Expresión de TGF-p como indicio temprano de lesión del tejido hepático en la enfermedad de hígado graso no alcohólico / Expression of TGF-p as an early sign of liver tissue injury in nonalcoholic fatty liver disease

Resumen Introducción: la enfermedad de hígado graso no alcohólico (NAFLD) constituye un problema de salud pública asociado con el síndrome metabólico; su patogénesis implica el inicio de una cascada de señalización bioquímica compleja y su estimulación continua podría consolidar un proceso de fibrogénesis en el tejido. El objetivo del estudio fue analizar expresión de genes implicados en daño hepático, en los procesos iniciales de la lesión en pacientes con NAFLD o con factores de riesgo relacionados a esta patología, en búsqueda de biomarcadores moleculares útiles a la práctica clínica tales como TGF-pi, COL1A2 y MMP20. Metodología: estudio analítico de corte transversal. Se estudiaron características epidemiológicas, bioquímicas, y expresión génica de TGF-pU, COL1A2 y MMP20 en tejido hepático, en individuos con factores de riesgo para NAFLD. Resultados: se incluyeron 83 participantes con factores de riesgo asociados a NAFLD, 22 individuos (26.5%) fueron diagnosticados con NAFLD mediante ultrasonografía. Los factores de riesgo hallados fueron hipertensión arterial (50.6%), obesidad (49.4%), diabetes mellitus (34.9%) y dislipidemia (21.7%). La dislipidemia fue significativamente asociada con el riesgo de desarrollar NAFLD (OR=4; p=0.011). Se encontraron diferencias significativas para colesterol total (p<0.05); y una expresión génica de TGF--31 (con NAFLD p<0.0001 y sin NAFLD p<0.0001 frente al control) y COL1A2 (con NAFLD p=0.002 y sin NAFLD p=0.955 frente al control) con un patrón de expresión creciente a mayor grado de lesión hepática. Conclusión: para concluir, sugerimos activación de las vías de señalización que conducen a fibrogénesis en individuos con factores de riesgo para NAFLD, y mucho más acentuada en pacientes con NAFLD.

Abstract Introduction: nonalcoholic fatty liver disease (NAFLD) is a public health problem associated with the metabolic syndrome; its pathogenesis implies the start of a complex biochemical signaling cascade and its continuous stimulation could consolidate a fibrogenesis process in the tissue. The aim of the study was to analyze expression of genes involved in liver damage in the initial processes of the lesion in patients with NAFLD or with risk factors related to this pathology, in search of molecular biomarkers useful to clinical practice such as TGF--31, COL1A2 and MMP20. Methodology: cross-sectional analytical study. Epidemiological, biochemical, and gene expression characteristics of TGF--31, COL1A2 and MMP20 in liver tissue in individuals with risk factors for NAFLD were studied. Results: 83 participants with risk factors associated to NAFLD were included; 22 individuals (26.5%) were diagnosed with NAFLD by ultrasonography. The risk factors found were hypertension (50.6%), obesity (49.4%), diabetes mellitus (34.9%) and dyslipidemia (21.7%). Dyslipidemia was significantly associated with the risk of developing NAFLD (OR = 4; p = 0.011). Significant differences were found for total cholesterol (p <0.05); and a gene expression of TGF-P1 (with NAFLD p <0.0001 and without NAFLD p <0.0001 versus control) and COL1A2 (with NAFLD p = 0.002 and without NAFLD p = 0.955 versus control) with a pattern of increasing expression at higher degree of liver injury. Conclusion: to conclude, we suggest activation of the signaling pathways that lead to fibrogenesis in individuals with risk factors for NAFLD, and much more accentuated in patients with NAFLD.

Metaloproteinasas de la matriz extracelular y su participación en el proceso de cicatrización / Matrix metalloproteinases and their participation in the healing process

