Rheumatoid Arthritis Joint Research Articles

Synovial fibroblast gene expression is associated with sensory nerve growth and pain in rheumatoid arthritis.

It has been presumed that rheumatoid arthritis (RA) joint pain is related to inflammation in the synovium; however, recent studies reveal that pain scores in patients do not correlate with synovial inflammation. We developed a machine-learning approach (graph-based gene expression module identification or GbGMI) to identify an 815-gene expression module associated with pain in synovial biopsy samples from patients with established RA who had limited synovial inflammation at arthroplasty. We then validated this finding in an independent cohort of synovial biopsy samples from patients who had early untreated RA with little inflammation. Single-cell RNA sequencing analyses indicated that most of these 815 genes were most robustly expressed by lining layer synovial fibroblasts. Receptor-ligand interaction analysis predicted cross-talk between human lining layer fibroblasts and human dorsal root ganglion neurons expressing calcitonin gene-related peptide (CGRP+). Both RA synovial fibroblast culture supernatant and netrin-4, which is abundantly expressed by lining fibroblasts and was within the GbGMI-identified pain-associated gene module, increased the branching of pain-sensitive murine CGRP+ dorsal root ganglion neurons in vitro. Imaging of solvent-cleared synovial tissue with little inflammation from humans with RA revealed CGRP+ pain-sensing neurons encasing blood vessels growing into synovial hypertrophic papilla. Together, these findings support a model whereby synovial lining fibroblasts express genes associated with pain that enhance the growth of pain-sensing neurons into regions of synovial hypertrophy in RA.

Dual-Channel/Localization Single-Molecule Fluorescence Probe for Monitoring ATP and HOCl in Early Diagnosis and Therapy of Rheumatoid Arthritis.

Rheumatoid arthritis (RA), a common chronic inflammatory illness, is still incurable, reducing the sufferers' quality of life significantly. Adenosine 5'-triphosphate (ATP) and hypochlorous acid (HOCl) are key indicators in RA, but their precise mechanisms in RA pathophysiology are unknown. As a result, in order to detect ATP and HOCl simultaneously, we created two new dual-channel/localization single-molecule fluorescence probes, RhTNMB and RhFNMB. Furthermore, RhFNMB outperformed RhTNMB in terms of detection performance. ATP and HOCl produce independent fluorescence responses in the light red channel (λex = 520 nm, λem = 586 nm) and deep red channel (λex = 620 nm, λem = 688 nm), respectively, without spectral crosstalk. It should be noted that the probe RhFNMB successfully imaged ATP in mitochondria and HOCl in cells. Surprisingly, the probe RhFNMB demonstrated remarkable detection ability in the diagnosis and treatment of Pseudomonas aeruginosa-induced abdominal inflammation in mice. We continued to apply the probe RhFNMB to track ATP and HOCl in RA and discovered that ATP and HOCl concentrations were considerably greater in RA joints than in normal joints. We also confirmed the therapeutic effect of methotrexate on RA. This study is the first to achieve dual-channel imaging of ATP and HOCl, which is of great value for the early diagnosis and therapy of RA.

