Ewing Sarcoma of the Larynx with Thyroid Cartilage Destruction: A Case Report.

Ewing sarcoma of the larynx is extremely rare, only a few number of cases have been reported. In this report, we describe a case of extraskeletal Ewing sarcoma of the larynx with thyroid cartilage destruction. Laryngoscope, 134:4577-4581, 2024.

Cartilage destruction in early rheumatoid arthritis patients correlates with CD21-/low double-negative B cells.

BACKGROUND: Involvement of B cells in the pathogenesis of rheumatoid arthritis (RA) is supported by the presence of disease-specific autoantibodies and the efficacy of treatment directed against B cells. B cells that express low levels of or lack the B cell receptor (BCR) co-receptor CD21, CD21-/low B cells, have been linked to autoimmune diseases, including RA. In this study, we characterized the CD21+ and CD21-/low B cell subsets in newly diagnosed, early RA (eRA) patients and investigated whether any of the B cell subsets were associated with autoantibody status, disease activity and/or joint destruction. METHODS: Seventy-six eRA patients and 28 age- and sex-matched healthy donors were recruited. Multiple clinical parameters were assessed, including disease activity and radiographic joint destruction. B cell subsets were analysed in peripheral blood (PB) and synovial fluid (SF) using flow cytometry. RESULTS: Compared to healthy donors, the eRA patients displayed an elevated frequency of naïve CD21+ B cells in PB. Amongst memory B cells, eRA patients had lower frequencies of the CD21+CD27+ subsets and CD21-/low CD27+IgD+ subset. The only B cell subset found to associate with clinical factors was the CD21-/low double-negative (DN, CD27-IgD-) cell population, linked with the joint space narrowing score, i.e. cartilage destruction. Moreover, in SF from patients with established RA, the CD21-/low DN B cells were expanded and these cells expressed receptor activator of the nuclear factor κB ligand (RANKL). CONCLUSIONS: Cartilage destruction in eRA patients was associated with an expanded proportion of CD21-/low DN B cells in PB. The subset was also expanded in SF from established RA patients and expressed RANKL. Taken together, our results suggest a role for CD21-/low DN in RA pathogenesis.

Schisandra extract ameliorates arthritis pathogenesis by suppressing the NF-κB and MAPK signalling pathways.

Schisandra chinensis is a medicinal plant used to treat various diseases. Extracts from the leaves or fruits of S. chinensis and their components are used in osteoarthritis (OA). The OA inhibitory effect of schisandrol A, one of its components, has been previously confirmed. We aimed to confirm the OA inhibitory effect of Schisandra (including components like schisandrol A) to identify why the inhibitory effect of the Schisandra extract is better. First, we investigated the effects of the Schisandra extract on OA as a potential therapeutic. Experimental OA was induced in a mouse model via destabilized medial meniscus surgery. The animals were orally administered the Schisandra extract; the inhibition of cartilage destruction was confirmed using histological analysis. In vitro analysis showed that the Schisandra extract attenuated osteoarthritic cartilage destruction by regulating IL-1ß-induced MMP3 and COX-2 levels. The Schisandra extract inhibited IL-1ß-induced degradation of IκB (NF-κB pathway) and IL-1ß-induced phosphorylation of p38 and JNK (mitogen-activated protein kinase (MAPK) pathway). RNA-sequencing analysis showed that the Schisandra extract decreased the expression of IL-1ß-induced MAPK and NF-κB signalling pathway-related genes more than schisandrol A alone. Therefore, Schisandra extract may be more effective than schisandrol A in preventing OA progression by regulating MAPK and NF-κB signalling.

Teriparatide prevented synovial inflammation and cartilage destruction in mice with DMM.

