were clearly elevated in synovial tissues and FLS from RA patients and hTNFtg mice, compared to the controls derived from OA patients and wt mice. Interestingly, this expression was shown to be particularly localized in focal adhesions of the FLS. As revealed by transmission electron microscopy, integrin alpha11beta1 expression was particularly evident in areas of direct cellular contact with the ECM of cartilage. Evaluations of clinical scorings and histomorphological analyses demonstrated that itga11-/-hTNFtg displayed alleviated clinical symptoms, higher bone volume, less cartilage destruction, and reduced FLS attachment to the cartilage in comparison to hTNFtg mice. Conclusions: The collagen-binding integrin alpha11beta1 is upregulated in the context of RA and its deficiency in mice with an inflammatory hTNFtg background leads to a significant reduction in the arthritic phenotype which makes integrin alpha11beta1 an interesting target for therapeutical intervention.

Evidence Needed for Efficacy of Antidepressant Medications Among Patients With Rheumatoid Arthritis

Patients with rheumatoid arthritis (RA) experience pain from inflammation, joint destruction, and neuropathy. Antidepressants may play a role among patients with RA and depression, fibromyalgia, or neuropathy to achieve desired outcomes. This commentary evaluated evidence for medications individually and identified important variables for future research. While we await the results of well-designed studies, a trial of duloxetine or milnacipran may be considered for patients with remnant pain and RA remission. Research is needed to evaluate the efficacy and safety of serotonin–norepinephrine reuptake inhibitors and tricyclic antidepressants in patients with RA and associated comorbid conditions.

Effect of Folic Acid Conjugated Silver Nanoparticles in Treatment of RA like Adjuvant Arthritis in Rats.

Objective: Nanomedicine has become one of the promising research areas, opening new horizons in disease diagnosis and treatment. Recent years have witnessed a surge in the development of nanomedicine for combating rheumatoid arthritis (RA), the most common autoimmune arthritis. RA is characterized by progressive inflammation and persistent synovitis, leading to joint destruction, functional incapability, and ultimately disability. Although there has been a tremendous evolution in disease assess­ment and treatment, many patients still fail to attain remission. Therefore, developing new drugs that specifically target inflamed joints and simultaneously attenuate other possible damages to healthy tissues is indispensable. This study was done to evaluate the potential of folic acid conjugated silver nanoparticles (FA-AgNPs) as RA therapy.Methods: In the CFA-arthritic rat model, FA-AgNPs & methotrexate were administered for 8 consecutive weeks. Therapeutic efficacy was evaluated by measuring paw volume, ESR, CRP, TNF-α, and IL-6 levels. For safety concerns, CBC, liver, and renal function tests were evaluated. Joints histological assessment was also carried out.Results: FA-AgNPs significantly reduced paw volume, paw weight, ESR, CRP, RF, TNF-α, and IL-6 levels compared with arthritic non-treated rats, demonstrating good anti-inflammatory activity. Likewise, histology of tarsal joints depicted comparatively lesser inflammatory cellular infiltration and diminished cartilage erosions. Methotrexate displayed comparable results. In contrast to methotrexate, FA-AgNPs showed normal CBC & significantly improved liver and renal function tests. Conclusion: FA-AgNPs exhibited substantial anti-arthritic activity. This notable anti-arthritic potential of FA-AgNPs was as good as the current standard treatment of MTX with higher biosafety.

The Efficacy of Denosumab in Patients With Rheumatoid Arthritis: A Systematic Review and Pooled Analysis of Randomized or Matched Data

ObjectiveThe purpose of this study was to evaluate the efficacy of denosumab treatment in patients with rheumatoid arthritis (RA).MethodsThe Medline, Embase and Cochrane Library databases were searched for relevant clinical studies. Studies that assessed the efficacy of denosumab in patients with RA were identified. The primary endpoints were the percent changes in bone mineral density (BMD), and the changes in modified total Sharp score (mTSS), modified Sharp erosion score and joint space narrowing (JSN) score. Pooled analyses were calculated using random-effect models.ResultsAfter searching the literature and performing further detailed assessments, 10 studies with a total of 1758 patients were included in the quantitative analysis. Pooled analyses showed that denosumab treatment significantly increased the percent changes in lumbar spine BMD [mean difference (MD): 5.12, confidence intervals (CI): 4.15 to 6.09], total hip BMD (MD: 2.72, 95% CI: 1.80 to 3.64) and femoral neck BMD (MD: 2.20, 95% CI: 0.94 to 3.46) compared with controls. Moreover, denosumab treatment significantly decreased the changes in mTSS (MD: -0.63, 95% CI: -0.86 to -0.41) and modified Sharp erosion score (MD: -0.62, 95% CI: -0.88 to -0.35). Subgroup analysis indicated that denosumab was superior to bisphosphonates for the improvement of BMD and the mitigation of joint destruction.ConclusionDenosumab treatment was associated with increased BMD and alleviated progression of joint destruction in RA patients, even when compared with bisphosphonates.