Immunological Roles of Fibroblast-Like Synoviocyte Cells in Rheumatoid Arthritis

Introduction: Fibroblast-like synoviocytes (FLS), also known as synovial fibroblasts or type B synoviocytes, are the primary cells responsible for the structure of the synovial lining. They are crucial for the formation of a healthy, organized synovial lining. In rheumatic synovium affected by inflammation, the typical three-layered synovial lining transforms into a pannus-like structure. Various pro-inflammatory conditions in the joints of rheumatoid arthritis (RA) patients, characterized by elevated levels of cytokines, growth factors, and infiltration of inflammatory cells, strongly activate FLS cells. Moreover, environmental conditions in the joints of RA patients, such as high pressure and hypoxia, induce changes that further contribute to FLS activation and the development of aggressive characteristics. These changes include increased proliferation, reduced apoptosis, and enhanced cell migration, collectively referred to as a tumor-like phenotype. Additionally, FLS cells release inflammatory cytokines, amplifying inflammation and attracting immune cells to the joint. They also play a role in degrading the extracellular matrix and causing cartilage and bone damage through the production of enzymes like matrix metalloproteinases (MMPs), collagenase, aggrecans, and cathepsins. Recent therapeutic approaches have been directed at targeting the signaling pathways that activate FLS cells and inhibiting factors and cytokines produced by these cells to alleviate inflammatory symptoms and reduce joint damage. It is anticipated that these treatment strategies will complement existing therapies in the near future.
 Conclusion: FLS cells are the main components of maintaining the health and nutrition of joints. These cells produce various cytokines, chemokines, angiogenic factors, as well as factors that contribute to the breakdown of matrix and cartilage. The main drivers of significant changes in inflamed joints are proliferation and resistance to apoptosis. Treatment strategies have been developed to target the signaling pathways that activate these cells, with a focus on improving inflammatory symptoms. It is expected that these treatment strategies will be incorporated into existing therapies in the near future.

Background and objectives: Acute coronary syndrome is the leading cause of death all over the world, there are many different risk factors as important etiology for this acute condition, this syndrome has been studied in different countries with a variety of results. The aim was to define different risk factors for the patients admitted to Erbil cardiac center and to

Background and objectives: The most prevalent and chronic form of systemic autoimmune disease, rheumatoid arthritis is characterized by persistent inflammation, deteriorating joint function with time, increasing comorbidity, and increased mortality. The aim of this study was to know the frequency of joints involved, to know the prevalence of seropositive Rheumatoid arthritis, and evaluation of demographic features of the patients with Rheumatoid arthritis. Methods: A cross-sectional, descriptive study was undertaken on 110 patients at Rizgary teaching hospital in Erbil city. From January 2022 and January 2023. We evaluated and diagnosed the patients. Serological investigations including Anti-cyclic citrullinated peptide and rheumatoid factor were done for all of the patients. Results: One hundred ten patients 80% were female and 20 % were male. The mean age (SD) was 51.39 (12.6) years, majority of the patients were obese (45.5%). Only 14.5% of the sample were smokers, and rate of illiteracy was 60%. The most common joints involved were metacarpo-pharyngeal joint 73.6% followed by wrist joint 63.6%. Most common comorbid disease was hypertension 29.1% followed by diabetes mellitus, and thyroid disease (15.5%, 10%) respectively. Prevalence of seropositive rheumatoid arthritis was 80.9%. Majority of the patients used methotrexate, while the most common biologic used by the patients was etanercept 12.7%. Conclusions: Our rheumatoid arthritis patients' demographics, joint involvement, and serological characteristics matched those of some regional and international studies, however we discovered a higher proportion of women and a higher percentage of illiteracy.

Non-coding autoimmune risk variant defines role for ICOS in T peripheral helper cell development

Fine-mapping and functional studies implicate rs117701653, a non-coding single nucleotide polymorphism in the CD28/CTLA4/ICOS locus, as a risk variant for rheumatoid arthritis and type 1 diabetes. Here, using DNA pulldown, mass spectrometry, genome editing and eQTL analysis, we establish that the disease-associated risk allele is functional, reducing affinity for the inhibitory chromosomal regulator SMCHD1 to enhance expression of inducible T-cell costimulator (ICOS) in memory CD4+ T cells from healthy donors. Higher ICOS expression is paralleled by an increase in circulating T peripheral helper (Tph) cells and, in rheumatoid arthritis patients, of blood and joint fluid Tph cells as well as circulating plasmablasts. Correspondingly, ICOS ligation and carriage of the rs117701653 risk allele accelerate T cell differentiation into CXCR5-PD-1high Tph cells producing IL-21 and CXCL13. Thus, mechanistic dissection of a functional non-coding variant in human autoimmunity discloses a previously undefined pathway through which ICOS regulates Tph development and abundance.