AIM: Emerging data have demonstrated that low-grade inflammation in osteoarthritis, a long-held degenerative disease. The inflamed synovium produces various cytokines that induce cartilage destruction and joint pain. A previous study showed that teriparatide, an FDA approved anti-osteoporotic drug, may enhance cartilage repair. Our study focuses on its role in OA synovitis. MATERIALS AND METHODS: Primary mouse articular chondrocytes were used to determine the most potent cytokines involved in OA inflammation and cartilage destruction. A destabilization of the medial meniscus mouse model was established to investigate the effect of teriparatide in OA, particularly, on synovial inflammation and cartilage degradation. RESULTS: In vitro experiments showed that TNF-α was the most potent inducer of cartilage matrix-degrading enzymes, and that teriparatide antagonized the TNF-α of effect. Consistently, articular cartilage samples from TNF-α transgenic mice contained more MMP-13 positive chondrocytes than those from wild type mice. In addition, more type II collagen was cleaved in human OA cartilage than in normal cartilage samples. CONCLUSIONS: Teriparatide can prevent synovitis and cartilage degradation by suppressing TNF-α mediated MMP-13 overexpression. Together with its chondroregenerative capability, teriparatide may be the first effective disease modifying osteoarthritis drug.

Immunomodulatory role of T helper cells in rheumatoid arthritis : a comprehensive research review.

Rheumatoid arthritis (RA) is an autoimmune disease that involves T and B cells and their reciprocal immune interactions with proinflammatory cytokines. T cells, an essential part of the immune system, play an important role in RA. T helper 1 (Th1) cells induce interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α), and interleukin (IL)-2, which are proinflammatory cytokines, leading to cartilage destruction and bone erosion. Th2 cells primarily secrete IL-4, IL-5, and IL-13, which exert anti-inflammatory and anti-osteoclastogenic effects in inflammatory arthritis models. IL-22 secreted by Th17 cells promotes the proliferation of synovial fibroblasts through induction of the chemokine C-C chemokine ligand 2 (CCL2). T follicular helper (Tfh) cells produce IL-21, which is key for B cell stimulation by the C-X-C chemokine receptor 5 (CXCR5) and coexpression with programmed cell death-1 (PD-1) and/or inducible T cell costimulator (ICOS). PD-1 inhibits T cell proliferation and cytokine production. In addition, there are many immunomodulatory agents that promote or inhibit the immunomodulatory role of T helper cells in RA to alleviate disease progression. These findings help to elucidate the aetiology and treatment of RA and point us toward the next steps. Cite this article: Bone Joint Res 2022;11(7):426-438.

The Role of Collagen Triple Helix Repeat-Containing 1 Protein (CTHRC1) in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease causing inflammation of joints, cartilage destruction and bone erosion. Biomarkers and new drug targets are actively sought and progressed to improve available options for patient treatment. The Collagen Triple Helix Repeat Containing 1 protein (CTHRC1) may have an important role as a biomarker for rheumatoid arthritis, as CTHRC1 protein concentration is significantly elevated in the peripheral blood of rheumatoid arthritis patients compared to osteoarthritis (OA) patients and healthy individuals. CTHRC1 is a secreted glycoprotein that promotes cell migration and has been implicated in arterial tissue-repair processes. Furthermore, high CTHRC1 expression is observed in many types of cancer and is associated with cancer metastasis to the bone and poor patient prognosis. However, the function of CTHRC1 in RA is still largely undefined. The aim of this review is to summarize recent findings on the role of CTHRC1 as a potential biomarker and pathogenic driver of RA progression. We will discuss emerging evidence linking CTHRC1 to the pathogenic behavior of fibroblast-like synoviocytes and to cartilage and bone erosion through modulation of the balance between bone resorption and repair.

Hypoxia-Inducible Factor Is Critical for Pathogenesis and Regulation of Immune Cell Functions in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a common autoimmune disease with characteristics of synovial inflammation, pannus formation, cartilage destruction, and bone erosion. Further, the inflammation is linked to increased oxygen consumption, resulting in hypoxia within the inflammatory area. Hypoxia-inducible factor (HIF) was reported to be associated with adaptation to the hypoxic microenvironment in the RA synovium. Here, we have briefly summarized the structure and expression of HIF. Moreover, the function of HIF in inflammation, angiogenesis, cartilage damage, and immune cells of RA has been discussed.

Neutrophil Extracellular Traps Induce Tissue-Invasive Monocytes in Granulomatosis With Polyangiitis.

