[Predatory journals in Orthopedics and Traumatology]. / Revistas depredadoras en Ortopedia y Traumatología.

Predatory journals are distinguished from legitimate journals by their lack of adequate reviews and editorial processes, compromising the quality of published content. These journals do not conduct peer reviews or detect plagiarism, and accept manuscripts without requiring substantial modifications. Their near 100% acceptance rate is driven by profit motives, regardless of the content they publish. While they boast a prestigious editorial board composed of renowned researchers, in most cases, it is a facade aimed at impressing and attracting investigators. Furthermore, these journals lack appropriate ethical practices and are non-transparent in their editorial processes. Predatory journals have impacted multiple disciplines, including Orthopedics and Traumatology, and their presence remains unknown to many researchers, making them unwitting victims. Their strategy involves soliciting articles via email from authors who have published in legitimate journals, promising quick, easy, and inexpensive publication. The implications and negative consequences of predatory journals on the scientific community and researchers are numerous. The purpose of this work is to provide general information about these journals, specifically in the field of Orthopedics and Traumatology, offering guidelines to identify and avoid them, so that authors can make informed decisions when publishing their manuscripts and avoid falling into the hands of predatory journals or publishers.

Las revistas depredadoras se diferencian de las revistas legítimas por su falta de adecuadas revisiones y procesos editoriales, lo que compromete la calidad del contenido publicado. Estas revistas no llevan a cabo revisiones por pares ni realizan acciones que detecten y prevengan el plagio y aceptan manuscritos sin exigir modificaciones sustanciales. Su tasa de aceptación cercana al 100% se debe a su enfoque lucrativo, sin importarles el contenido que publican. Aunque presumen tener un comité editorial compuesto por investigadores destacados, en la mayoría de los casos es una simulación destinada a impresionar y atraer a los investigadores. Además, estas revistas carecen de prácticas éticas adecuadas y no son transparentes en sus procesos editoriales. Las revistas depredadoras han afectado a múltiples disciplinas, incluida la Ortopedia y Traumatología y su presencia es aún desconocida para muchos investigadores, lo que los convierte en víctimas sin saberlo. Su estrategia consiste en solicitar artículos por correo electrónico a autores que han publicado en revistas legítimas, prometiendo una publicación rápida, sencilla y económica. Las implicaciones y consecuencias negativas de las revistas depredadoras en la comunidad científica y los investigadores son numerosas. El propósito de este trabajo es proporcionar información general sobre estas revistas y específicamente en el campo de la Ortopedia y Traumatología, brindando pautas para identificarlas y evitarlas, para que los autores puedan tomar decisiones informadas al publicar sus manuscritos y evitar caer en manos de revistas o editoriales depredadoras.

Hemiartroplastía por interposición utilizando el extensor hallucis brevis para el tratamiento de hallux rigidus con involucro unicompartimental lateral: reporte de un caso / Interposition hemiarthroplasty using extensor hallucis brevis for the treatment of hallux rigidus with lateral unicompartmental involvement: a case report

Resumen: Hallux rigidus es la patología degenerativa de la articulación metatarsofalángica del hallux. Esta patología provoca dolor y disminución en el movimiento. Existen múltiples tratamientos quirúrgicos para esta patología, todas con sus respectivas indicaciones. Presentamos el caso de un paciente de 54 años de edad con el diagnóstico de hallux rigidus quien tenía afectación únicamente del aspecto lateral de la cabeza del metatarsiano. Este paciente fue tratado con un procedimiento quirúrgico novedoso, se realizó una hemiartroplastía de interposición utilizando el extensor hallucis brevis asociado a una queilectomía y exostectomía. El paciente tuvo una favorable evolución clínica con mejoría evidenciado por escalas clínicas, con resolución de la sintomatología y sin complicaciones. La hemiartroplastía de interposición utilizando el extensor hallucis brevis es un tratamiento exitoso de preservación articular y del movimiento para el hallux rigidus en pacientes jóvenes en los que hay afectación unicompartimental lateral de la cabeza metatarsiana, en quienes es importante preservar el movimiento.