Apoptotic extracellular vesicles restore homeostasis of the articular microenvironment for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a severe autoimmune disease with symptoms including synovial inflammation, cartilage erosion, and bone loss in RA lesions, which eventually lead to joint deformity and function loss. Most current treatments fail to achieve satisfying therapeutic outcomes with some adverse effects. Extracellular vesicles derived from apoptotic cells (apoEVs) have emerged as important mediators in intercellular communication regulating diverse physiological and pathological processes. In this study, we investigated the therapeutic efficacy of macrophage-derived and osteoclast-derived apoEVs (Mφ-apoEVs and OC-apoEVs) on RA. The in vitro results showed that both Mφ-apoEVs and OC-apoEVs induced macrophage repolarization toward the anti-inflammatory M2 phenotype, promoted chondrocyte functions and chondrogenesis, and inhibited osteoclast formation and maturation. In addition, OC-apoEVs promoted osteogenic differentiation. The in vivo study on the CIA mouse model further demonstrated that apoEVs could couple various functions and exert synergistic effects on the joint with RA, as evidenced by the regression of synovial inflammation, the reversal of cartilage damage and bone erosion, and the preservation of joint structure. These findings demonstrated that Mφ-apoEVs and OC-apoEVs contributed to restoring the homeostasis of the overall microenvironment in the RA joint and highlighted their potential application as a promising alternative to treat RA.

Biomimetic and inflammation-targeted nanoparticles for rheumatoid arthritis therapy via M1-macrophages apoptosis and polarization

M1 macrophages enrich in rheumatoid arthritis (RA) joints and contribute to persistent progression of inflammation and destruction. Their apoptosis and polarization toward M2 phenotype play crucial roles in anti-inflammation. Herein, we developed three kinds of biomimetic nanoparticles (NPs) derived from different cells for dual-targeting to inflamed site and M1 macrophages. These NPs were aimed to induce M1 macrophages apoptosis and re-polarization for efficient RA therapy via dually targeting drug delivery to inflamed joints and M1 macrophages. Results demonstrated that the NPs had a massive accumulation at inflamed site and high internalization efficiency in M1 macrophages. After loading methotrexate, the NPs substantially suppressed the viability of activated macrophages and the expression of pro-inflammatory cytokines. Furthermore, they dramatically promoted the expression of anti-inflammatory cytokines, and induced M1-to-M2 transition of macrophages. In an adjuvant-induced arthritis mouse model, the NPs efficiently reduced the number of inflammatory macrophages, secretion of pro-inflammatory cytokines and destruction of cartilage or bone tissues. Additionally, the swelling of paw and ankle joint was significantly alleviated by the NPs after 17 days treatment, especially the activated macrophage-derived NPs. The findings highlight the potential of NPs with dual-targeting ability in the treatment of RA by apoptosis and re-polarization of M1 macrophages.

Synovial-tissue resident macrophages play proinflammatory functions in the pathogenesis of RA while maintaining the phenotypes in the steady state

Synovial tissue-resident macrophages (STRMs) maintain normal joint homeostasis in a steady state. However, it is unclear whether STRMs still play homeostatic roles or change the functions in the joint of rheumatoid arthritis (RA), where infiltrating peripheral blood monocyte-derived macrophages (PBMoMs) play proinflammatory roles. In the present study, we examined changes in the phenotypes and functions of STRMs in response to RA-related stimuli in vitro. STRMs were prepared from non-inflammatory osteoarthritis (OA) joint synovium, which is histologically indistinguishable from normal joint synovium. PBMoMs were prepared and used for comparison. After stimulation with plate-bound IgG, which mimics anti-citrullinated protein antibody immunocomplex formed in RA joints, or with combinations of RA-related inflammatory mediators, namely tumor necrosis factor-α (TNF-α) and prostaglandin E2 or interferon-γ, PBMoMs downregulated surface markers and genes associated with anti-inflammatory macrophages, and upregulated cytokine and marker genes of proinflammatory macrophages in RA. On the other hand, STRMs hardly changed the expression of surface molecules and marker genes but altered the pattern of cytokine gene expression after stimulation like PBMoMs. Furthermore, in vitro stimulated STRMs promote proinflammatory functions of cocultured synovial fibroblasts. Thus, STRMs might play proinflammatory roles in RA joints, while maintaining their phenotypes in the steady state.