RESUMEN Introducción: las metaloproteinasas son enzimas fundamentales para el mantenimiento estructural de la matriz extracelular, así como para su degradación en situaciones donde se requiere un proceso de reparación tisular. Objetivo: realizar una revisión de los aspectos más actuales de las metaloproteinasas y su papel en la cicatrización. Metodología de búsqueda: se realizó una revisión de 95 artículos, durante el período comprendido entre el 18 de julio de 2015 y 20 de septiembre de 2016 se utilizó las bases de datos Medline, Scopus, Scielo y Science Direct. Resultados: existen seis subfamilias de metaloproteinasas: colagenasas, estromalisinas, elastasas, gelatinasas, matrilisinas y las metaloproteinasas asociadas a la membrana plasmática. Las células endoteliales vasculares las secretan en donde hay daño epitelial y se requiere de un proceso de cicatrización. Conclusiones: las metaloproteinasas son endopeptidasas dependientes de zinc fundamentales para el mantenimiento y degradación de la matriz extracelular. Cuando el mecanismo de regulación falla y las metaloproteinasas tienen una sobreexpresión, ocurren procesos de cicatrización deficientes, condicionando la aparición de heridas crónicas, cicatrices hipertróficas o queloides, pterigión, fibrosis pulmonar y hepática, entre otras condiciones. MÉD.UIS. 2017;30(2):55-62.

ABSTRACT Introduction: Matrix metalloproteinases are essential for structural maintenance of extracellular matrix enzymes, as well as degradation in situations where tissue repair process is warranted. Objective: To review the most current aspects of matrix metalloproteinases and their role in the healing process. Research Methodology: A review of about 95 papers was conducted during the period from July 18, 2015 to September 20, 2016; PubMed, Scopus, Scielo and Science Direct were used. Results: There are six subfamilies of metalloproteinases: collagenases, stromalysins, elastases, gelatinases, matrilysins and metalloproteinases associated with the plasma membrane. Vascular endothelial cells secrete them where there is epithelial damage and a healing process is required. Conclusions: Metalloproteinases are zinc dependent endopeptidases that are essential for the maintenance and degradation of the extracellular matrix. When the adjustment mechanism fails and matrix metalloproteinases are overexpressed, poor healing processes occur, causing problems such as liver chronic wounds, keloids or hypertrophic scars, pterygium, pulmonary and liver fibrosis, among other clinical conditions. MÉD.UIS. 2017;30(2):55-62.

Expressão de MMPs, marcadores angiogênicos e proliferação celular em tumores odontogênicos / Expression of MMPs, angiogenic and proliferation cell markers in odontogenic tumors

INTRODUÇÃO E OBJETIVO: O conhecimento do comportamento biológico de lesões de natureza odontogênica é essencial para tornar a abordagem terapêutica adequada e estabelecer um prognóstico. A produção de metaloproteinases da matriz extracelular (MMPs), a angiogênese e a proliferação celular fornecem subsídios para o crescimento tumoral. O presente artigo tem como objetivo fazer uma revisão de literatura de pesquisas em tumores odontogênicos (TOs) selecionados a partir da nova classificação da Organização Mundial da Saúde (OMS) de 2005 sobre a expressão de MMPs, marcadores angiogênicos e proliferação celular e verificar, nestes estudos, a relação desses marcadores quanto ao comportamento biológico dessas lesões. RESULTADOS: Nota-se que as MMPs -1, -2, -7, -9 e -26 encontram-se mais expressas no componente epitelial e estroma e, particularmente, a -13 em estroma. Uma maior angiogênese é observada em TOs mais agressivos. CD 105 foi mais expresso no TO ceratocístico (TOC) e CD34 em ameloblastomas sólidos (ASs). Relata-se elevada expressão do Ki-67 e p53 no TOC e no AS e baixo índice de proliferação celular no TO adenomatoide (TOA). CONCLUSÃO: Esses resultados mostram que as MMPs participam no processo de invasão e recorrência de algumas lesões odontogênicas, estando associadas ao comportamento biológico desses tumores. A angiogênese é fundamental para fornecer suporte à proliferação celular e esses dois eventos em conjunto estão correlacionados com diferentes níveis de comportamento biológico nos TOs, quando comparados com cistos de natureza odontogênica, o que pode sugerir o uso de inibidores angiogênicos como provável abordagem terapêutica nessas lesões.

