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Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated. A randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699). Tofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo. Tofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response. NCT00976599.

Background Matrix metalloproteinases (MMPs) are critical enzymes involved in the remodeling and defense mechanisms of dental pulp tissue. While their role in permanent teeth has been extensively studied, research focusing on MMPs in primary teeth remains limited. This gap highlights the need for further investigations to understand the specific contributions of MMPs to pulpal defense in primary teeth. Moreover, the clinical efficacy of Biodentine as a pulpotomy material in primary teeth warrants further exploration through well-designed studies to establish its success and long-term outcomes in pediatric dentistry. Aim This study aims to compare the expression levels of MMP-2, MMP-8, and MMP-9 in cases of reversible and irreversible pulpitis. Additionally, it seeks to evaluate the clinical success of Mineral Trioxide Aggregate (MTA) and Biodentine when used as pulpotomy agents in primary molars. By analyzing the differential expression of these MMPs, the study will contribute to a better understanding of their role in pulpal inflammation and the potential therapeutic outcomes of MTA and Biodentine in primary molars. Design In this parallel randomized controlled trial, 63 mandibular primary second molars were assigned to two main groups: Group 1, consisting of 42 teeth diagnosed with reversible pulpitis, and Group 2, consisting of 21 teeth diagnosed with irreversible pulpitis. Group 1 was further divided into two randomized subgroups, each containing 21 teeth. The expression levels of MMP-2, MMP-8, and MMP-9 were evaluated in all samples. Pulpotomy treatments were performed using MTA and Biodentine in Group 1. Clinical and radiographic evaluations were conducted over an 18-month follow-up period. Statistical analyses were carried out using The Kolmogorov-Smirnov test, t-test and Fisher’s exact test ( p  < 0.05). Results The study revealed that MMP-2 and MMP-9 expression levels were significantly elevated in specimens with irreversible pulpitis ( p  = 0.01), indicating a potential correlation between these matrix metalloproteinases and the severity of pulpal inflammation. However, no significant difference was observed in the clinical success rates of pulpotomies performed with MTA and Biodentine, suggesting that both materials are equally effective in the treatment of primary molars with reversible pulpitis. Conclusions The expression of MMP-2 and MMP-9 in pulpal blood presents a promising biomarker for assessing the degree of pulpal inflammation in primary teeth, offering a potentially valuable diagnostic tool. Additionally, the clinical success of Biodentine in pulpotomy procedures supports its viability as an effective alternative to MTA, providing a reliable option. Clinical Trial Registration ID The study protocol has been registered with an ID: NCT05145686. Registration Date: 9th November 2021.

The premetastatic niche hypothesis proposes an active priming of the metastatic site by factors secreted from the primary tumor prior to the arrival of the first cancer cells. We investigated several extracellular matrix (ECM) structural proteins, ECM degrading enzymes, and ECM processing proteins involved in the ECM remodeling of the premetastatic niche. Our in vitro model consisted of lung fibroblasts, which were exposed to factors secreted by nonmalignant breast epithelial cells, nonmetastatic breast cancer cells, or metastatic breast cancer cells. We assessed ECM remodeling in vivo in premetastatic lungs of female mice growing orthotopic primary breast tumor xenografts, as compared to lungs of control mice without tumors. Premetastatic lungs contained significantly upregulated Collagen (Col) Col4A5, matrix metalloproteinases (MMPs) MMP9 and MMP14, and decreased levels of MMP13 and lysyl oxidase (LOX) as compared to control lungs. These in vivo findings were consistent with several of our in vitro cell culture findings, which showed elevated Col14A1, Col4A5, glypican-1 (GPC1) and decreased Col5A1 and Col15A1 for ECM structural proteins, increased MMP2, MMP3, and MMP14 for ECM degrading enzymes, and decreased LOX, LOXL2, and prolyl 4-hydroxylase alpha-1 (P4HA1) for ECM processing proteins in lung fibroblasts conditioned with metastatic breast cancer cell media as compared to control. Taken together, our data show that premetastatic priming of lungs by primary breast tumors resulted in significant ECM remodeling which could facilitate metastasis by increasing interstitial fibrillar collagens and ECM stiffness (Col14A1), disruptions of basement membranes (Col4A5), and formation of leaky blood vessels (MMP2, MMP3, MMP9, and MMP14) to promote metastasis.

