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Objective This study is designed to investigate the roles of MMP-2, MMP-9, and MMP-13 in intervertebral disc destruction resulting from different types of spinal infections and their correlations with clinical quantitative data. Methods Disc tissue samples were collected from 60 patients with spinal infections (20 cases each of STB, BS, and PS in the infection group) and 20 patients with intervertebral disc herniation (control group). The expressions of MMP-2, MMP-9, and MMP-13 were detected by RT-qPCR. Correlation analysis was carried out with clinical quantitative data such as preoperative erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin (PCT), and related blood routine indicators in the infection group. Results In the analysis between the infection group and the control group, MMP-13 was expressed in the diseased intervertebral disc tissue of STB patients, but the result was not statistically significant ( P  = 0.2172). There was a significant difference in the expression of MMP-13 in the diseased intervertebral discs of BS and PS patients. The expressions of MMP-9 and MMP-2 were markedly increased in the diseased intervertebral disc tissue of STB, BS, and PS patients (all P  < 0.05). In the inter-group analysis of the infection group, the expression of MMP-13 in the diseased intervertebral disc tissue of PS patients was significantly different from that of STB and BS ( P  < 0.0001), while there was no significant difference between the STB and BS groups ( P  = 0.2393). The expression of MMP-9 in the diseased intervertebral disc tissue of STB patients was significantly different from that of BS and PS ( P  < 0.0001), but there was no statistically significant difference between the BS and PS groups ( P  = 0.9643). There was no statistically significant difference in the expression of MMP-2 among the STB, BS, and PS groups. In the correlation analysis with clinical quantitative data, MMP-13 was positively correlated with CRP, ESR, IL-6, WBC, and NEUT levels ( r values were 0.7346, 0.3465, 0.3326, 0.6347, and 0.5152 respectively), and negatively correlated with LYM level ( r = -0.5152, P  < 0.05), and had no correlation with PCT and MXD levels. MMP-9 was positively correlated with ESR level ( r  = 0.3412, P  < 0.05) and had no correlation with CRP, IL-6, PCT, WBC, NEUT, and LYM levels. MMP-2 was positively correlated with NEUT and LYM levels ( r values were 0.3021 and 0.3306 respectively, P  < 0.05) and had no correlation with ESR, CRP, IL-6, PCT, and WBC levels. Conclusion MMP-2, MMP-9, and MMP-13 play crucial roles in intervertebral disc destruction due to spinal infections. The differential expression of MMPs may be one of the reasons for the varying degrees of intervertebral disc destruction in different types of spinal infections. Moreover, when clinical indicators such as CRP, ESR, IL-6, WBC, and NEUT increase, it suggests that the expression of MMP-13 in the intervertebral disc at the lesion site significantly rises, and it may become a new target for the treatment of spinal infections in the future.

ATP6V1H is a component of a large protein complex with vacuolar ATPase (V-ATPase) activity. We identified two generations of individuals in which short stature and osteoporosis co-segregated with a mutation in ATP6V1H. Since V-ATPases are highly conserved between human and zebrafish, we generated loss-of-function mutants in atp6v1h in zebrafish through CRISPR/Cas9-mediated gene knockout. Homozygous mutant atp6v1h zebrafish exhibited a severe reduction in the number of mature calcified bone cells and a dramatic increase in the expression of mmp9 and mmp13. Heterozygous adults showed curved vertebra that lack calcified centrum structure and reduced bone mass and density. Treatment of mutant embryos with small molecule inhibitors of MMP9 and MMP13 significantly restored bone mass in the atp6v1h mutants. These studies have uncovered a new, ATP6V1H-mediated pathway that regulates bone formation, and defines a new mechanism of disease that leads to bone loss. We propose that MMP9/MMP13 could be therapeutic targets for patients with this rare genetic disease.

Metastasis associated in lung adenocarcinoma transcript-1 (MALAT-1) is overexpressed during cancer progression and promotes cell migration and invasion in many solid tumors. However, its role in ovarian cancer remains poorly understood. Expressions of MALAT-1 were detected in 37 normal ovarian tissues and 45 ovarian cancer tissues by reverse transcription polymerase chain reaction (RT-PCR). Cell proliferation was observed by CCK-8 assay; Flow cytometry was used to measure cell cycle and apoptosis; Cell migration was detected by transwell migration and invasion assay. In order to evaluate the function of MALAT-1, shRNA combined with DNA microarray and Functional enrichment analysis were performed to determine the transcriptional effects of MALAT-1 silencing in OVCAR3 cells. RNA and protein expression were measured by qRT-PCR and Western blotting, respectively. We found that upregulation of MALAT-1 mRNA in ovarian cancer tissues and enhanced MALAT-1 expression was associated with FIGO stage. Knockdown of MALAT-1 expression in OVCAR3 cells inhibited cell proliferation, migration, and invasion, leading to G0/G1 cell cycle arrest and apoptosis. Overexpressed MALAT-1 expression in SKOV3 cells promoted cell proliferation, migration and invasion. Downregulation of MALAT-1 resulted in significant change of gene expression (at least 2-fold) in 449 genes, which regulate proliferation, cell cycle, and adhesion. As a consequence of MALAT-1 knockdown, MMP13 protein expression decreased, while the expression of MMP19 and ADAMTS1 was increased. The present study found that MALAT-1 is highly expressed in ovarian tumors. MALAT-1 promotes the growth and migration of ovarian cancer cells, suggesting that MALAT-1 may be an important contributor to ovarian cancer development.