Dietary oleacein, a secoiridoid from extra virgin olive oil, prevents collagen-induced arthritis in mice.

Olacein (OLA), one of the main secoiridoids derived from extra virgin olive oil (EVOO), has been shown to modulate oxidative and inflammatory responses in various pathological conditions; however, its potential benefit in joint disorders such as rheumatoid arthritis (RA) is unknown. Therefore, this study was designed to evaluate the preventive role of the effects of an OLA-supplemented diet in the murine model of collagen-induced arthritis (CIA), delving into the possible mechanisms and signaling pathways involved. Animals were fed an OLA-enriched preventive diet for 6 weeks prior to CIA induction and until the end of the experimental time course. On day 43 after the first immunization, mice were sacrificed: blood was collected, and paws were histologically and biochemically processed. Dietary OLA prevented collagen-induced rheumatic bone, joint and cartilage conditions. Circulating matrix metalloproteinase (MMP)-3 and proinflammatory cytokine (IL-6, IL-1β, TNF-α, IL-17) levels were significantly decreased in the joint, as well as MMP-9 and cathepsin-K (CatK) expression in secoiridoid-fed animals. In addition, dietary OLA was able to decrease COX-2, mPGES-1 and iNOS protein expressions and, also, PGE2 levels. The mechanisms possibly involved in these protective effects could be related to the activation of the Nrf-2/HO-1 axis and the inhibition of proinflammatory signaling pathways, including JAK-STAT, MAPKs and NF-κB, involved in the production of inflammatory and oxidative mediators. These results support the interest of OLA, as a nutraceutical intervention, in the management of RA.

“Rice bodies” symptoms on magnetic resonance imaging of the shoulder in a patient with rheumatoid arthritis

The “rice bodies” symptom on magnetic resonance imaging of the shoulder joint in patients with rheumatoid arthritis is a rare but specific finding characterized by the presence of multiple small, round, rice-grain-like structures in the synovial fluid of the joint, synovial pouches, or sheaths. The etiology of the “rice bodies” is still not fully understood. They are suggested as the result of microinfarcts of the synovial membrane in patients with rheumatoid arthritis or other inflammatory joint diseases. Clinically, the “rice bodies” symptom may cause pain, but not in every case. Among radiological diagnostic methods, magnetic resonance imaging is the leading method for the detection of rice bodies. This article presents a clinical case of “rice bodies” symptoms diagnosed by magnetic resonance imaging in a patient with a long history of rheumatoid arthritis who presented with a painless enlargement in the left shoulder. Computed tomography and magnetic resonance imaging of the left shoulder could detect “rice bodies” as a manifestation of an underlying disease and determine further treatment techniques.

A novel biomarker of MMP-cleaved cartilage intermediate layer protein-1 is elevated in patients with rheumatoid arthritis, ankylosing spondylitis and osteoarthritis

Rheumatic joints have an altered cartilage turnover. Cartilage intermediate layer protein 1 (CILP-1) is secreted from articular chondrocytes and deposited into the cartilage extracellular matrix. We developed an immunoassay targeting a Matrix Metalloproteinase (MMP)-generated neo-epitope of CILP-1, named CILP-M. Human articular cartilage was cleaved with proteolytic enzymes and CILP-M levels were measured. We also quantified CILP-M in two studies from patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and osteoarthritis (OA) and explored the monitoring and prognostic potential of CILP-M in TNF-α inhibitory treatment and modified Stoke AS Spine Score (mSASSS) progression. CILP-M was generated by MMP-1, -8 and -12. In the discovery study, CILP-M was significantly higher in patients with RA, AS and OA than healthy donors (p < 0.01, p < 0.001, p < 0.05) with an area under the curve (AUC) between the diseased groups and healthy donors > 0.95 (p < 0.001). In the validation study, patients with RA and AS had significantly higher CILP-M levels than healthy controls (p < 0.001) and AUC > 0.90 (p < 0.001). Patients with AS treated with TNF- α inhibitory treatment in the validation study had significantly lower CILP-M levels after treatment (p = 0.004). CILP-M may provide useful insights into cartilage degradation processes in rheumatic diseases.