Abstract: Hallux rigidus is the degenerative pathology of the metatarsophalangeal joint of the hallux. This pathology causes pain and decreased movement. There are multiple surgical treatments for this pathology, all with their respective indications. We present the case of a 54-year-old patient diagnosed with hallux rigidus who had only the lateral aspect of the metatarsal head affected. This patient was treated with a novel surgical procedure, performing an interposition hemiarthroplasty using the hallucis brevis extender associated with a cheilectomy and exostectomy. The patient had a favorable clinical evolution with improvement evidenced by clinical scales, with resolution of the symptoms and without complications. Interposition hemiarthroplasty using the extensor hallucis brevis is a successful joint and movement preservation treatment for hallux rigidus in young patients with lateral unicompartmental involvement of the metatarsal head, in whom it is important to preserve movement.

[Interposition hemiarthroplasty using extensor hallucis brevis for the treatment of hallux rigidus with lateral unicompartmental involvement: a case report]. / Hemiartroplastía por interposición utilizando el extensor hallucis brevis para el tratamiento de hallux rigidus con involucro unicompartimental lateral: reporte de un caso.

Hallux rigidus is the degenerative pathology of the metatarsophalangeal joint of the hallux. This pathology causes pain and decreased movement. There are multiple surgical treatments for this pathology, all with their respective indications. We present the case of a 54-year-old patient diagnosed with hallux rigidus who had only the lateral aspect of the metatarsal head affected. This patient was treated with a novel surgical procedure, performing an interposition hemiarthroplasty using the hallucis brevis extender associated with a cheilectomy and exostectomy. The patient had a favorable clinical evolution with improvement evidenced by clinical scales, with resolution of the symptoms and without complications. Interposition hemiarthroplasty using the extensor hallucis brevis is a successful joint and movement preservation treatment for hallux rigidus in young patients with lateral unicompartmental involvement of the metatarsal head, in whom it is important to preserve movement.

Hallux rigidus es la patología degenerativa de la articulación metatarsofalángica del hallux. Esta patología provoca dolor y disminución en el movimiento. Existen múltiples tratamientos quirúrgicos para esta patología, todas con sus respectivas indicaciones. Presentamos el caso de un paciente de 54 años de edad con el diagnóstico de hallux rigidus quien tenía afectación únicamente del aspecto lateral de la cabeza del metatarsiano. Este paciente fue tratado con un procedimiento quirúrgico novedoso, se realizó una hemiartroplastía de interposición utilizando el extensor hallucis brevis asociado a una queilectomía y exostectomía. El paciente tuvo una favorable evolución clínica con mejoría evidenciado por escalas clínicas, con resolución de la sintomatología y sin complicaciones. La hemiartroplastía de interposición utilizando el extensor hallucis brevis es un tratamiento exitoso de preservación articular y del movimiento para el hallux rigidus en pacientes jóvenes en los que hay afectación unicompartimental lateral de la cabeza metatarsiana, en quienes es importante preservar el movimiento.

Aplicaciones del ácido tranexámico en cirugía Ortopédica y Traumatología / Applications of tranexamic acid in Orthopaedics and Traumatology

Resumen: Introducción: El ácido tranexámico (ATX) es un medicamento antifibrinolítico que se ha utilizado en diversas disciplinas de la medicina, entre ellas en la Ortopedia y Traumatología con el objetivo de prevenir y disminuir el sangrado y evitar la necesidad de transfusiones. El presente trabajo tiene el objetivo de revisar los usos, indicaciones y contraindicaciones del ATX en Ortopedia y Traumatología. Material y métodos: Se realizó una búsqueda de la evidencia más importante y reciente acerca del uso del ATX en Ortopedia y Traumatología, así como sus indicaciones, contraindicaciones y efectos adversos. Resultados: El ATX tiene una gran cantidad de aplicaciones dentro de las que destacan las artroplastías de rodilla, cadera (primarias y de revisión), la cirugía de columna y el trauma, observándose con su uso una disminución en el sangrado perioperatorio y en la necesidad de transfusiones. El ATX es seguro, no aumenta el riesgo de desarrollar efectos trombóticos en pacientes sanos. Existen múltiples vías de administración, así como múltiples regímenes de dosis, todas siendo eficaces, por lo que aún no se ha estandarizado la mejor vía de administración ni la dosis más eficaz. Conclusiones: El ATX es un medicamento seguro y eficaz para la disminución del sangrado perioperatorio.