New Proteins Contributing to Immune Cell Infiltration and Pannus Formation of Synovial Membrane from Arthritis Diseases

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.

Regulation of TNF-Induced Osteoclast Differentiation

Increased osteoclast (OC) differentiation and activity is the critical event that results in bone loss and joint destruction in common pathological bone conditions, such as osteoporosis and rheumatoid arthritis (RA). RANKL and its decoy receptor, osteoprotegerin (OPG), control OC differentiation and activity. However, there is a specific concern of a rebound effect of denosumab discontinuation in treating osteoporosis. TNFα can induce OC differentiation that is independent of the RANKL/RANK system. In this review, we discuss the factors that negatively and positively regulate TNFα induction of OC formation, and the mechanisms involved to inform the design of new anti-resorptive agents for the treatment of bone conditions with enhanced OC formation. Similar to, and being independent of, RANKL, TNFα recruits TNF receptor-associated factors (TRAFs) to sequentially activate transcriptional factors NF-κB p50 and p52, followed by c-Fos, and then NFATc1 to induce OC differentiation. However, induction of OC formation by TNFα alone is very limited, since it also induces many inhibitory proteins, such as TRAF3, p100, IRF8, and RBP-j. TNFα induction of OC differentiation is, however, versatile, and Interleukin-1 or TGFβ1 can enhance TNFα-induced OC formation through a mechanism which is independent of RANKL, TRAF6, and/or NF-κB. However, TNFα polarized macrophages also produce anabolic factors, including insulin such as 6 peptide and Jagged1, to slow down bone loss in the pathological conditions. Thus, the development of novel approaches targeting TNFα signaling should focus on its downstream molecules that do not affect its anabolic effect.

Peculiarities of knee replacement in patients with rheumatoid arthritis

Introduction. Rheumatoid arthritis (RA), as a steadily progressive disease leading to joint destruction and functional instability of the knee joints, often requires orthopedic correction.The aim. Of the review was to analyze the surgery strategy and technical features of knee arthroplasty and replacement in patients with RA.Basic provisions. RA is characterized by a number of abnormalities not only due to erosive arthritis and active persistent synovitis, but also caused by a decrease in bone mineral density, damage to the periarticular structures and patella, the formation of bone defects, as well as a high risk of postoperative complications. All these factors should be taken into account while choosing relevant surgical treatment and knee replacement technique. The article presents the optimal approaches for performing knee replacement in RA patients, taking into account the peculiarities of the existing structural and functional disorders.Conclusion. TEC in patients with RA requires a personalized approach based on evaluation of disease-associated risk factors affecting the results of orthopedic correction and the likelihood of complications.

The Role of Nutraceuticals in Osteoarthritis Prevention and Treatment: Focus on n-3 PUFAs

Osteoarthritis (OA) is a disease caused by joint degeneration with massive cartilage loss, and obesity is among the risk factors for its onset, though the pathophysiological mechanisms underlying the disease and better therapeutic approach still remain to be assessed. In recent years, several nutraceutical interventions have been investigated in order to define better solutions for preventing and treating OA. Among them, polyunsaturated fatty acids (n-3 PUFAs) appear to represent potential candidates in counteracting OA and its consequences, due to their anti-inflammatory, antioxidant, and chondroinductive effects. PUFAs have been found to counteract the onset and progression of OA by reducing bone and cartilage destruction, inhibiting proinflammatory cytokine release, reactive oxygen species (ROS) generation, and the NF-κB pathway’s activation. Moreover, a diet rich in n-3 PUFAs and their derivatives (maresins and resolvins) demonstrates beneficial effects on associated pain reduction. Finally, it has been shown that together with the anti-inflammatory and antioxidant properties of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, their antiapoptotic and antiangiogenic effects contribute in reducing OA development. The present review is aimed at assessing evidence suggesting the potential benefit of nutraceutical supplementation with PUFAs in OA management according to their efficacy in targeting relevant pathophysiological mechanisms responsible for inflammation and joint destruction processes, and this may represent a novel and potentially useful approach in OA prevention and treatment. For that purpose, a PubMed literature survey was conducted with a focus on some in vitro and in vivo studies and clinical trials from 2015 to 2020.