Skin cutaneous melanoma (SKCM) and squamous cell carcinoma (SCC) are two prevalent forms of skin cancer, both characterized by extensive remodeling of the extracellular matrix (ECM), which facilitates tumor progression and metastasis. To investigate ECM-related gene expression alterations in SCC and assess their diagnostic and prognostic relevance in SKCM by integrating transcriptomic data with clinical outcomes. RNA-sequencing data from NCBI Gene Expression Omnibus (GEO) were analyzed to identify differentially expressed genes in SCC. Key findings were validated in The Cancer Genome Atlas (TCGA) SKCM dataset. Functional enrichment and protein–protein interaction (PPI) analyses were conducted to identify ECM-related pathways and hub genes. Matrix metalloproteinases MMP7, MMP11, and MMP14 were significantly upregulated in SCC and showed elevated expression in primary SKCM tumors, confirmed by RT-qPCR analysis. Functional enrichment revealed dysregulation of ECM–receptor interaction and IL-17 signaling pathways. PPI analysis identified MMP14 as central hub interacting with TIMPs, CD44, and FURIN. Kaplan–Meier survival analysis showed that elevated MMP11 and MMP14 expression correlated with worse overall survival. ROC curve analysis confirmed their strong diagnostic value, with MMP14 achieving an AUC of 0.955. MMP7, MMP11, and MMP14 play key roles in skin cancer progression. They show strong potential as diagnostic and prognostic biomarkers and may serve as therapeutic targets in SCC and SKCM.

Purpose The purpose of this study was to compare the modulation effects of Microcurrent Therapy (MT) and Low-Level Laser Therapy (LLLT) on Matrix Metalloproteinases (MMPs) and tissue inhibitors of Metalloproteinases (TIMPs) expressions during healing of surgical wounds using appendectomy wound as a model. Methods Ninety patients who recently underwent appendectomy were randomly divided into 3 main groups of equal numbers. All cases in the three groups received ordinary medical therapy. Moreover, group A (MT group) received Microcurrent Therapy for 20 min. In addition to a designed physical therapy treatment protocol for 20 min. Group B (LLLT group) received Low-Level Laser Therapy for 20 min., plus the same designed physical therapy treatment protocol for 20 min. Group C (placebo group) received placebo shame LLLT for 20 min. plus the same designed physical therapy treatment protocol for 20 min. Enzyme-linked immunosorbent assay (ELISA) and Western Blot Technique (WBT) were used to determine expression levels of MMP-8, MMP-9, and TIMP-1 at the beginning of treatment and after the end of twelve successive sessions. Results Following therapies, results showed a statistically significant decrease in the MMP-8 and MMP-9 expressions with significantly increased expression levels of TIMP-1 in each group separately ( P  < 0.05). These changes in the expression levels towards proper healing of surgical wounds were more obvious in MT and LLLT groups compared to the placebo group, with significantly better effect in the LLLT group compared to the MT group . Conclusion Microcurrent therapy and low-level laser therapy have a notable impact in improving wound healing process as they can significantly affect the expression levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases towards good prognosis of healing process and decreasing possible wound healing complication, with superior effect of low-level laser therapy.