Abstract: Introduction: Tranexamic acid is an antifibrinolytic drug which has been used in many disciplines of Medicine, as well as in Orthopaedics and Traumatology, with the objective of diminishing and preventing blood loss and the necessity of allogenic blood transfusion. This study has the objective to demonstrate the uses, indications and contraindications of tranexamic acid in the different subspecialties of Orthopaedics and Traumatology. Material and methods: A through search was performed looking at the most recent evidence regarding the use of tranexamic acid in the different subspecialties of Orthopaedics and Traumatology, as well as its indications, contraindications and adverse effects. Results: Tranexamic acid has a great amount of applications in Orthopaedics and Traumatology, especially in primary and revision knee and hip arthroplasties, spine surgery and trauma. It has been observed that tranexamic acid is effective in diminishing perioperative bleeding, less necessity of blood transfusion, among other benefits. Tranexamic acid is a safe drug, which does not increase the risk of developing thrombotic events in healthy patients. There are a number of administration routes of tranexamic acid as well as many dosage regimens, all being efficient. Therefore, no standardization regarding the best administration route and most effective dose has been established. Conclusions: Tranexamic acid is a safe and effective drug for diminishing perioperative bleeding and to avoid the necessity of blood transfusion, with many applications in Orthopaedics and Traumatology.

[Applications of tranexamic acid in Orthopaedics and Traumatology]. / Aplicaciones del ácido tranexámico en cirugía Ortopédica y Traumatología.

INTRODUCTION: Tranexamic acid is an antifibrinolytic drug which has been used in many disciplines of Medicine, as well as in Orthopaedics and Traumatology, with the objective of diminishing and preventing blood loss and the necessity of allogenic blood transfusion. This study has the objective to demonstrate the uses, indications and contraindications of tranexamic acid in the different subspecialties of Orthopaedics and Traumatology. MATERIAL AND METHODS: A through search was performed looking at the most recent evidence regarding the use of tranexamic acid in the different subspecialties of Orthopaedics and Traumatology, as well as its indications, contraindications and adverse effects. RESULTS: Tranexamic acid has a great amount of applications in Orthopaedics and Traumatology, especially in primary and revision knee and hip arthroplasties, spine surgery and trauma. It has been observed that tranexamic acid is effective in diminishing perioperative bleeding, less necessity of blood transfusion, among other benefits. Tranexamic acid is a safe drug, which does not increase the risk of developing thrombotic events in healthy patients. There are a number of administration routes of tranexamic acid as well as many dosage regimens, all being efficient. Therefore, no standardization regarding the best administration route and most effective dose has been established. CONCLUSIONS: Tranexamic acid is a safe and effective drug for diminishing perioperative bleeding and to avoid the necessity of blood transfusion, with many applications in Orthopaedics and Traumatology.

INTRODUCCIÓN: El ácido tranexámico (ATX) es un medicamento antifibrinolítico que se ha utilizado en diversas disciplinas de la medicina, entre ellas en la Ortopedia y Traumatología con el objetivo de prevenir y disminuir el sangrado y evitar la necesidad de transfusiones. El presente trabajo tiene el objetivo de revisar los usos, indicaciones y contraindicaciones del ATX en Ortopedia y Traumatología. MATERIAL Y MÉTODOS: Se realizó una búsqueda de la evidencia más importante y reciente acerca del uso del ATX en Ortopedia y Traumatología, así como sus indicaciones, contraindicaciones y efectos adversos. RESULTADOS: El ATX tiene una gran cantidad de aplicaciones dentro de las que destacan las artroplastías de rodilla, cadera (primarias y de revisión), la cirugía de columna y el trauma, observándose con su uso una disminución en el sangrado perioperatorio y en la necesidad de transfusiones. El ATX es seguro, no aumenta el riesgo de desarrollar efectos trombóticos en pacientes sanos. Existen múltiples vías de administración, así como múltiples regímenes de dosis, todas siendo eficaces, por lo que aún no se ha estandarizado la mejor vía de administración ni la dosis más eficaz. CONCLUSIONES: El ATX es un medicamento seguro y eficaz para la disminución del sangrado perioperatorio.

[The 50 most cited articles in orthopedics and traumatology by Mexican authors]. / Los 50 artículos más citados en ortopedia y traumatología de autores mexicanos.