Objective: Granulomatosis with polyangiitis (GPA) is a multi-organ vasculitic syndrome typically associated with neutrophil extracellular trap (NET) formation and aggressive tissue inflammation. Manifestations in head and neck (H&N) GPA include septal perforations, saddle-nose deformities, bony erosions of the orbital and sinus walls, middle ear damage and epiglottitis, indicative of bone, cartilage, and connective tissue destruction. Whether H&N-centric lesions engage disease pathways distinctive from the ischemic tissue damage in the lungs, kidneys, skin, and peripheral nerves is unknown. We have compared inflammatory responses triggered by neutrophilic NETs in patients with H&N GPA and systemic GPA (sGPA). Methods: Neutrophils and monocytes were isolated from the peripheral blood of patients with H&N GPA, sGPA, and age/gender matched healthy individuals. Neutrophil NETosis was induced. NETs were isolated and cocultured with monocytes. Gene induction was quantified by RT-PCR, protein upregulation by flow cytometry. Tissue invasiveness of monocytes was measured in a 3D collagen matrix system. Expression of MMP-9 in tissue-residing macrophages was assessed by immunohistochemistry in tissue biopsies. Results: Neutrophils from H&N GPA patients showed more intense NETosis with higher frequencies of netting neutrophils (P < 0.001) and release of higher amounts of NETs (P < 0.001). Isolated NETs from H&N GPA functioned as an inducer of danger-associated molecular patterns in monocytes; specifically, alarmin S100A9. NET-induced upregulation of monocyte S100A9 required recognition of DNA. S100A9 release resulted in the induction of metalloproteinases, including MMP-9, and enabled monocytes to invade into extracellular matrix. Anti-MMP-9 treatment attenuated the tissue invasiveness of monocytes primed with NETs from H&N GPA patients. MMP-9-producing macrophages dominated the tissue infiltrates in naso-sinal biopsies from H&N GPA patients. Conclusion: Distinct disease patterns in GPA are associated with differences in NET formation and NET content. H&N GPA patients with midline cartilaginous and bony lesions are highly efficient in generating NETs. H&N GPA neutrophils trigger the induction of the alarmin S100A9, followed by production of MMP-9, endowing monocytes with tissue-invasive capabilities.

Osteostatin Inhibits Collagen-Induced Arthritis by Regulation of Immune Activation, Pro-Inflammatory Cytokines, and Osteoclastogenesis.

In chronic inflammatory joint diseases, such as rheumatoid arthritis, there is an important bone loss. Parathyroid hormone-related protein (PTHrP) and related peptides have shown osteoinductive properties in bone regeneration models, but there are no data on inflammatory joint destruction. We have investigated whether the PTHrP (107-111) C-terminal peptide (osteostatin) could control the development of collagen-induced arthritis in mice. Administration of osteostatin (80 or 120 µg/kg s.c.) after the onset of disease decreased the severity of arthritis as well as cartilage and bone degradation. This peptide reduced serum IgG2a levels as well as T cell activation, with the downregulation of RORγt+CD4+ T cells and upregulation of FoxP3+CD8+ T cells in lymph nodes. The levels of key cytokines, such as interleukin(IL)-1ß, IL-2, IL-6, IL-17, and tumor necrosis factor-α in mice paws were decreased by osteostatin treatment, whereas IL-10 was enhanced. Bone protection was related to reductions in receptor activator of nuclear factor-κB ligand, Dickkopf-related protein 1, and joint osteoclast area. Osteostatin improves arthritis and controls bone loss by inhibiting immune activation, pro-inflammatory cytokines, and osteoclastogenesis. Our results support the interest of osteostatin for the treatment of inflammatory joint conditions.

Knockdown of FOXM1 attenuates inflammatory response in human osteoarthritis chondrocytes.