INTRODUCTION AND OBJECTIVE: The study of biological behavior of odontogenic lesions is essential to the establishment of appropriate therapeutic approach and prognosis. The production of extracellular matrix metalloproteinases (MMPs), angiogenesis and cell proliferation contribute to tumor growth. This paper aims to review the literature on odontogenic tumors (OT) selected according to the new World Health Organization classification (WHO- 2005) by evaluating the expression of MMPs, angiogenic and cell proliferation. Furthermore, it aims to verify the relation between these markers and the biological behavior of these lesions. RESULTS: it was found that MMPs -1, -2, -7, -9 and -26 had a higher expression in both epithelial component and stroma, and 13 particularly in the stroma. Increased angiogenesis was observed in more aggressive OT. CD105 expression was higher in keratocystic odontogenic tumour (KOT) and CD34 in solid ameloblastomas (SA). It was observed a higher expression of Ki-67 and p53 in SA and KOT and a low cell proliferation rate in the adenomatoid odontogenic tumour (AOT). CONCLUSION: These results show that MMPs are involved in invasion and recurrence of some odontogenic lesions and are associated with the biological behavior of these tumors. Angiogenesis is critical to provide support to cell proliferation and these concomitant events are correlated with different levels of biological behavior in OT when compared to odontogenic cysts, hence the use of angiogenic inhibitors may be a potential therapeutic approach in these lesions.

Mecanismos envolvidos na resposta imune e inflamatória frente à implantação de membrana de cortical óssea bovina no tecido subcutâneo de camundongos: caracterização histomorfométrica, imunoenzimática e molecular / Mechanisms involved in immune and inflammatory response to implantation of bovine bone cortical membrane in subcutaneous tissue of mice: characterization histomorphometric, imunoenzimatic and molecular

Os avanços relacionados à ciência dos biomateriais e engenharia tecidual buscam esclarecer os mecanismos envolvidos na resposta biológica associada ao uso desses dispositivos e sua interação com o sistema imune. Neste estudo, avaliou-se a resposta imune e inflamatória desenvolvida em camundongos frente à implantação de membrana de cortical óssea bovina no tecido subcutâneo, em implantação única e sequencial de duas membranas, assim como os possíveis mecanismos envolvidos no processo de reconhecimento e reabsorção desse biomaterial, de acordo com análise histomorfométrica, enzimática e molecular. Após a implantação da membrana, sinais de reabsorção que antes eram notados em pontos isolados, aos poucos se unem até sua completa degradação, observada somente após 15 dias. Todo o processo de reabsorção da membrana é acompanhado por uma reação inflamatória de magnitude moderada, seguida pelo declínio do número de leucócitos, surgimento de células gigantes multinucleadas e formação de uma cápsula de tecido conjuntivo fibroso. A cinética de TNF-α e MMP-2, MMP-8, MMP-9 e MMP-13 apresentou um padrão de produção decrescente, entretanto os níveis dos inibidores de metaloproteinases (TIMPs) e TGF-β parecem atuar de forma inversa. A velocidade de reabsorção após duas implantações consecutivas da membrana foi maior quando comparada ao grupo de animais que sofreu apenas uma implantação, porém os resultados do teste de hipersensibilidade do tipo tardia (DTH) demonstraram que a membrana é biocompatível, pois não elicitou resposta imunológica exacerbada após uma segunda implantação, confirmando então a natureza não imunogênica desse biomaterial. Finalmente, os animais CD14KO e MyD88KO apresentaram uma reabsorção mais lenta da membrana implantada, quando comparados aos animais C57Bl/6 (WT)...

Advances related to the biomaterials science and tissue engineering seek to clarify the mechanisms involved in the biological response associated with the use of those devices and their interaction with the immune system. This study evaluated the inflammatory and immune response developed in mice after implantation bovine bone cortical membrane in subcutaneous tissue, in both, unique and sequential implantation of 2 membranes, as the mechanisms involved in this biomaterial recognition and resorption process, on regards to histomorphometric, enzymatic and molecular analysis. After membrane implantation, previously observed signs of resorption in isolated spots, gradually unite until their complete degradation after 15 days. The whole membrane resorption process is accompanied by a moderate inflammatory reaction, followed by a decline in the leukocytes number, appearance of multinucleated giant cells and formation of a capsule of fibrous connective tissue. The kinetics of TNF-α, MMP-2, MMP-8, MMP-9 e MMP-13 showed a pattern of decreasing production, however, levels of metalloproteinases inhibitors (TIMPs) and TGF-β seem to act in reverse way. The resorption rate after two successive membrane implantations was higher when compared to the group which suffered only one implantation, however, the results of delayed test hypersensity (DTH) demonstrated that the membrane is biocompatible, that is, it does not elicited too high immune response after a second position, confirming the non immunogenic nature of this biomaterial. Eventually, CD14KO and MyD88KO strains showed a slower membrane resorption when compared to animals C57Bl/6, demonstrating that the CD14 and MyD88 molecules are involved in biomaterial recognition and play an important role in bovine cortical bone membrane resorption process, indicating that PAMPs and/or DAMPs are involved in biological response generated by this biomaterial.