In early rheumatoid arthritis, anticitrullinated peptide antibodies associate with low number of affected joints and rheumatoid factor associates with systemic inflammation

ObjectivesTo investigate how individual rheumatoid arthritis (RA) autoantibodies associate with individual signs and symptoms at the time of RA diagnosis.MethodsIgA, IgG, IgM rheumatoid factor (RF), antibodies against cyclic citrullinated peptide...

Hierarchical Microcarriers Loaded with Peptide Dendrimer‐Grafted Methotrexate for Rheumatoid Arthritis Treatment

Rheumatoid arthritis (RA) is one of the leading causes of disability due to the autoimmune destruction of synovial joints. Great efforts have been put into developing multifunctional drug delivery systems for delaying the progression of RA. Herein, a novel locally injectable, hierarchically structured delivery system with a hyaluronic acid (HA) microparticle and an MTX‐conjugated nanoparticle for promoted RA treatment is proposed. In this system, MTX is chemically grafted onto a peptide dendrimer‐based nanoparticle (G‐MTX). These nanoparticles are encapsulated inside HA microparticles (H‐G‐MTX) using microfluidics to realize the system. The G‐MTX can be released from the degradable HA microparticles in the acidic environment of inflamed RA joints. As the G‐MTX shows an enhanced intracellular delivery of the conjugated MTX, the H‐G‐MTX can reverse the dominant macrophage phenotype from M1 to M2. Through a collagen‐induced arthritis (CIA) rat model, the great therapeutic outcomes of this hierarchically structured delivery system are demonstrated, including inflammation reduction, cartilage protection, and bone mineral density promotion. These results indicate that the proposed hierarchical delivery system has potential clinical value in the treatment of RA and other diseases.

Carrier-free nanodrug targeting glucose metabolism for enhanced rheumatoid arthritis treatment

Dramatically increased glycolysis has been found in inflamed joints in rheumatoid arthritis (RA) due to the increased demand for energy and biosynthetic precursors to support the expansion of inflammation. Therefore, regulating the elevated glycolysis level in RA progress might hold potential to achieve inflammation remission. 2-deoxy-D-glucose (2-DG) is a well-characterized glycolysis inhibitor. However, the rapid clearance and indiscriminate distribution of 2-DG have hampered its application. Although nanocarriers can facilitate targeted delivery to improve drug bioavailability, they often suffer from undesirable drug loading and potential toxicity caused by carrier materials. Thus, carrier-free nanodrugs formed by pure therapeutic drugs with satisfying biological activity might possess promising potential for RA therapy. Herein, we reported the carrier-free nanodrug self-assembled from 2-DG and Curcumin (Cur) without any other ingredient. Cur is a natural anti-inflammatory agent and has been widely investigated for inflammatory diseases therapy. The self-assembly of 2-DG/Cur nanodrug (2-DCNP) does not require any additional material. Therefore, the application of 2-DCNP can avoid the potential side effects caused by carrier materials. Inflammatory cells usually exhibited high expression of glucose transporter protein 1 (GLUT1) to facilitate glucose utilization. Thus, 2-DCNP with 2-DG on the surface might promote selective drug delivery to inflamed joints due to the high affinity between 2-DG and GLUT1. Our results indicated that 2-DCNP treatment could effectively inhibit glycolysis level to finally achieve desirable therapeutic efficacy in arthritic rats. This carrier-free nanodrug aiming at regulating glucose metabolism in inflamed joints might provide new insight for RA therapy.