BACKGROUND: The amount of quotation a scientific article receives is important for the academic impact. In the present study, we analyzed the 50 most cited articles in orthopedics and related areas published by mexican authors, as well as analyzing their main characteristics. MATERIAL AND METHODS: A search was conducted using Web of Science, of the 50 articles with the largest number of quotation on orthopedics and related areas, in which the principal author or corresponding author had an address in Mexico. We analyzed the articles of 66 scientific journals within the category Orthopedics. We examined the quantity and density of citations, Origin institution, subspeciality to which the article corresponds, and level of evidence. RESULTS: The most cited article had 222 cites. The 50 most cited articles accumulated a total of 1,944, with an average of 3.6 cites per year per article. The year with the largest number of publications was the 2011, and the year with the largest number of quotation was 2008. Public institutions had a larger number of publications in relation to private institutions. The subspecialty with the largest number of publications was arthroscopy and sport medicine. Most publications with a large number of citations refer to studies with a low level of evidence. CONCLUSIONS: The present study points out the 50 most cited articles published by mexican authors in orthopedics and related areas. There is a tendency towards publishing articles on some subspecialities, in particular on arthroscopy and sport medicine. Most publications have a low level of evidence.

ANTECEDENTES: La cantidad de veces que un artículo es citado es importante para analizar el impacto académico. En el presente estudio se analizan los 50 artículos más citados en ortopedia y áreas afines publicados por autores mexicanos y sus principales características. MATERIAL Y MÉTODOS: Se realizó una búsqueda utilizando Web of Science de los 50 artículos más citados sobre ortopedia y áreas afines cuyo autor principal o autor correspondiente tuviera una dirección en México. Se analizaron los artículos de 66 revistas científicas dentro de la categoría Orthopedics. Se examinaron la cantidad y densidad de citas, institución de procedencia, subespecialidad a la que corresponde el artículo y nivel de evidencia. RESULTADOS: El artículo más citado tuvo 222 citas. Los 50 artículos más citados acumularon un total de 1,944, con un promedio de 3.6 citas por año por artículo. El año con mayor cantidad de publicaciones fue 2011 y el año con mayor número de citas fue 2008. Las instituciones públicas tuvieron un volumen más alto de publicaciones en comparación con las instituciones privadas. La subespecialidad con mayor volumen de publicaciones fue artroscopía y medicina del deporte. La mayoría de publicaciones con un número considerable de citas hacen referencia a estudios con un nivel bajo de evidencia. CONCLUSIONES: El presente estudio señala los 50 artículos más citados publicados por autores mexicanos en ortopedia y áreas afines. Existe una tendencia a publicar artículos sobre algunas subespecialidades, en particular sobre artroscopía y medicina del deporte. La mayoría de las publicaciones tienen un bajo nivel de evidencia.

Los 50 artículos más citados en ortopedia y traumatología de autores mexicanos / The 50 most cited articles in orthopedics and traumatology by Mexican authors

Resumen: Antecedentes: La cantidad de veces que un artículo es citado es importante para analizar el impacto académico. En el presente estudio se analizan los 50 artículos más citados en ortopedia y áreas afines publicados por autores mexicanos y sus principales características. Material y métodos: Se realizó una búsqueda utilizando Web of Science de los 50 artículos más citados sobre ortopedia y áreas afines cuyo autor principal o autor correspondiente tuviera una dirección en México. Se analizaron los artículos de 66 revistas científicas dentro de la categoría Orthopedics . Se examinaron la cantidad y densidad de citas, institución de procedencia, subespecialidad a la que corresponde el artículo y nivel de evidencia. Resultados: El artículo más citado tuvo 222 citas. Los 50 artículos más citados acumularon un total de 1,944, con un promedio de 3.6 citas por año por artículo. El año con mayor cantidad de publicaciones fue 2011 y el año con mayor número de citas fue 2008. Las instituciones públicas tuvieron un volumen más alto de publicaciones en comparación con las instituciones privadas. La subespecialidad con mayor volumen de publicaciones fue artroscopía y medicina del deporte. La mayoría de publicaciones con un número considerable de citas hacen referencia a estudios con un nivel bajo de evidencia. Conclusiones: El presente estudio señala los 50 artículos más citados publicados por autores mexicanos en ortopedia y áreas afines. Existe una tendencia a publicar artículos sobre algunas subespecialidades, en particular sobre artroscopía y medicina del deporte. La mayoría de las publicaciones tienen un bajo nivel de evidencia.