Ovarian carcinoma is one of the fatal gynecological cancers due to the lack of clinical symptoms at earlier stages of disease leading to metastasis and lower survival rates. Hence, an in-depth exploration of the mechanisms of metastasis facilitates the development of novel-targeted therapeutic strategies to treat the disease. Research studies have reported that three predominant Matrix metalloproteinases (MMPs), namely, MMP14, MMP2 and MMP9 can induce the migration of ovarian cancer cells, Epithelial-Mesenchymal transition, breakdown of extracellular matrix, upregulation of expression of transcription factors etc. in the microenvironment of ovarian tumors. In our current research, these predominant MMPs were used as target proteins and docked with potential anti-cancerous phyto-nutraceuticals present in Allium ascalonicum species. Allium ascalonicum , commonly referred to as Shallots is being used in various cuisines worldwide and is still largely unexploited for its anti-cancer properties. Docking results, revealed three potential phyto-nutraceuticals, of which, 1-[[3,5-bis(phenylmethoxy)phenyl]methyl]-6-methoxy-2-methyl-3,4-dihydro-1 H -isoquinoline, an isoquinoline alkaloid was considered the best, since it exhibits significant binding affinity when compared to that of the standard drug, Melphalan. Molecular dynamic simulation studies exhibited that MMP2 is highly flexible and can form more stable interactions. Furthermore, simulation studies of finest interaction pose of the target MMPs with the best phyto-nutraceutical, revealed stable interactions and occurrence of conformational changes. The results, also suggested that, the best phyto-nutraceutical of Allium ascalonicum is a novel isoquinoline alkaloid, with favorable bioavailability scores that interact with target MMPs to control the progression and metastasis of ovarian cancer, proposing the prospect of formulating it into sustainable medications for treating metastasized Ovarian Cancer.

Collective cell migration (CCM) is a coordinated process involving cell–cell and cell–environment interactions occurring in many physiological systems, including development, wound healing, and metastasis. Using zebrafish keratocytes as a wound healing model provides a unique system to investigate the interplay of matrix metalloproteinases (MMPs) in CCM. MMPs play an important role in CCM as they generate bioactive molecules that regulate proliferation, differentiation, angiogenesis, apoptosis, and cell migration. Secreted as pro-enzymes, MMPs must be activated, frequently by another MMP. As a group, MMPs have been reported to have a pro-migratory role during CCM, yet our data reveal that one MMP, MMP13, is not pro-migratory. Treatment of keratocytes with recombinant MMP13 resulted in a dose-dependent decrease in migration, reduced MMP13 activity, and increased MMP9 mRNA expression. Treatment with an MMP13-specific inhibitor resulted in a dose-dependent increase in migration with no change in the rate of cellular proliferation, an increase in total MMP activity, and increased MMP2 mRNA expression. Similarly, inhibition of MMP14 also resulted in a significant, dose-dependent decrease in migration. However, MMP14 inhibition resulted in both an increase in MMP2 mRNA expression and a decrease in MMP9 mRNA expression. The increase in MMP2 and/or MMP9 activity was observed on gel zymography for both treatments. Our data support the hypothesis that MMP13 is anti-migratory while MMP2, MMP9 and MMP14 have a pro-migratory effect on zebrafish keratocytes. Taken together, our results outline a novel inhibitory role for MMP regulation of CCM that has implications for many other processes in multicellular organisms.

Aim The aim of this prospective study is to investigate if there is a relationship between inguinal hernia, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs). Materials and methods This case control study was performed on patients admitted to the general surgery department of Erzincan University Hospital. Four groups were created: control, indirect hernia, direct hernia, and bilateral hernia. All groups were comprised of 11 patients. Serum and tissue levels of MMP-1, MMP-2, MMP-9, MMP-13, TIMP-1, TIMP-2, TIMP-3, and hydroxyproline were evaluated. Results MMPs values were significantly high at hernia groups, especially at bilateral hernia group ( p  < 0.05), whereas TIMPs values were significantly low at bilateral hernia group ( p  < 0.05). MMPs values were increasing at hernia groups in an order as control, indirect, direct, and bilateral. TIMPs values were decreasing at hernia groups in an order as control, indirect, direct, and bilateral. Conclusion Increased levels of MMP-1-2-9-13 and decreased levels of TIMP-1-2-3 may have played role in the formation of inguinal hernia. Hernia is not only a local defect, but a reflection of systemic disease. This is even more significant for bilateral hernias.