Background Oxidative stress is proposed as an important factor in osteoarthritis (OA). Objective To investigate the expression of the three superoxide dismutase (SOD) antioxidant enzymes in OA. Methods SOD expression was determined by real-time PCR and immunohistochemistry using human femoral head cartilage. SOD2 expression in Dunkin–Hartley guinea pig knee articular cartilage was determined by immunohistochemistry. The DNA methylation status of the SOD2 promoter was determined using bisulphite sequencing. RNA interference was used to determine the consequence of SOD2 depletion on the levels of reactive oxygen species (ROS) using MitoSOX and collagenases, matrix metalloproteinase 1 (MMP-1) and MMP-13, gene expression. Results All three SOD were abundantly expressed in human cartilage but were markedly downregulated in end-stage OA cartilage, especially SOD2. In the Dunkin–Hartley guinea pig spontaneous OA model, SOD2 expression was decreased in the medial tibial condyle cartilage before, and after, the development of OA-like lesions. The SOD2 promoter had significant DNA methylation alterations in OA cartilage. Depletion of SOD2 in chondrocytes increased ROS but decreased collagenase expression. Conclusion This is the first comprehensive expression profile of all SOD genes in cartilage and, importantly, using an animal model, it has been shown that a reduction in SOD2 is associated with the earliest stages of OA. A decrease in SOD2 was found to be associated with an increase in ROS but a reduction of collagenase gene expression, demonstrating the complexities of ROS function.

Anti-rheumatoid arthritis (RA) effects of α-tocopherol (α-T) have been shown in human patients in a double-blind trial. However, the effects of α-T and its derivatives on fibroblast-like synoviocytes (FLS) during the pathogenesis of RA remain unclear. In the present study, we compared the expression levels of genes related to RA progression in FLS treated with α-T, succinic ester of α-T (TS), and phosphate ester of α-T (TP), as determined via RT-PCR. The mRNA levels of interleukin (IL)-6, tumor necrosis factor-α (TNF-α), matrix metalloproteinase (MMP)-3, and MMP-13 were reduced by treatment with TP without cytotoxicity, while α-T and TS did not show such effects. Furthermore, intraperitoneal injection of TP ameliorated the edema of the foot and joint and improved the arthritis score in laminarin-induced RA model mice. Therefore, TP exerted anti-RA effects through by inhibiting RA-related gene expression.

Tenuigenin (TEN), the main active component of Polygala tenuifolia , has been reported to have anti-inflammatory effects. However, the effects of TEN on IL-1β-stimulated osteoarthritis chondrocytes have not been reported. The purpose of this study was to investigate the anti-inflammatory effects and mechanism of TEN on IL-1β-stimulated human osteoarthritis chondrocytes. Human osteoarthritis chondrocytes were pretreated with or without TEN for 1 h and then stimulated with IL-1β. The production of NO and PGE2 were detected by the Griess reagent and ELISA. The expression of NF-κB and MAPKs (p38, JNK, ERK) were measured by Western blot analysis. The production of MMP-1, MMP3, and MMP13 were measured by ELISA. The results showed that treatment of TEN significantly inhibited IL-1β-induced NO and PGE2 production. TEN also suppressed IL-1β-induced MMP-1, MMP3, and MMP13 expression. Furthermore, TEN was found to inhibit IL-1β-induced NF-κB activation, PI3K, and AKT phosphorylation. In conclusion, these results suggest that TEN inhibits IL-1β-induced inflammation in human osteoarthritis chondrocytes by inhibiting PI3K/AKT/NF-κB signaling pathway.

Osteoarthritis (OA) is characterized by the progressive destruction of articular cartilage, which is involved in the imbalance between extracellular matrix (ECM) synthesis and degradation. MicroRNA-140-5p (miR-140) is specifically expressed in cartilage and plays an important role in OA-induced matrix degradation. The aim of this study was to investigate (1) whether intra-articular injection of melatonin could ameliorate surgically induced OA in mice and (2) whether melatonin could regulate matrix-degrading enzymes at the posttranscriptional level by targeting miR-140. In an in vitro OA environment induced by interleukin-1 beta (IL-1β), melatonin treatment improved cell proliferation of human chondrocytes, promoted the expression of cartilage ECM proteins (e.g., type II collagen and aggrecan), and inhibited the levels of IL-1β-induced proteinases, such as matrix metalloproteinase 9 (MMP9), MMP13, ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4), and ADAMTS5. Both the microarray and polymerase chain reaction (PCR) experiments revealed that miR-140 was a melatonin-responsive microRNA and melatonin upregulated miR-140 expression, which was suppressed by IL-1β stimulation. In vivo experiments demonstrated that intra-articular injection of melatonin prevented disruptions of cartilage matrix homeostasis and successfully alleviated the progression of surgery-induced OA in mice. Transfection of miR-140 antagomir completely counteracted the antiarthritic effects of melatonin by promoting matrix destruction. Our findings demonstrate that melatonin protects the articular cartilage from OA-induced degradation by targeting miR-140, and intra-articular administration of melatonin may benefit patients suffering from OA.