Abstract: Background: The amount of quotation a scientific article receives is important for the academic impact. In the present study, we analyzed the 50 most cited articles in orthopedics and related areas published by mexican authors, as well as analyzing their main characteristics. Material and methods: A search was conducted using Web of Science , of the 50 articles with the largest number of quotation on orthopedics and related areas, in which the principal author or corresponding author had an address in Mexico. We analyzed the articles of 66 scientific journals within the category Orthopedics . We examined the quantity and density of citations, Origin institution, subspeciality to which the article corresponds, and level of evidence. Results: The most cited article had 222 cites. The 50 most cited articles accumulated a total of 1,944, with an average of 3.6 cites per year per article. The year with the largest number of publications was the 2011, and the year with the largest number of quotation was 2008. Public institutions had a larger number of publications in relation to private institutions. The subspecialty with the largest number of publications was arthroscopy and sport medicine. Most publications with a large number of citations refer to studies with a low level of evidence. Conclusions: The present study points out the 50 most cited articles published by mexican authors in orthopedics and related areas. There is a tendency towards publishing articles on some subspecialities, in particular on arthroscopy and sport medicine. Most publications have a low level of evidence.

TIMP-1 regulation of cell cycle in human breast epithelial cells via stabilization of p27(KIP1) protein.

Increasing evidence suggests that tissue inhibitor of metalloproteinases-1 (TIMP-1) can directly regulate cell growth and apoptosis independent of its matrix metalloproteinases (MMPs)-inhibitory activity. While TIMP-1's antiapoptotic activity has been well demonstrated, conflicting data has been reported regarding TIMP-1's role in growth regulation. Here we show that TIMP-1 reduces the growth rate of human breast epithelial (MCF10A) cells by inducing cell cycle arrest at G(1). TIMP-1-mediated cell cycle arrest is associated with its downregulation of cyclin D(1) and upregulation of p27(KIP1), resulting in inhibition of cyclin-dependent kinase activity necessary for phosphorylation of the tumor suppressor retinoblastoma protein. We further show that TIMP-1 modulation of cyclin D(1) and p27(KIP1) is achieved through TIMP-1-mediated differential regulation of protein stability independent of growth factor signaling. We also show that TIMP-1-mediated differential regulation of cyclin D(1) and p27(KIP1) is independent of cell adhesion signaling. Whereas approximately 50% of MCF10A cells with reduced TIMP-1 expression underwent cell death following loss of cell adhesion (anoikis), TIMP-1 overexpressing cells remained viable with prominent cell cycle arrest without detectable cell death. Taken together, we propose that TIMP-1-mediated cell survival independent of cell adhesion is accompanied with cell cycle arrest in human breast epithelial cells, although cell cycle regulation may not be a prerequisite for TIMP-1 regulation of apoptosis in general.

Expression of latent matrix metalloproteinase 9 (MMP-9) predicts survival in advanced ovarian cancer.

OBJECTIVE: Matrix metalloproteinases (MMPs) are frequently expressed in malignant tumors and play an important role in tumor invasion and metastasis. MMP-2 and MMP-9 expression has been correlated with poor survival in some tumors, but data for ovarian cancer are lacking, despite clinical trials with MMP inhibitors. The aim of this study was to assess activity of MMP-2 and MMP-9 and correlate it to prognosis in ovarian cancer. METHODS: MMP-2 and MMP-9 gelatinolytic activity was analyzed in 84 patients with advanced ovarian cancer FIGO stage III and 19 benign ovarian tumors by gelatin zymography. MMP-9 immunoreactivity was detected by immunohistochemistry and gelatinolytic activity was localized in ovarian cancer tissue by in situ zymography. RESULTS: were correlated with patient survival, with a median follow-up period of 55 months. Results. Median pro-MMP-9 activity was at 0.00 U/microg protein in benign ovarian tissues and 4.82 U/microg protein in ovarian cancer (P = 0.001); activated MMP-9 was not detected. Pro-MMP-2 expression in benign ovarian tissue did not differ from that of malignant ovarian tissue, whereas active MMP-2 was present in 52% of ovarian cancers, but absent in benign ovarian tissues. Analyzing all patients high pro-MMP-9 activity was associated with short overall survival (P = 0.019) while pro-MMP-2 and activated MMP-2 did not predict overall survival. When analyzing the subgroups of patients with and without residual tumor mass at the time of surgery, pro-MMP-9 was of prognostic value only in the subgroup of patients with no residual tumor mass. In univariate analysis pro-MMP-9 activity, residual tumor mass, age, ascites volume, and grading were of prognostic significance for overall survival. However, in multivariate analyses, including all biological and clinicopathologic variables, only pro-MMP-9 and residual disease remained statistically independent prognostic factors. In situ zymography localized gelatinolytic activity predominantly to the tumor cell nests displaying MMP-9 immunoreactivity. CONCLUSIONS: Pro-MMP-9 gelatinolytic activity, but not active MMP-2 or MMP-9, serves as a useful statistically independent prognostic factor in ovarian cancer FIGO stage III, thus helping to identify ovarian cancer patients with an aggressive form of the disease.