Effect of TIMP-2, MT1-MMP and MMP-2 expression on the in vitro invasive capacity of acute monocytic leukemia SHI-1 cells / 中华血液学杂志

<p><b>OBJECTIVE</b>To study the effect of matrix metalloproteinase 2 (MMP-2), membrane type 1 MMP (MT1-MMP) and tissue inhibitor of metalloproteinase 2 (TIMP-2) expressions on the in vitro invasive capacity of acute monocytic leukemia SHI-1 cells.</p><p><b>METHODS</b>SHI-1, NB4, K562, M937 and THP-1 human leukemia cell lines were cultured in vitro. The mRNA and protein expressions of TIMP-2, MMP-2 and MT1-MMP in different cells were detected by quantitative RT-PCR and western blot. A retroviral vector carrying human TIMP-2 cDNA was constructed and transfected into SHI-1 cells. Three subclone cells (S1, S2 and S3) were screened by G418 and selected by limiting dilution. RNA interference (RNAi) was used to knock down the expression of MMP-2, MT1-MMP and TIMP-2. Cell invasion capacity was performed through a reconstituted human basement membrane assays. Zymography was used to analyze the expression of MMP-2 in the supernatant of co-culture.</p><p><b>RESULTS</b>The expressions of MMP-2, MT1-MMP and TIMP-2 in SHI-1 cells were higher than that in other leukemic cells at both mRNA and protein levels (P < 0.05). The amount of proMMP-2 and activated MMP-2 in the conditioned media from SHI-1 cells co-cultured with bone marrow stromal cells (BMSCs) was more than that from other cells (P < 0.05). The in vitro invasive capacity of SHI-1 cells were higher than that of other cells (P < 0.05). The mRNA levels of TIMP-2 were increased by about 3 fold, 2 fold and 1.5 fold in S1, S2 and S3 cells, respectively (P < 0.05), while the protein levels were by about 2.6 fold, 1.5 fold and 1.3 fold than that of SHI-1 cells, respectively (P < 0.01). The invasion rates of subclone cells demonstrated a 1.5 - 2.5 fold' elevation (P < 0.05) and activated MMP-2 from their supernatants increased by 1.5 - 2.0 fold (P < 0.01). The knock-down efficiency of siRNA was 85% to 98%. The down-regulation of TIMP-2, MMP-2 and MT1-MMP decreased the invasion rates of SHI-1 cells by 60% - 70%, 50% - 60% and 40% - 50%, respectively (P < 0.05). No activated MMP-2 in the supernatants from any knock-down cells could be found.</p><p><b>CONCLUSIONS</b>SHI-1 cells constitutively overexpress MMP-2, MT1-MMP and TIMP-2 at both mRNA and protein levels. After co-cultured with BMSCs the SHI-1 cells increased MMP-2 activation and cell invasion. An increase of TIMP-2 expression in SHI-1 cells reflects an activating effect on cells invasion and MMP-2 activation.</p>

Inhibitory effects of RNA interference on MMP-24 expression and invasiveness of ovarian cancer SKOV(3) cells / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the inhibitory effect of RNA interference (RNAi) on MMP-24 expression and invasiveness of ovarian cancer SKOV(3) cells.</p><p><b>METHOD</b>Two pairs of small interfering RNA (siRNA) specific to MMP-24 mRNA were designed and transfected into SKOV(3) cells. RT-PCR and Western blotting were used to detect the mRNA and protein expressions of MMP-24, and the cell invasiveness was assessed using an in vitro invasion test.</p><p><b>RESULTS</b>After transfection with siRNA, the mRNA and protein expression levels of MMP-24 were obviously reduced in SKOV(3) cells, which also showed significantly decreased invasiveness in vitro.</p><p><b>CONCLUSIONS</b>MMP-24 gene silencing by RNAi can suppress the invasiveness of ovarian cancer SKOV(3) cells in vitro, which may provide a new therapeutic approach of ovarian cancer.</p>

Correlation between MMP-2 activation and MT1-MMP mRNA expression in thymic epithelial tumors / 中华病理学杂志