GLI1 facilitates collagen-induced arthritis in mice by collaborative regulation of DNA methyltransferases.

Rheumatoid arthritis (RA) is characterized by joint synovitis and bone destruction, the etiology of which remains to be explored. Many types of cells are involved in the progression of RA joint inflammation, among which the overactivation of M1 macrophages and osteoclasts has been thought to be an essential cause of joint inflammation and bone destruction. Glioma-associated oncogene homolog 1 (GLI1) has been revealed to be closely linked to bone metabolism. In this study, GLI1 expression in the synovial tissue of RA patients was positively correlated with RA-related scores and was highly expressed in collagen-induced arthritis (CIA) mouse articular macrophage-like cells. The decreased expression and inhibition of nuclear transfer of GLI1 downregulated macrophage M1 polarization and osteoclast activation, the effect of which was achieved by modulation of DNA methyltransferases (DNMTs) via transcriptional regulation and protein interactions. By pharmacological inhibition of GLI1, the proportion of proinflammatory macrophages and the number of osteoclasts were significantly reduced, and the joint inflammatory response and bone destruction in CIA mice were alleviated. This study clarified the mechanism of GLI1 in macrophage phenotypic changes and activation of osteoclasts, suggesting potential applications of GLI1 inhibitors in the clinical treatment of RA.

Targeting FGFR3 is a Useful Therapeutic Strategy for Rheumatoid Arthritis Treatment.

Rheumatoid arthritis (RA) is a systemic inflammatory disease in which TNF-α plays an important role. Fibroblast growth factor receptor 3 (FGFR3) is reportedly involved in RA by regulating the expression of inflammatory cytokines. This study examined the expression profile of FGFR3 in human synovial biopsy tissues and evaluated its gene-silencing effects on behaviors of synovial cells. Immunohistochemical staining was used to measure FGFR3 expression in human RA joint tissues. Cell proliferation, migration, and apoptosis assays were used to monitor behavioral changes in cultured synovial SW-982 cells with siRNA-mediated FGFR3 gene silencing. Immunofluorescent staining and western blotting were used to detect molecular changes in the FGFR3 gene-silenced cells. FGFR3 up-regulation was noted in both cytoplasms and nuclei of synovial cells in human RA joints. FGFR3 siRNA delivery experiments corroborated that FGFR3 knockdown decreased proliferation and migration, and triggered apoptosis of synovial cells. The FGFR3 gene knockdown enhanced constitutive expression of epithelial marker E-cadherin and conversely suppressed expression of epithelial-mesenchymal transition (EMT) markers, including Snail, fibronectin, and vimentin. In addition, FGFR3 silencing significantly reduced the constitutive expressions of TNF-α, transcription factor NF-κΒ, and downstream COX-2 protein and collagenolytic enzyme MMP-9. MAPK inhibition markedly suppressed constitutive levels of NF-κΒ, COX-2, and MMP-9. Genetic interference of FGFR3 could modulate the expression of inflammatory mediators and EMT markers in the synovial cells. Targeting the FGFR3/MAPK signal axis may be considered a useful therapeutic strategy to ameliorate the development of RA.

Rheumatoid Synovial Fluid and Acidic Extracellular pH Modulate the Immunomodulatory Activity of Urine-Derived Stem Cells.