Osteoarthritis (OA) is the most common inflammatory joint disease that is mainly characterized by articular cartilage destruction. Forkhead box M1 (FOXM1) is a transcription factor that acts as a critical mediator of inflammatory response. However, the role of FOXM1 in OA has not been investigated. Interleukin (IL)-1ß is a major proinflammatory cytokine, which is associated with cartilage destruction in the pathophysiology of OA. In the present study, we used IL-1ß to stimulate chondrocytes for the establishment of OA in vitro model. We found that FOXM1 was up-regulated in IL-1ß-induced chondrocytes. Knockdown of FOXM1 attenuated IL-1ß-caused decrease in cell viability. Knockdown of FOXM1 suppressed the IL-1ß-induced production of inflammatory cytokines including tumor necrosis factor (TNF)-α, and IL-6. Besides, several inflammatory mediators, such as nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthases (iNOS), and cyclooxygenase-2 (COX-2) were also repressed by knockdown of FOXM1. FOXM1 silencing also inhibited the production of matrix metalloproteinases (MMPs) including MMP-3 and MMP-13. Furthermore, we found that knockdown of FOXM1 blocked the IL-1ß-induced NF-κB activation in chondrocytes. These findings indicated that FOXM1 might play an important role in the pathogenesis of OA, suggesting that FOXM1 might be a potential therapeutic target for the treatment of OA.

Downregulation of long noncoding RNA LOC101928134 inhibits the synovial hyperplasia and cartilage destruction of osteoarthritis rats through the activation of the Janus kinase/signal transducers and activators of transcription signaling pathway by upregulating IFNA1.

Osteoarthritis (OA) is the most common disease of arthritis, a chronic joint disease that is always correlated with massive destruction such as cartilage destruction, inflammation of the synovial membrane, and so on. This study aims to explore the role of long noncoding RNA (lncRNA) LOC101928134 in the synovial hyperplasia and cartilage destruction, more specifically, in the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway in an OA rat model. Microarray-based gene expression analysis was conducted to screen out the lncRNA differentially expressed in OA and predict the target gene of the lncRNA with the involvement of the signaling pathway through Kyoto encyclopedia of genes and genomes (KEGG) analysis. A model of OA was established and treated with the small interfering RNA LOC101928134/inhibitor of JAK/STAT signaling pathway to investigate the relationship among LOC101928134, IFNA1, and the JAK/STAT signaling pathway in OA. The effect of LOC101928134 on the serum levels of IFNA1, interleukin-1ß, and tumor necrosis factor-α, and the apoptosis of synovial and cartilage cells was evaluated. LOC101928134, which was found to be highly expressed in knee joint synovial tissues of OA rats, regulated the expression of IFNA1 gene and inhibited JAK/STAT signaling pathway. Downregulation of LOC101928134 resulted in reduced knee joint synovitis, relived inflammatory damage, and knee joint cartilage damage of OA rats. Besides, synovial cell apoptosis was enhanced upon LOC101928134 downregulation, while cartilage cell apoptosis of OA rats was suppressed. These results demonstrate that downregulation of LOC101928134 suppresses the synovial hyperplasia and cartilage destruction of OA rats via activation of JAK/STAT signaling pathway by upregulating IFNA1, providing a new candidate for the treatment of OA.

Guava leaf extract suppresses osteoarthritis progression in a rat anterior cruciate ligament transection model.

Guava leaf extract and ellagic acid, one of its polyphenolic components, inhibit the activity of a disintegrin and metalloproteinase with thrombospondin type 5 (ADAMTS-5), which is associated with aggrecan degeneration during the early stage of osteoarthritis (OA). To investigate the efficacy of guava leaf extract for preventing OA, we examined the effect of its dietary intake on cartilage destruction in anterior cruciate ligament-transected (ACLT) rats. Rats were randomly assigned to four groups: ACLT control rats fed with control diet, ACLT rats fed with diet containing 0.2% guava leaf extract, ACLT rats fed with diet containing 0.5% guava leaf extract, and sham-operated rats fed with control diet. Mankin's scores, an index of cartilage damage, were higher in rats that underwent ACLT. Guava leaf extract treatment dose-dependently led to lower Mankin's scores and higher concentrations of ellagic acid in the serum and synovial membrane. Ellagic acid levels in the synovial membrane negatively correlated with cartilage destruction scores. These results suggest that dietary guava leaf extract suppresses OA progression in ACLT rats through ellagic acid-mediated inhibition of early joint destruction.