Purinergic signaling has been implicated in the regulation of many cellular processes. A high concentration of ATP has been observed in the tumor microenvironment, suggesting a possible role of extracellular ATP in tumor progression. The P2X7 receptor, which belongs to the ligand-gated ion channel receptor family, is involved in tumor development and metastasis. In the present study, we found that extracellular ATP stimulated the invasion and migration of human T47D breast cancer cells, in a dose-dependent manner. BzATP (ATP analogue), but not ADP, also promoted invasion and migration. We further found that the P2X7 receptor was highly expressed in the T47D cells. After knockdown of the P2X7 receptor, ATP-stimulated invasion and migration were markedly inhibited. Moreover, activation of the P2X7 receptor by ATP downregulated the protein level of E-cadherin and upregulated the production of MMP-13. In addition, ATP time-dependently induced the activation of AKT via the P2X7 receptor, and the AKT pathway was required for the ATP-mediated invasion and migration. Taken together, our results revealed that activation of the P2X7 receptor by ATP promotes breast cancer cell invasion and migration, possibly via activation of the AKT pathway and regulation of E-cadherin and MMP-13 expression. Therefore, the P2X7 receptor may be a useful therapeutic target for the treatment of breast cancer.

Osteoarthritis (OA) is the most common type of arthritis and is a leading cause of disability worldwide, resulting in pain, reduced quality of life and socioeconomic burden. Current therapies for OA focus on mitigating the symptoms of advanced disease, but novel therapeutic agents are needed to inhibit the processes leading to OA. The present study aimed to investigate the effects of Icariin on matrix metalloproteinase (MMP)-1, MMP-3 and MMP-13 expression in interleukin (IL)-1β-stimulated human SW1353 chondrosarcoma cells, and to investigate the possible mechanism underlying the chondroprotective effects of Icariin. In the present study, IL-1β was applied on SW1353 chondrosarcoma cells to mimic the microenvironment of osteoarthritis. The cells were treated with Icariin and mitogen-activated protein kinase (MAPK) signaling pathway activators or inhibitors. MMP-1, MMP-3, MMP-13, phosphorylated (P)-p38, P-c-Jun N-terminal kinase (JNK) and P-extracellular signal-regulated kinase (ERK) expression was assessed using reverse transcription-quantitative polymerase chain reaction, ELISA and western blot analysis. The results of the present study demonstrated that Icariin inhibited the expression of MMP-1, MMP-3, MMP-13, P-p38, P-ERK and P-JNK. Furthermore, it was revealed that the inhibition of p38 and ERK contributed to the inhibition of MMP-1 and MMP-3 by Icariin, whereas the inhibition of p38 and JNK contributed to the inhibition of MMP-13. The present results suggested that Icariin may have a chondroprotective effect, exerted through the inhibition of MMP-1, MMP-3 and MMP-13 via MAPK pathways. Therefore, Icariin may have potential as a novel therapeutic strategy for the treatment of osteoarthritis.

The progression of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) marks a critical step in the evolution of breast cancer. There is some evidence to suggest that dynamic interactions between the neoplastic cells and the tumour microenvironment play an important role. Using the whole-genome cDNA-mediated annealing, selection, extension and ligation assay (WG-DASL, Illumina), we performed gene expression profiling on 87 formalin-fixed paraffin-embedded (FFPE) samples from 17 patients consisting of matched IDC, DCIS and three types of stroma: IDC-S (<3 mm from IDC), DCIS-S (<3 mm from DCIS) and breast cancer associated-normal stroma (BC-NS; >10 mm from IDC or DCIS). Differential gene expression analysis was validated by quantitative real time-PCR, immunohistochemistry and immunofluorescence. The expression of several genes was down-regulated in stroma from cancer patients relative to normal stroma from reduction mammoplasties. In contrast, neoplastic epithelium underwent more gene expression changes during progression, including down regulation of SFRP1 . In particular, we observed that molecules related to extracellular matrix (ECM) remodelling (e.g. COL11A1 , COL5A2 and MMP13 ) were differentially expressed between DCIS and IDC. COL11A1 was overexpressed in IDC relative to DCIS and was expressed by both the epithelial and stromal compartments but was enriched in invading neoplastic epithelial cells. The contributions of both the epithelial and stromal compartments to the clinically important scenario of progression from DCIS to IDC. Gene expression profiles, we identified differential expression of genes related to ECM remodelling, and specifically the elevated expression of genes such as COL11A1 , COL5A2 and MMP13 in epithelial cells of IDC. We propose that these expression changes could be involved in facilitating the transition from in situ disease to invasive cancer and may thus mark a critical point in disease development.