Cartilage Destruction In Patients Research Articles

Elevation of Pro-Inflammatory Cytokine Levels Following Intra-Articular Fractures-A Systematic Review.

Introduction: Intra-articular fractures are a major cause of post-traumatic osteoarthritis (PTOA). Despite adequate surgical treatment, the long-term risk for PTOA is high. Previous studies reported that joint injuries initiate an inflammatory cascade characterized by an elevation of synovial pro-inflammatory cytokines, which can lead to cartilage degradation and PTOA development. This review summarizes the literature on the post-injury regulation of pro-inflammatory cytokines and the markers of cartilage destruction in patients suffering from intra-articular fractures. Methods: We searched Medline, Embase, and Cochrane databases (1960–February 2020) and included studies that were performed on human participants, and we included control groups. Two investigators assessed the quality of the included studies using Covidence and the Newcastle–Ottawa Scale. Results: Based on the surveyed literature, several synovial pro-inflammatory cytokines, including interleukins (IL)-1β, IL-2, IL-6, IL-8, IL-12p70, interferon-y, and tumor necrosis factor-α, were significantly elevated in patients suffering from intra-articular fractures compared to the control groups. A simultaneous elevation of anti-inflammatory cytokines such as IL-10 and IL-1RA was also observed. In contrast, IL-13, CTX-II, and aggrecan concentrations did not differ significantly between the compared cohorts. Conclusions: Overall, intra-articular fractures are associated with an increase in inflammation-related synovial cytokines. However, more standardized studies which focus on the ratio of pro- and anti-inflammatory cytokines at different time points are needed.

A novel CD209 polymorphism is associated with rheumatoid arthritis patients in Taiwan

Single nucleotide polymorphisms (SNPs) in the promoter region of CD209 (cluster of differentiation 209) may influence expression levels, and higher expression of CD209 on immune cells correlate with severity of cartilage destruction in patients with rheumatoid arthritis (RA). Due to the lack of a comprehensive study, this study aimed to investigate the CD209 promoter variants and haplotypes in a Taiwanese population and the association with RA development. Deoxyribonucleic acid (DNA) of peripheral blood mononuclear cells from 126 RA patients and 124 healthy controls was purified, and the CD209 gene promoter was amplified by polymerase chain reaction and analyzed by Sanger sequencing. Results showed that a novel variant −96C>A polymorphism in CD209 promoter was identified in the Taiwanese population, and the frequency was significantly higher in RA patients than in controls (11.51% vs. 2.42%, P < .0001). The odds ratio (OR) for the development of RA was 5.88 (95% CI 2.35–14.74, P < .0001). Other known variants were also evaluated; for instance, −1180 T/T (rs7359874) was increased in RA patients, and the OR for the development of RA was 3.26, 95% CI 0.85–12.52, P = .07). Besides, the haplotype frequencies were calculated; −1180A‐939C‐871 T‐336 T‐139 T‐96A and −1180 T‐939 T‐871C‐336 T‐139C‐96A were increased in RA patients (P = .004 and 0.05, respectively). In summary, CD209‐96A variant could be an important factor for the development of RA in the Taiwanese population.

Novel molecular diagnostic marker in the evaluation of cartilage destruction in patients with rheumatoid arthritis

AimThe aim of this study was to evaluate the serum levels of cartilage oligomeric matrix protein (COMP) in rheumatoid patients in correlation with disease severity and cartilage destruction and to evaluate the therapeutic effectiveness of slow-remitting agents such as leflunomid on this marker of cartilage destruction.Patients and methodsFifty patients with rheumatoid arthritis (RA) diagnosed on the basis of the 2010 ACR/EULAR Rheumatoid Arthritis Classification Criteria and 20 age-matched and sex-matched controls were enrolled in the study. C-reactive protein, erythrocyte sedimentation rate (ESR), rheumatoid factor, anti- cyclic citrullinated peptide, and COMP were determined. Patients were classified into two groups according to Disease Activity Score-28: group 1 (29 patients) included patients with severe activity with a score of greater than 5.1; and group 2 (21 patients) included patients with moderate activity with a score of greater than 3.2 and less than and equal to 5.1. The studied patients were classified into two groups on the basis of the time of receiving leflunomid therapy (20 mg daily after initial therapy 100 mg daily for 3 days) for 3 months: group 3 received before treatment and group 4 received after treatment.ResultsSerum COMP was significantly higher in patients with RA when compared with controls (P = 0.000). The COMP levels were found to be positively correlated with Joint space narrowing score (JSN) (r = 0.832, P = 0.000) and erosion score (r = 0.863, P = 0.000) of radiography and negatively correlated with rheumatoid factor (r=−0.313, P = 0.027); however, COMP levels did not correlate with age (r = 0.231, P = 0.106), duration of disease (r = −0.060, P = 0.678), Disease Activity Score-28 (r = −0.098, P = 0.498), C-reactive protein (r = −0.242, P = 0.090), ESR first hour (r = −0.096, P = 0.509), ESR second hour (r = −0.101, P = 0.484), or anti-cyclic citrullinated peptide (r = 0.041, P = 0.775).ConclusionCOMP could be a useful biomarker for the detection of early cartilage and bone destruction and in the follow-up of disease severity and treatment in RA.