Urine-derived stem cells (UdSCs) possess a remarkable anti-inflammatory and immune-modulating activity. However, the clinical significance of UdSCs in autoimmune inflammatory diseases such as rheumatoid arthritis (RA) is yet to be explored. Hence, we tested the UdSCs response to an articular RA microenvironment. To simulate the inflamed RA joint more authentically in vitro, we treated cells with rheumatoid synovial fluids (RASFs) collected from RA patients, serum deprivation, acidosis (pH 7.0 and 6.5), and their combinations. Firstly, the RASFs pro-inflammatory status was assessed by cytokine quantification. Then, UdSCs were exposed to the RA environmental factors for 48 h and cell proliferation, gene expression and secretion of immunomodulatory factors were evaluated. The immunosuppressive potential of pre-conditioned UdSCs was also assessed via co-cultivation with activated peripheral blood mononuclear cells (PBMCs). In all experimental conditions, UdSCs' proliferation was not affected. Conversely, extracellular acidosis considerably impaired the viability/proliferation of adipose tissue-derived stem cells (ATSCs). In the majority of cases, exposure to RA components led to the upregulated expression of IL-6, TSG6, ICAM-1, VCAM-1, and PD-L1, all involved in immunomodulation. Upon RASFs and acidic stimulation, UdSCs secreted higher levels of immunomodulatory cytokines: IL-6, IL-8, MCP-1, RANTES, GM-CSF, and IL-4. Furthermore, RASFs and combined pretreatment with RASFs and acidosis promoted the UdSCs-mediated immunosuppression and the proliferation of activated PBMCs was significantly inhibited. Altogether, our data indicate that the RA microenvironment certainly has the capacity to enhance UdSCs' immunomodulatory function. For potential preclinical/clinical applications, the intra-articular injection might be a reasonable approach to maximize UdSCs' therapeutic efficiency in the RA treatment.

Arthrodesis of the interphalangeal joints of the hand by two-dimensional intraosseous wiring

BackgroundNumerous techniques for arthrodesis have been described to fix interphalangeal (IP) joints, and the fixation method should be considered on a case-by-case basis. This study aimed to investigate the availability of IP joint arthrodesis of the hand, using a two-dimensional intraosseous wiring (two-DIOW) method.MethodsA total of 43 joints (19 thumb IP joints, 9 proximal finger interphalangeal (PIP) joints and 15 distal interphalangeal (DIP) joints in 29 patients with a mean age of 66 years (range, 24–85 y) were retrospectively analyzed. All operations were performed with two-DIOW method. We evaluated the bone union rate, correction loss, presence of any surgical complications, and oral steroid use in cases of joint fixation using the two-DIOW method.ResultsOf these 43 digits, 42 achieved bone union (97.7%). Non-union was seen in a thumb IP joint of mutilans rheumatoid arthritis. Mean correction loss of deviation was 1.0°, and flexion or extension angulation was 1.6° in the direction of extension. Surgical complications included mild nail deformity in 2 digits and wire irritation necessitating wire removal in 2 digits. Oral steroids were used for 18 of the 43 digits, including 2 digits complicated by nail deformities. There was no infection and skin necrosis in all digits with or without steroid use.ConclusionsThe two-DIOW method appears to offer an effective method of IP joint fixation, but caution should be exercised in digits of severe joint destruction and in the treatment of wire knot.

Enhanced intra-articular therapy for rheumatoid arthritis using click-crosslinked hyaluronic acid hydrogels loaded with toll-like receptor antagonizing peptides