Human periodontal ligament cells (hPDLCs) express matrix metalloproteinases (MMPs), a group of enzymes responsible for the destruction of most extracellular matrix proteins in dental tissues, especially MMP-1, MMP-2, and MMP-13. Exploring the regulatory mechanism of MMPs is crucial for understanding external root resorption (ERR), one of the most severe complications, along with substantial loss of dental tissue, induced by trauma, pulpal infection, tooth bleaching, and orthodontic treatment, etc. Discoidin domain receptor 1 (DDR1), a cell surface receptor binding to collagen, has the potential to regulate the expression of MMP-1, MMP-2, and MMP-13, but the mechanism remains unclear. Thus, the present study aimed to investigate the connection and underlying mechanism between MMP-1, MMP-2, MMP-13, and DDR1 in hPDLCs. Our post-replantation ERR model revealed that Mmp-1, Mmp-2, Mmp-13, and Ddr1 all increased in the sites of ERR. hPDLCs with DDR1 knockdown exhibited a substantial reduction in MMP-1, MMP-2, and MMP-13 expression. To further confirm the underlying mechanism, we conducted further in vitro experiments, including RNA sequencing, RNA interference, RT-qPCR, Western blotting, and ELISA. Based on our results, MMP-1 was positively regulated by the Smad2/3 and MEK-ERK1/2 pathways and negatively regulated by the PI3K-Akt pathway through CCN2. MMP-2 and MMP-13 were positively regulated by the Smad2/3 pathway. MMP-13 was positively regulated by the MEK-ERK1/2 and PI3K/Akt signaling pathways. Collectively, DDR1 is a potent regulator of MMP-1, MMP-2, and MMP-13 expression through the Smad2/3, MEK-ERK1/2, and PI3K/Akt signaling pathways. Clarifying the significance and underlying mechanism by which DDR1 is involved in ERR might bring the chances to hinder the pathogenic process of ERR, hence reducing its incidence rate.

Prediction of radiographic progression (RP) in early rheumatoid arthritis (eRA) would be very useful for optimal choice among available therapies. We evaluated a multi-biomarker disease activity (MBDA) score, based on 12 serum biomarkers as a baseline predictor for 1-year RP in eRA. Baseline disease activity score based on erythrocyte sedimentation rate (DAS28-ESR), disease activity score based on C-reactive protein (DAS28-CRP), CRP, MBDA scores and DAS28-ESR at 3 months were analysed for 235 patients with eRA from the Swedish Farmacotherapy (SWEFOT) clinical trial. RP was defined as an increase in the Van der Heijde-modified Sharp score by more than five points over 1 year. Associations between baseline disease activity measures, the MBDA score, and 1-year RP were evaluated using univariate and multivariate logistic regression, adjusted for potential confounders. Among 235 patients with eRA, 5 had low and 29 moderate MBDA scores at baseline. None of the former and only one of the latter group (3.4%) had RP during 1 year, while the proportion of patients with RP among those with high MBDA score was 20.9% (p=0.021). Among patients with low/moderate CRP, moderate DAS28-CRP or moderate DAS28-ESR at baseline, progression occurred in 14%, 15%, 14% and 15%, respectively. MBDA score was an independent predictor of RP as a continuous (OR=1.05, 95% CI 1.02 to 1.08) and dichotomised variable (high versus low/moderate, OR=3.86, 95% CI 1.04 to 14.26). In patients with eRA, the MBDA score at baseline was a strong independent predictor of 1-year RP. These results suggest that when choosing initial treatment in eRA the MBDA test may be clinically useful to identify a subgroup of patients at low risk of RP. WHO database at the Karolinska Institute: CT20080004; and clinicaltrials.gov: NCT00764725.