Acquiring chondrocyte phenotype from human mesenchymal stem cells under inflammatory conditions.

An inflammatory milieu breaks down the cartilage matrix and induces chondrocyte apoptosis, resulting in cartilage destruction in patients with cartilage degenerative diseases, such as rheumatoid arthritis or osteoarthritis. Because of the limited regenerative ability of chondrocytes, defects in cartilage are irreversible and difficult to repair. Mesenchymal stem cells (MSCs) are expected to be a new tool for cartilage repair because they are present in the cartilage and are able to differentiate into multiple lineages of cells, including chondrocytes. Although clinical trials using MSCs for patients with cartilage defects have already begun, its efficacy and repair mechanisms remain unknown. A PubMed search conducted in October 2014 using the following medical subject headings (MeSH) terms: mesenchymal stromal cells, chondrogenesis, and cytokines resulted in 204 articles. The titles and abstracts were screened and nine articles relevant to “inflammatory” cytokines and “human” MSCs were identified. Herein, we review the cell biology and mechanisms of chondrocyte phenotype acquisition from human MSCs in an inflammatory milieu and discuss the clinical potential of MSCs for cartilage repair.

Relations of Serum COMP to Cardiovascular Risk Factors and Endothelial Function in Patients with Rheumatoid Arthritis Treated with Methotrexate and TNF-α Inhibitors

To examine whether serum level of cartilage oligomeric matrix protein (S-COMP) is related to methotrexate (MTX) or to MTX and tumor necrosis factor-α (TNF-α) combination treatment for rheumatoid arthritis (RA); and to investigate whether S-COMP is related to cardiovascular risk factors including endothelial dysfunction and level of anticitrullinated protein antibodies (ACPA) in patients with RA. Clinical and laboratory measures, including S-COMP and reactive hyperemic index (RHI), were examined in 55 consecutive patients with RA starting with either MTX (n = 34) or MTX and anti-TNF-α treatment (n = 21) at baseline, and after 6 weeks and 6 months. S-COMP was similar in the 2 treatment regimens during followup. We found a positive relationship between S-COMP at baseline and the use of disease-modifying antirheumatic drugs the last year preceding the study (p = 0.001), and a negative relation to current use of systemic glucocorticosteroids (p = 0.044). The nonsignificant change in S-COMP between baseline and the 6-month followup was positively and independently related to change in ACPA level (p = 0.009). There was no significant association between RHI and level of S-COMP at baseline. The cartilage turnover marker S-COMP did not change significantly after 6 months' treatment with MTX with or without a TNF-α inhibitor in patients with RA. The positive association between S-COMP and ACPA suggests that these factors might interact, and could both be contributors to an unknown link between inflammation and cartilage destruction in patients with RA. S-COMP was not related to endothelial function in patients with RA, or to other cardiovascular risk factors studied. Clinical Trials registration number NCT00902005.

Panax ginseng C.A. Meyer modulates the levels of MMP3 in S12 murine articular cartilage cell line