<p><b>OBJECTIVE</b>To study the relationship between activation of pro-MMP-2 and expression of matrix metalloproteinases (MMP)-2, MT1-MMP and tissue inhibitor of metalloproteinases (TIMP)-2 mRNA in thymoma and thymic carcinoma; and to study the molecular mechanism of invasion and metastasis of thymic epithelial tumors.</p><p><b>METHODS</b>Fresh tissue specimens of thymoma, thymic carcinoma and normal thymus were included. The mRNA expression of MMP-2, MT1-MMP and TIMP-2 were analyzed by real-time reverse transcription polymerase chain reaction. The pro-MMP-2 activation ratio and its localization were determined by gelatin zymography and film in-situ gelatin-Zymography, respectively. Correlation of mRNA expression of MMP-2, MT1-MMP and TIMP-2 was investigated in tumors with different histological subtypes and clinical stages.</p><p><b>RESULTS</b>There were no significant differences in the expressions of MMP-2, MT1-MMP and TIMP-2 mRNA between I and II stage or III and IV stage thymomas (P > 0.05). However, significant differences of the expressions were observed between three tumor groups: I-II stage, III-IV stage and thymic carcinomas (P < 0.005), and between three histological subtypes: AB-B1 (lymphocyte-rich and mixed types), B2-B3 (cortical and predominantly polygonal cells types) and thymic carcinomas (P < 0.05). Expression levels of MT1-MMP and TIMP-2 mRNA were correlated with pro-MMP-2 activation ratio (Spearman rank correlation: r = 0.7235, r = 0.7647, P < 0.005). The expression of MMP-9 did not show significant differences between thymomas and thymic carcinomas.</p><p><b>CONCLUSIONS</b>MMP-2, MT1-MMP and TIMP-2 mRNA expression levels are correlated with the histologic subtypes and clinical stages of thymoma. The mRNA expressions of MT1-MMP and TIMP-2 are correlated with the activation ratio of pro-MMP-2. It is speculated that upregulation of MT1-MMP gene expression may induce an activation of pro-MMP-2 through TIMP-2.</p>

Expression of MT-1 MMP, MMP2, MMP9 and TIMP2 mRNAs in Ductal Carcinoma in Situ and Invasive Ductal Carcinoma of the Breast

We investigated the expression of membrane type-1 (MT1)-MMP, MMP2, MMP9 and TIMP2 mRNAs and their roles in ductal carcinoma in situ (DCIS) and T1 and T2 invasive ductal carcinoma of the breast. We further compared these two types of carcinomas for differences in microvessel density, and expression of angiogenic factors and CD44std. MT1-MMP, MMP2, MMP9 and TIMP2 mRNA were expressed in both DCIS and invasive ductal carcinomas. Expression rates of MT1-MMP, MMP2, MMP9 and TIMP2 mRNAs were not statistically different between DCIS and invasive ductal carcinomas, nor did they differ statistically when grouped by tumor size, histologic grade or nuclear grade of invasive ductal carcinoma. Microvessel density and expression of VEGF and TGF-beta were not statistically different between DCIS and invasive ductal carcinoma. CD44std expression was significantly increased in DCIS compared to invasive ductal carcinoma (p < 0.05) and it was also significantly increased in lower clinical stage, histologic grade and nuclear grade of invasive ductal carcinoma (p < 0.05). Axillary node metastasis was significantly correlated with MT1-MMP mRNA, VEGF and TGF-beta expression (p < 0.05) and MT1-MMP mRNA was positively correlated with VEGF expression and TIMP2 mRNA (p < 0.05). In summary, patterns of MMP mRNA expression in DCIS and invasive ductal carcinoma suggest that the invasive potential of breast carcinoma is already achieved before morphologically overt invasive growth is observed. As MT1-MMP mRNA expression is significantly correlated with axillary nodal metastasis, it may be useful as a prognostic indicator of invasive ductal carcinoma. Considering the positive correlation of MT1-MMP mRNA and TIMP2mRNA expression, our finding supports a role for TIMP2 in tumor growth, as well as the utility of CD44std as a prognostic indicator of breast cancer.