Increased expression of matrix metalloproteinases (MMP)-2, MMP-9, and the urokinase-type plasminogen activator is associated with progression from benign to advanced ovarian cancer.

Proteases are linked to the malignant phenotype of different solid tumors. Therefore, the expression of the matrix metalloproteinase (MMP)-2 and MMP-9 and of the serine protease urokinase-type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor type 1 (PAI-1) in the progression of ovarian cancer was investigated. Gelatinolytic activity and protein expression of MMP-2 and MMP-9 were analyzed in tissue extracts of 19 cystadenomas and 18 low malignant potential (LMP) tumors, as well as 41 primary tumors of advanced ovarian cancer stage International Federation of Gynecology and Obstetrics IIIc/IV and their corresponding omentum metastases by quantitative gelatin zymography and Western blot. In the same tissue extracts, antigen levels of uPA and its inhibitor PAI-1 were determined by ELISA. Protein expression of pro-MMP-2 (72 kDa) and pro-MMP-9 (92 kDa as well as antigen levels of uPA and PAI-1 were low in benign ovarian tumors but increased significantly from LMP tumors to advanced ovarian cancers. The highest values of all of the proteolytic factors were detected in omentum metastases. Active MMP-2 enzyme (62 kDa) was detected only in ovarian cancer (66%) and corresponding metastases (93%) but never in benign or LMP tumors. The activation rate of MMP-2 to its active isoform was higher in the metastases. Comparing both proteolytic systems, higher PAI-1 concentrations were consistently found in cancers with high pro-MMP-9 expression. These data indicate that members of the plasminogen activator system, as well as the metalloproteinases MMP-2/9, increase with growing malignant potential of ovarian tumors. These findings are of particular relevance to the development of protease inhibitors as new therapeutic approaches in ovarian cancer.

Differential regulation of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 expression in co-cultures of prostate cancer and stromal cells.

Tumor-stromal interactions have been suggested to be a critical factor in both tumor invasion and tumor metastasis. Here, we examined the role of tumor-stromal interactions using co-cultures of prostate cancer (PC) cells derived from primary and metastatic tumors with primary or immortalized stromal (fibroblast and smooth muscle) cells and their effect on matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) expression. Co-cultures of PC and stromal cells showed enhanced levels of pro-MMP-9 and reduced levels of TIMP-1 and TIMP-2. Whereas enhanced expression of pro-MMP-9 occurred in PC cells, the TIMPs were down-regulated in stromal cells. Induction of pro-MMP-9 and reduction of TIMP expression did not require cell-cell contact and were mediated by a soluble factor(s) present in the conditioned medium of the effector cell. Collagen I is a potent inducer of pro-MMP-9 in PC cells. Consistently, preliminary characterization of the soluble factor in the fibroblast conditioned medium revealed m.w. of approximately 100 to 250 kDa, and its effect on pro-MMP-9 expression was partly inhibited by an anti-alpha2 integrin antibody, a major collagen I receptor. Expression of pro-MMP-9 protein and mRNA was also induced in metastatic PC-3 cells grown in human fetal bone implants in SCID mice. Together, these findings demonstrate the importance of tumor-stromal interactions in the regulation of MMP and TIMP expression and their potential role in PC progression.

Insight into the complex and dynamic process of activation of matrix metalloproteinases.

Matrix metalloproteinases (MMPs) are important hydrolytic enzymes with profound physiological and pathological functions in living organisms. MMPs are produced in their inactive zymogenic forms, which are subsequently proteolytically activated in an elaborate set of events. The propeptide in the zymogen blocks the active site, with a cysteine side-chain thiolate from this propeptide achieving coordination with the catalytically important zinc ion in the active site. Molecular dynamics simulations, ab initio calculations, and wet chemistry experiments presented herein argue for the critical importance of a protonation event at the coordinated thiolate as a prerequisite for the departure of the propeptide from the active site. Furthermore, a catalytically important glutamate is shown to coordinate transiently to the active-site zinc ion to "mask" the positive potential of the zinc ion and lower the energy barrier for dissociation of the protonated cysteine side chain from the zinc ion. In addition, a subtle conformational change by the propeptide is needed in the course of zymogen activation. These elaborate processes take place in concert in the activation process of MMPs, and the insight into these processes presented herein sheds light on a highly regulated physiological process with profound consequences for eukaryotic organisms.