Aim of the study The destruction of cartilage in patients with osteoarthritis occurs due to an imbalance between matrix synthesis and degradation. Cartilage degradation is induced by the activation of matrix metalloproteinases (MMPs). Therefore, this study was conducted to evaluate the cartilage protective effect of Panax ginseng C.A. Meyer (PG). Materials and methods S12 cells were treated with various concentrations of extract of PG and gensenosides Rd and Rb 3 for 3 h, after which 10 ng/ml interleukin-1β (IL-1β) was added to the culture media. The levels of MMP3 in the conditioned media were then evaluated using an enzyme-linked immunosorbent assay (ELISA). In addition, reverse transcriptase-polymerase chain reaction (RT-PCR) was used to evaluate the mRNA expression of Type II Collagen and Pro-collagenase. Furthermore, Western blot analysis was performed to identify the roles that PG played in the ERK and p38 signaling pathways. Results The MMP3 secretion levels of S12 cells were significantly lowered in response to treatment with PG and gensenosides Rd and Rb 3 at a concentration of 100 μg/ml when compared to cells that were treated with IL-1β. In addition, PG induced the mRNA expression of Type II Collagen dose dependently. Furthermore, phosphorylated p38 and ERK were detected in S12 articular cartilage cell line that was treated with IL-1β. PG decreased the phosphorylation of p38, but PG did not exert any effect on phospho-ERK. Conclusions These findings indicate that PG and gensenosides Rd and Rb 3 suppress MMP3 secretion and that gensenosides Rd and Rb 3 are the major elements involved in the suppression of MMP3 by PG. Furthermore, the suppression of MMP3 by PG occurs via the inhibition of phospho-p38 activation. Therefore, PG may exert a protective effect against the cartilage degradation of OA.

The Effect of Electrical Fields on Gene and Protein Expression in Human Osteoarthritic Cartilage Explants

The destruction of cartilage in patients with osteoarthritis is a consequence of an imbalance between matrix synthesis and degradation. The purpose of the present study was to determine the effects of electrical stimulation on these processes in full-thickness osteoarthritic adult human articular cartilage explants. Full-thickness articular cartilage explants from osteoarthritic adult human knee joints were cultured in the absence or presence of interleukin-1beta (IL-1beta) and in the absence or presence of a specifically defined capacitively coupled electrical signal for seven or fourteen days. Total collagen and proteoglycan production were assessed by means of hydroxyproline and hexosamine analyses, respectively. Quantitative real-time polymerase chain reaction assays were used to measure mRNA expression levels of aggrecan, type-II collagen, collagenase-1 (MMP-1), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), aggrecanase-1 (ADAM-TS4), and aggrecanase-2 (ADAM-TS5). Electrical stimulation of cultured explants for seven or fourteen days resulted in significant increases (p < 0.007) in proteoglycan and collagen production and a highly significant upregulation (p <or= 0.005) of aggrecan and type-II collagen mRNA expression. This occurred even in the presence of IL-1beta. In the absence of IL-1beta, the expression of metalloproteinases was at barely detectable levels in these explants. Treatment with IL-1beta led to the significant upregulation of metalloproteinase expression (p < 0.03), but simultaneous administration of the capacitively coupled electrical signal dramatically inhibited this stimulation. The data show that, even in the presence of IL-1beta, a specific, defined capacitively coupled electrical signal can result in significant upregulation of cartilage matrix protein expression and production while simultaneously significantly attenuating the upregulation of metalloproteinase expression. These results support the contention that delivery of a specific, defined electrical field to articular cartilage could result in matrix preservation.

Evidence of cartilaginous benefit of treatment with infliximab in rheumatoid arthritis using measurement of serum COMP

Recently, it has become possible to measure the concentration of serum cartilage oligomeric matrix protein (COMP) in various arthritis, and it is expected to be a novel biomarker indicative of cartilage destruction. In this study, we evaluated the diagnostic effectiveness of serum COMP in rheumatic diseases and analyzed the inhibition of cartilage destruction in patients with rheumatoid arthritis who were prescribed with infliximab (IFX) for one year. The changes in the concentration of serum COMP and the joint narrow space of Sharp score (Delta Sharp-JNS) were evaluated. The level of serum COMP decreased from 23.04+/-7.14 U/l to 8.69+/-2.89 U/l (p<0.005) and improved Delta Sharp-JNS (-0.50+/-6.38 points). We believed that these results were influenced by the effects of methotrexate (MTX) that was prescribed together with IFX, and we analyzed the group that was administered only MTX therapy as a reference. However, the serum COMP concentration and Sharp-JNS in the MTX group did not decrease. The serological and radiological results revealed that IFX inhibited cartilage destruction, and it is possible that serum COMP is one of the novel biomarkers in RA patients treated with anti-tumor necrosis factor-alpha antibody therapy.