Traditional Chinese medicine formula Bi-Qi capsule alleviates rheumatoid arthritis-induced inflammation, synovial hyperplasia, and cartilage destruction in rats.

BACKGROUND: Traditional Chinese medicine (TCM) formula Bi-Qi capsule (Bi-Qi) is a commonly prescribed drug to treat rheumatoid arthritis (RA). However, the mechanism of Bi-Qi-mediated amelioration of RA pathogenesis is still a mystery. Collagen induced arthritis (CIA) in rats is an established model that shares many similarities with RA in humans. In this study we investigated the effect of Bi-Qi on the pathogenesis of CIA in rats. METHODS: CIA was developed in Sprague-Dawley (S.D) rats (n = 60, female) and used as a model resembling RA in humans. Rats were treated with a high or moderate dose of Bi-Qi, or methotrexate (MTX). Effects of the treatment on local joint and systemic inflammation, synovial hyperplasia, cartilage destruction, and other main features in the pathogenesis of CIA were analyzed. RESULTS: Inflamed and swollen ankles and joints were observed in arthritic rats, while Bi-Qi or MTX treatment alleviated these symptoms. Only the Bi-Qi moderate dose decreased RA-induced serum levels of tumor necrosis factor-alpha (TNF-α). Both Bi-Qi and MTX reduced the interleukin (IL)-18 serum level. Protein levels of cartilage oligomeric matrix protein and osteopontin in serum, synovium, and cartilage were elevated in arthritic rats, while Bi-Qi alleviated these effects. Synovial hyperplasia, inflammatory cell infiltration in synovium and a high degree of cartilage degradation was observed in RA, and Bi-Qi or MTX alleviated this effect. Bi-Qi at the moderate dose was the most effective in mitigating CIA-related clinical complications. CONCLUSIONS: Our findings showed that Bi-Qi alleviates CIA-induced inflammation, synovial hyperplasia, cartilage destruction, and the other main features in the pathogenesis of CIA. This provides fundamental evidence for the anti-arthritic properties of Bi-Qi and corroborates the use of Bi-Qi TCM formula for the treatment of RA.

The degree of cartilage degradation assessed by serum biomarker levels changes after arthroscopic knee synovectomy in rheumatoid arthritis patients.

PURPOSE: In order to test the validity of the selected surgical technique as a way to manage persistent synovitis of the knee joint, as well as to slow down the cartilage and bone destruction, we studied the dynamics of biomarkers of inflammatory conditions, and bone and cartilage destruction after total arthroscopic synovectomy (TAS) of the knee joint. METHODS: The sampling comprised 124 RA patients (158 knees) who had undergone the TAS procedure between 2003 and 2015. Before surgery the rheumatoid factor (IgM), C-reactive protein (CRP), erythrocyte sedimentation rate test was completed for all patients. Blood serum samples were collected (prior to surgery, and three, six and 12 months after surgery) and frozen at -70°Ð¡. The content of CRP, Matrix metalloproteinase-3 (MMP-3), Cartilage Oligomeric Matrix Protein, as well as cross-linked Ctelopeptides of types I and II were measured in blood serum by means of polarization fluoroimmunoassay with the use of a standard set of reagents. RESULTS: The average duration of the disease in the studied group was 8.7 ± 6.6 years. Concentration of the inflammation markers showed that only MMP-3 displayed statistical significance. CONCLUSIONS: The obtained results can be used as basis in assessing the efficiency and effectiveness of this method of treatment of persistent knee joint synovitis associated with the RA.

Adenovirus-mediated osteoprotegerin ameliorates cartilage destruction by inhibiting proteoglycan loss and chondrocyte apoptosis in rats with collagen-induced arthritis.