Expression of MT-1 MMP, MMP2, MMP9 and TIMP2 mRNAs in Ductal Carcinoma in Situ and Invasive Ductal Carcinoma of the Breast

We investigated the expression of membrane type-1 (MT1)-MMP, MMP2, MMP9 and TIMP2 mRNAs and their roles in ductal carcinoma in situ (DCIS) and T1 and T2 invasive ductal carcinoma of the breast. We further compared these two types of carcinomas for differences in microvessel density, and expression of angiogenic factors and CD44std. MT1-MMP, MMP2, MMP9 and TIMP2 mRNA were expressed in both DCIS and invasive ductal carcinomas. Expression rates of MT1-MMP, MMP2, MMP9 and TIMP2 mRNAs were not statistically different between DCIS and invasive ductal carcinomas, nor did they differ statistically when grouped by tumor size, histologic grade or nuclear grade of invasive ductal carcinoma. Microvessel density and expression of VEGF and TGF-beta were not statistically different between DCIS and invasive ductal carcinoma. CD44std expression was significantly increased in DCIS compared to invasive ductal carcinoma (p < 0.05) and it was also significantly increased in lower clinical stage, histologic grade and nuclear grade of invasive ductal carcinoma (p < 0.05). Axillary node metastasis was significantly correlated with MT1-MMP mRNA, VEGF and TGF-beta expression (p < 0.05) and MT1-MMP mRNA was positively correlated with VEGF expression and TIMP2 mRNA (p < 0.05). In summary, patterns of MMP mRNA expression in DCIS and invasive ductal carcinoma suggest that the invasive potential of breast carcinoma is already achieved before morphologically overt invasive growth is observed. As MT1-MMP mRNA expression is significantly correlated with axillary nodal metastasis, it may be useful as a prognostic indicator of invasive ductal carcinoma. Considering the positive correlation of MT1-MMP mRNA and TIMP2mRNA expression, our finding supports a role for TIMP2 in tumor growth, as well as the utility of CD44std as a prognostic indicator of breast cancer.

Expression of mRNA for membrane-type 1, 2, and 3 matrix metalloproteinases in human laryngeal cancer / 中国医学科学杂志(英文版)

<p><b>OBJECTIVE</b>To investigate correlation of expressions of membrane-type 1, 2, and 3 matrix metalloproteinases (MT1, MT2, and MT3-MMP) to the invasion and metastases in laryngeal cancer.</p><p><b>METHODS</b>Reverse transcription-polymerase chain reaction (RT-PCR) was used to examine the mRNA level of MT1, MT2, and MT3-MMP in 24 patients with laryngeal cancer. The relationships of these three MT-MMP expressions to clinicopathology were analyzed by statistics.</p><p><b>RESULTS</b>The expressions of MT1, MT2, and MT3-MMP were significantly higher in laryngeal cancer tissues than those in para-tumorous tissues (P < 0.01) and had a close relationship with invasive depth (P < 0.05). But no significantly different expressions of these three MT-MMPs were found in different primary location and different histological grade of laryngeal cancer (P > 0.05). The expression of MT1-MMP was obviously higher in patients with metastatic lymph nodes than that in patients without metastatic lymph nodes (P < 0.05).</p><p><b>CONCLUSION</b>MT1, MT2, and MT3-MMP play an important role in the progression of laryngeal cancer, and MT1-MMP may serve as a reliable marker in estimating invasive and metastatic potency of laryngeal cancer. Suppressing expressions of MT1, MT2, and MT3-MMP early may inhibit the invasion and metastases of laryngeal cancer.</p>

Dynamic expression of matrix metalloproteinase-2, membrane type-matrix metalloproteinase-2 in experimental hepatic fibrosis and its reversal in rat / 中华实验和临床病毒学杂志

<p><b>OBJECTIVE</b>To investigate the expression dynamics and significance of matrix metalloproteinase-2 (MMP-2) membrane type-matrix metalloproteinase-2 (MT-MMP-2) in hepatic fibrosis and its reversal counterpart.</p><p><b>METHODS</b>An experimental CCl4 induced hepatic fibrosis rat model was established by intraperitoneal administration of carbon tetrachloride for 2, 4, 6, 8, 10 weeks, and normal rats were used as a control group. The immunohistochemical methods and in situ hybridization were used to detect MMP-2,MT-MMP-2 mRNA and related antigens in the liver.</p><p><b>RESULTS</b>MMP-2,MT-MMP-2 mRNA and related antigens were expressed in mesenchymal cells and parts of hepatocytes besides active pathological changes, especially in the fibrous septum and portal area. Expression of MMP-2,MT-MMP-2 mRNA and related antigens were increased in hepatic fibrosis and decreased gradually in its reversal counterpart.</p><p><b>CONCLUSION</b>This study suggested that mesenchymal cells are the main cellular origins of MMPs. The levels of MMP-2 and MT-MMP-2 antigens and gene expression were closely related to hepatic fibrosis. MMP-2 and MT-MMP-2 may play important roles in hepatic fibrosis and its reversal counterpart.</p>