Hyaluronans in the treatment of osteoarthritis of the knee: evidence for disease-modifying activity

Although available nonsurgical pharmacotherapies for treatment of osteoarthritis (OA) are considered to be solely symptom-modifying agents, recent advances have been made in the search for agents that may modify disease progression. Intra-articular hyaluronan (HA) therapy is one symptom-modifying approach that has been found to be safe and effective for reducing pain due to OA of the knee. Presented here is a review of the evidence that HAs may also modify the rate of OA disease progression in addition to providing symptomatic efficacy. A review of the literature based on a MEDLINE search through June 2004, using the terms HA, sodium hyaluronate, hyaluronic acid, hylan, hylan G-F 20, OA, disease modification, structure modifying and joint structure. Evidence for disease-modifying activity of HAs stems from 1) the complex biochemical effects of HAs in the synovium and extracellular matrix of the articular cartilage, including interactions between exogenously administered HA and articular cartilage, subchondral bone, matrix proteoglycans, and collagens; 2) the effects of HA administration in animal models of OA, including total or partial meniscectomy and anterior cruciate ligament transectomy; 3) results of clinical trials using one HA, Hyalgan (sodium hyaluronate, molecular weight 500-730 kDa) that evaluated structural outcomes, such as joint-space width, chondrocyte density and vitality, and arthroscopic evaluation of chondropathy. Growing preclinical and clinical evidence supports the notion that, in addition to relieving the symptoms of OA, HAs also modify the structure of the diseased joint and the rate of OA disease progression, at least early in the evolution of the disease process.

Characterization of infiltrating T cells and Th1/Th2-type cytokines in the synovium of patients with osteoarthritis

Objective It has been suggested that osteoarthritis (OA) is induced by mechanical stress followed by cartilage destruction, and it is generally accepted that there is little involvement of an immune response in OA compared with that in rheumatoid arthritis (RA). We have previously found clonally expanded transcripts of Vβ chain of the T cell receptor (TCR) in the synovium of patients with OA. To test the hypothesis that an immune response is involved in OA, we determined: (a) whether CD3+, CD4+, and CD8+ T-cells were infiltrating the synovial membrane of patients with OA; (b) the Th1/Th2-type cytokines produced at the protein level in the synovium of patients with OA.Methods Immunohistochemical analysis was performed to identify T-cells that infiltrated the synovium of patients with OA using specific antibodies against CD3+, CD4+, and CD8+ T-cell differential antigens, interferon-gamma (IFN-γ as a marker for Th1 cells, and interleukin-4 (IL-4) as a marker for Th2 cells.Results CD4+ T-cells were strongly detected in the sublining layer of the synovium of patients with OA compared with the number detected in the same synovial layer of normal subjects. The number of IFN-γ+ cells was significantly higher than that of IL-4+ cells in the synovium of patients with OA (P< 0.05).Conclusions These observations suggest that Th1 cells predominate in the synovium of patients with OA, which clearly indicates that immune regulation occurs and may play critical roles in inflammation and cartilage destruction in patients with OA.

関節炎モデルにおける血中ピリジノリン測定の有用性

Urinary pyridinoline (U-Py) is a useful marker of bone and cartilage loss in rheumatoid arthritis (RA) . The serum pyridinoline (S-Py) concentration instead of U-Py was measured both in rats with adjuvant-induced (AA) and mice with collagen-induced (CIA) arthritis by high perfomance liquid chromatography (HPLC) . On the seventh day after adjuvant innoculation, the AA rats showed a significant increase in S-Py levels. The level of S-Py was gradually increased with the development of AA. Moreover, in CIA mouse, another arthritic model, on sixty days after innoculation of the type II collagen the S-Py level was also significantly higher than that in the normal mice.These findings indicate that the measurement of S-Py instead of U-Py may be useful as marker of bone and cartilage destruction in patients with rheumatoid arthritis.

Quantitative analysis of pyridinium crosslinks of collagen in the synovial fluid of patients with rheumatoid arthritis using high-performance liquid chromatography.

The pyridinium crosslinks are important and definite biomarkers of mature hard tissue collagen degradation. A gradient ion-paired reversed-phase high-performance liquid chromatographic method was used for the simultaneous determination of both crosslinks in synovial fluid (SF) samples of 25 patients with rheumatoid arthritis (RA). The mean +/- SD levels of pyridinoline (Pyd) and deoxypyridinoline (Dpyd) in SF were 107.7 +/- 182.3 nmol/l and 4.8 +/- 8.3 nmol/l, respectively. The Pyd/Dpyd ratio, which indicates the amount of Pyd released from cartilage rather than bone, amounted to 30.8 +/- 29.5. This value is significantly higher than in urine or serum of the same patients. These data suggest increased destruction of joint cartilage in patients with RA and the release of collagen II fragments in SF. In addition, the levels of the crosslinks in SF reflect considerable interindividual variation, indicating substantial individual differences in the amount of collagenous material that is degraded.