Our aim is to elucidate the effects of osteoproteogerin (OPG) on cartilage destruction in rats as a model of collagen-induced arthritis (CIA). To establish the CIA model, Sprague Dawley rats were injected with bovine type II collagen solution subcutaneously via the tails. Adenovirus-mediated OPG (Ad-OPG) was then injected intra-articularly either at the beginning of CIA (early OPG treatment) or one week after CIA establishment (late OPG treatment); vehicle or Ad-green fluorescent protein were injected as controls. The rats were killed 4 weeks after treatment. Ankle-joint sections were obtained for histology. Serum samples were collected for enzyme-linked immunosorbent assay. Safranin O staining showed that proteoglycan loss was inhibited in the early and late Ad-OPG groups. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining revealed that both early and late Ad-OPG treatments significantly prevented chondrocyte apoptosis in CIA rats. Furthermore, disintegrin and metalloproteinase with thrombospondin motif-5 expression decreased remarkably in the early and late OPG treatment groups. However, the cartilage destruction score, cartilage oligomeric matrix protein level and caspase-3 expression were only decreased in the early Ad-OPG treatment group. Additionally, ankle-joint swelling and the interleukin-1ß expression level in CIA rats were not notably altered by Ad-OPG treatment. Taken together, our results suggest that early Ad-OPG treatment has potent protective effects against cartilage destruction during rheumatoid arthritis progression, mainly by reducing proteoglycan loss and chondrocyte apoptosis.

Poly(ADP-ribose) polymerase 1 inhibition prevents interleukin-1ß-induced inflammation in human osteoarthritic chondrocytes.

Osteoarthritis (OA) is an age-related joint disease that is characterized by the degeneration of articular chondrocytes. Nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1) is associated with inflammation response. We investigated the role of PARP-1 in interleukin-1ß (IL-1ß)-stimulated human articular chondrocytes and its underlying mechanism. Cell viability and apoptosis were evaluated by using 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide assay and flow cytometry, respectively. Tumor necrosis factor-α (TNF-α) level was measured by enzyme-linked immunosorbent assay. The mRNA and protein expression levels of PARP-1, IL-1 receptor (IL-1R), inducible nitric oxide synthase (iNOS), matrix metalloproteinases (MMPs), and tissue inhibitor of metalloproteinases-1 (TIMP-1) were determined by real-time reverse transcriptase-polymerase chain reaction and western blot analysis, respectively. The expression and phosphorylation of NF-кB p65 were measured by western blot analysis. Results showed that stimulation of chondrocytes with IL-1ß caused a significant up-regulation of PARP-1 and IL-1R, resulting in NF-кB p65 nuclear translocation and phosphorylation associated with an increase of TNF-α secretion and iNOS expression. PARP-1 was inhibited by siRNA transfection. Results showed that PARP-1 inhibition suppressed IL-1ß-induced reduction of cell viability and up-regulation of cell apoptosis, with a reduced IL-1R expression. PARP-1 inhibition also effectively reversed IL-1ß-induced inflammatory response through inhibiting the IL-1R/NF-кB pathway. These data suggested that PARP-1 inhibition prevents IL-1ß-induced inflammation response at least partly by inhibiting the IL-1R/NF-кB signaling pathway in human articular chondrocytes. Moreover, PARP-1 inhibition reduced MMPs expression and increased TIMP-1 expression, suggesting that PARP-1 inhibition could suppress cartilage destruction by modulating the balance between MMPs and TIMP-1. Inhibition of PARP-1 might be useful in the treatment of OA.

Deficiency of cathepsin K prevents inflammation and bone erosion in rheumatoid arthritis and periodontitis and reveals its shared osteoimmune role.

Using rheumatoid arthritis (RA) and periodontitis mouse models, we demonstrate that RA and periodontitis share many pathological features, such as deregulated cytokine production, increased immune-cell infiltration, increased expression of Toll-like receptors (TLRs), and enhanced osteoclast activity and bone erosion. We reveal that genetic deletion of cathepsin K (Ctsk) caused a radical reduction in inflammation and bone erosion within RA joint capsules and periodontal lesions, a drastic decrease in immune-cell infiltration, and a significant reduction in osteoclasts, macrophages, dendritic and T-cells. Deficiency of Ctsk greatly decreased the expression of TLR-4, 5, and 9 and their downstream cytokines in periodontal gingival epithelial lesions and synovial RA lesions. Hence, Ctsk may be targeted to treat RA and periodontitis simultaneously due to its shared osteoimmune role.