Rheumatoid arthritis (RA) is a chronic inflammatory disorder that results in the deterioration of joint cartilage and bone. Toll-like receptor 4 (TLR4) has been pinpointed as a key factor in RA-related inflammation. While Toll-like receptor antagonizing peptide 2 (TAP2) holds potential as an anti-inflammatory agent, its in vivo degradation rate hinders its efficacy. We engineered depots of TAP2 encapsulated in click-crosslinked hyaluronic acid (TAP2+Cx-HA) for intra-articular administration, aiming to enhance the effectiveness of TAP2 as an anti-inflammatory agent within the joint cavity. Our data demonstrated that FI-TAP2+Cx-HA achieves a longer retention time in the joint cavity compared to FI-TAP2 alone. Mechanistically, we found that TAP2 interacts with TLR4 on the cell membranes of inflammatory cells, thereby inhibiting the nuclear translocation of NF-κB and maintaining it in an inactive cytoplasmic state. In a rat model of RA, the TAP2+Cx-HA formulation effectively downregulated the inflammatory cytokines TNF-α and IL-6, while upregulating the anti-inflammatory cytokine IL-10 and the therapeutic protein 14-3-3ζ. This led to a more rapid restoration of cartilage thickness, increased deposition of glycosaminoglycans, and new bone tissue formation in the regenerated cartilage, in comparison to a single TAP2 treatment after a six-week period. Our results suggest that TAP2+Cx-HA could serve as a potent intra-articular treatment for RA, offering both symptomatic relief and promoting cartilage regeneration. This innovative delivery system holds significant promise for improving the management of RA and other inflammatory joint conditions. Statement of significanceIn this study, we developed a therapy by creating toll-like receptor 4 (TLR4)-antagonizing peptide (TAP2)-loaded click-crosslinked hyaluronic acid (TAP2+Cx-HA) depots for direct intra-articular injection. Our study demonstrates that FI-TAP2+Cx-HA exhibits a more than threefold longer lifetime in the joint cavity compared to FI-TAP2 alone. Furthermore, we found that TAP2 binds to TLR4 and masks the nuclear localization signals of NF-κB, leading to its sequestration in an inactive state in the cytoplasm. In a rat model of RA, TAP2+Cx-HA effectively suppresses inflammatory molecules, specifically TNF–α and IL-6, while upregulating the anti-inflammatory cytokine IL-10 and the therapeutic protein 14-3-3ζ. This resulted in faster regeneration of cartilage thickness, increased glycosaminoglycan deposits in the regenerated cartilage, and a twofold increase in new bone tissue formation compared to a single TAP2 treatment.

Exploring the therapeutic potential of Prinsepia utilis Royle seed oil: A comprehensive study on chemical composition, physicochemical properties, anti-inflammatory, and analgesic activities

Ethnopharmacological relevancePrinsepiautilis (PU) Royle, native to the Himalayan region, is a deciduous thorny shrub with numerous traditional uses of its roots, leaves and seeds for treatment of conditions such as rheumatic pain, joint pain, arthritis, and inflammation. Aim of the studyKeeping in mind the growing demand of products of natural origin as alternate medicine, the present study was undertaken to scientifically validate for the first time the traditional claims of healing pain and inflammation by evaluating the fatty oil isolated from the seeds using established in vitro and in vivo models. Materials and methodsPU Seeds were Soxhlet extracted using n-hexane and fatty oil was isolated. Chemical composition of the oil was established with the aid of Gas Chromatography-Flame Ionization Detection (GC-FID) and Gas Chromatography-Mass Spectrometry (GC-MS). The oil was then subjected to in vitro anti-inflammatory activity by following the established protocols of trypsin inhibitory and bovine serum albumin denaturation assays. The acute toxicity of the oil was also studied using OECD guidelines 423. The anti-inflammatory property of the oil was further evaluated using carrageenan-induced and formalin-induced edema in the rat paw. Moreover, hot plate latency and tail immersion assay were employed to evaluate analgesic activity of the oil. To establish the quality of the oil, various physicochemical properties were also studied. ResultsGC-FID and GC-MS analysis of the oil revealed the presence of linoleic acid (59.06 ± 0.00%), oleic acid (28.11 ± 0.01%), palmitic acid (9.51 ± 0.01%) and stearic acid (3.32 ± 0.01%). In vitro trypsin inhibitory and bovine serum albumin denaturation assay revealed dose-dependent notable activity of the oil with IC50 value of 63.57 μg/mL and 518.14 μg/mL, respectively. The physico-chemical characterization demonstrated that the oil possesses a low acidity and a high oxidative stability index. The oil was found to be non-toxic and displayed effective anti-inflammatory activities with significant inhibition till 4 h in carrageenan-induced and formalin-induced rat paw edema at maximum tested dose of 200 mg/kg b.w. The oil also exhibited significant results in hot plate latency and tail immersion assay with positive effects showing up to 4 h after dose administration. ConclusionThese findings, besides supporting the traditional claims, suggest that P. utilis seed oil has potential therapeutic applications as a natural anti-inflammatory and analgesic agent. Further studies are warranted to explore its mechanisms of action and potential use in pharmaceutical and nutraceutical industries.