X-ray absorption studies of human matrix metalloproteinase-2 (MMP-2) bound to a highly selective mechanism-based inhibitor. comparison with the latent and active forms of the enzyme.

Malignant tumors express high levels of zinc-dependent endopeptidases called matrix metalloproteinases (MMPs), which are thought to facilitate tumor metastasis and angiogenesis by hydrolyzing components of the extracellular matrix. Of these enzymes, gelatinases A (MMP-2) and B (MMP-9), have especially been implicated in malignant processes, and thus, they have been a target for drugs designed to block their activity. Therefore, understanding their molecular structure is key for a rational approach to inhibitor design. Here, we have conducted x-ray absorption spectroscopy of the full-length human MMP-2 in its latent, active, and inhibited states and report the structural changes at the zinc ion site upon enzyme activation and inhibition. We have also examined the molecular structure of MMP-2 in complex with SB-3CT, a recently reported novel mechanism-based synthetic inhibitor that was designed to be highly selective in gelatinases. It is shown that SB-3CT directly binds the catalytic zinc ion of MMP-2. Interestingly, the novel mode of binding of the inhibitor to the catalytic zinc reconstructs the conformational environment around the active site metal ion back to that of the proenzyme.

Differential roles of TIMP-4 and TIMP-2 in pro-MMP-2 activation by MT1-MMP.

The tissue inhibitors of metalloproteinases (TIMPs) are specific inhibitors of MMP enzymatic activity. However, TIMP-2 can promote the activation of pro-MMP-2 by MT1-MMP. This process is mediated by the formation of a complex between MT1-MMP, TIMP-2, and pro-MMP-2. Binding of TIMP-2 to active MT1-MMP also inhibits the autocatalytic turnover of MT1-MMP on the cell surface. Thus, under certain conditions, TIMP-2 is a positive regulator of MMP activity. TIMP-4, a close homologue of TIMP-2 also binds to pro-MMP-2 and can potentially participate in pro-MMP-2 activation. We coexpressed MT1-MMP with TIMP-4 and investigated its ability to support pro-MMP-2 activation. TIMP-4, unlike TIMP-2, does not promote pro-MMP-2 activation by MT1-MMP. However, TIMP-4 binds to MT1-MMP inhibiting its autocatalytic processing. When coexpressed with TIMP-2, TIMP-4 competitively reduced pro-MMP-2 activation by MT1-MMP. A balance between TIMP-2 and TIMP-4 may be a critical factor in determining the degradative potential of cells in normal and pathological conditions.

[Liver function test impairment induced by propafenone in a 73 year old woman].

Propafenone hydrochloride is a drug used for treating arrhythmia. The drug is usually well tolerated, although there are cardiovascular as well as non-cardiovascular side effects. The latter usually occur in the digestive tract and the neurological system. The rarest side effect is cholestasis. The literature cites five reported cases. This phenomenon is generally accompanied by clinical symptoms and upon discontinuation of the treatment with propafenone, the liver function tests return to the normal range. We review the literature dealing with liver damage resulting from treatment using propafenone. This is a case study of a 73-year old woman with three exposures of cholestasis connected to treatment with propafenone. The literature background and the case history were presented in order to heighten the physician's awareness of this rare phenomenon.

MMP-2 colocalizes with caveolae on the surface of endothelial cells.

We examined the spatial distribution of MMP-2 on the surface of human endothelial cells using immunofluorescence and confocal microscopy. Staining endothelial cells with MMP-2-specific antibodies revealed a punctate labeling at the basolateral side of the cell periphery, which colocalized with patches of caveolin-1, a major constituent of the caveolae. This colocalization was confirmed by immunogold electron microscopy. MT1-MMP, TIMP-2, and the alphavbeta3 integrin exhibited a similar pattern of staining, with pericellular patches that colocalized with either MMP-2 or caveolin-1. The presence of MT1-MMP and TIMP-2 in caveolae patches could be seen only after treatment with concanavalin A, which induced MMP-2 activation but had no noticeable effect on the pattern or intensity of MMP-2 immunostaining. In contrast, MMP-9 and TIMP-1 staining showed a pattern completely different from that of MMP-2 and TIMP-2, with positive spots uniformly distributed throughout the cell body. Our data show that MMP-2, its activator the MT1-MMP, and its proposed receptor, the alphavbeta3 integrin, are all targeted to the same membrane microdomains on the endothelial cell, thereby restricting matrix proteolysis to a limited microenvironment at the cell surface.

Assessment of Gelatinases (MMP-2 and MMP-9 by Gelatin Zymography.

The invasion and metastasis of tumor cells has been shown to require proteolytic activity in order to degrade components of the extracellular matrix (ECM). The hydrolysis of the ECM appears to facilitate tumor cell migration contributing to the metastatic dissemination of malignant cells (1). A major group of proteases that has been directly associated with tumor metastasis is the matrix metalloproteinases (MMPs), a family of endopeptidases known to cleave many ECM proteins (1). The MMPs are multidomain proteases that contain a zinc atom in the active site and are produced in a latent inactive form (zymogen) (2). Acquisition of enzymatic activity requires cleavage of the inhibitory N-terminal domain (3). Thus, generation of the active form usually occurs concomitantly with a decrease in molecular mass and exposure of the active site. Once activated, all the MMPs are specifically inhibited by a group of endogenous protease inhibitors known as the tissue inhibitors of metalloproteinases (TIMPs), which bind to the active site inhibiting catalytic activity (4).

Membrane-type matrix metalloproteinases in mice intracorneally infected with Pseudomonas aeruginosa.

PURPOSE: To establish the presence of membrane-type matrix metalloproteinases (MT-MMPs) in the cornea and their expression in naive and immunized mice intracorneally infected with Pseudomonas aeruginosa. METHODS: Naive (unimmunized) and immunized C57BL/6J mice were infected with P. aeruginosa, and gene expression of MT-MMPs were detected by RT-PCR. Immunoblot analysis and immunostaining were also used to characterize the MT-MMP response in both sets of animals. RESULTS: Expression of MT1-MMP, MT2-MMP, and MT3-MMP (MMP 14, 15, and 16) was detected by RT-PCR and immunoblot analysis. Of the three MT-MMPs detected, MT1-MMP exhibited the greatest expression at protein levels. In general, a bell-shaped curve was obtained for each of the MT-MMPs in naive mice, but all of them showed much less expression in the immunized mice. MT1-MMP was localized in the epithelial tissue of the cornea, whereas MT2-MMP and MT3-MMP were mainly found in the interface between the epithelium and substantia propria. CONCLUSIONS: MT1-MMP was detected and expressed to a greater extent in naive mice than MT2-MMP and MT3-MMP. Peak expression of all three MT-MMPs showed a good correlation with the overall inflammatory response.

Tissue inhibitor of metalloproteinase (TIMP)-2 acts synergistically with synthetic matrix metalloproteinase (MMP) inhibitors but not with TIMP-4 to enhance the (Membrane type 1)-MMP-dependent activation of pro-MMP-2.

The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been shown to be a key enzyme in tumor angiogenesis and metastasis. MT1-MMP hydrolyzes a variety of extracellular matrix components and is a physiological activator of pro-MMP-2, another MMP involved in malignancy. Pro-MMP-2 activation by MT1-MMP involves the formation of an MT1-MMP.tissue inhibitors of metalloproteinases 2 (TIMP-2). pro-MMP-2 complex on the cell surface that promotes the hydrolysis of pro-MMP-2 by a neighboring TIMP-2-free MT1-MMP. The MT1-MMP. TIMP-2 complex also serves to reduce the intermolecular autocatalytic turnover of MT1-MMP, resulting in accumulation of active MT1-MMP (57 kDa) on the cell surface. Evidence shown here in Timp2-null cells demonstrates that pro-MMP-2 activation by MT1-MMP requires TIMP-2. In contrast, a C-terminally deleted TIMP-2 (Delta-TIMP-2), unable to form ternary complex, had no effect. However, Delta-TIMP-2 and certain synthetic MMP inhibitors, which inhibit MT1-MMP autocatalysis, can act synergistically with TIMP-2 in the promotion of pro-MMP-2 activation by MT1-MMP. In contrast, TIMP-4, an efficient MT1-MMP inhibitor, had no synergistic effect. These studies suggest that under certain conditions the pericellular activity of MT1-MMP in the presence of TIMP-2 can be modulated by synthetic and natural (TIMP-4) MMP inhibitors.