The matrix metalloproteinases (MMPs) are a large family of proteolytic enzymes, which are involved in the degradation of many different components of the extracellular matrix. The MMPs have been classified into different groups including collagenases, gelatinases, stromelysins, membrane-type MMPs, etc. There is increasing evidence to indicate that MMPs play important roles in tumour invasion and metastasis. Moreover, MMPs not only play a direct role in tumour invasion by facilitating extracellular matrix degradation, but as a consequence they also have an important role in maintaining the tumour micro-environment and thus promoting tumour growth. In this paper, the structure, function and regulation of MMPs were reviewed.
Matrix Metalloproteinases ; chemistry ; physiology

The physiological reconstruction of bone is strictly dependent on bone resorption. Bone resorption is believed to be a complicated molecular reaction process that occurs in the microcircumstance of bone tissue. A lot of enzymes and factors take part in this process, yet there are not enough data with reference to the activation of osteoclast, resorption of bone matrix, regulation of bone resorption. In this paper we review the importance of matrix metalloproteinases (MMPs) in transfer of osteoclast and degradation of bone matrix, and the function of receptor activator of NF-kappaB-ligand (RANKL) and osteoprotegerin (OPG) in regulation of bone resorption.
Bone Resorption ; Humans ; Matrix Metalloproteinases ; metabolism ; Osteoclasts ; physiology ; Osteoprotegerin ; physiology ; RANK Ligand ; physiology

Diabetic Foot ; enzymology ; physiopathology ; Humans ; Matrix Metalloproteinases ; metabolism ; Wound Healing ; physiology

Matrix metalloproteinases (MMPs) are endocellular proteolytic enzymes. They are so named because they need Ca2+, Zn2+ and other metal ions as their cofactors. MMPs play an important biological role in regulating the formation, remodeling and degradation of extracellular matrix and participate in various physiological and pathological processes of cells. Bone marrow-derived mesenchymal stem cells (BMSCs) are a kind of pluripotent stem cell which has the ability to self-renew and differentiate into functional cells. Meanwhile, they can respond to the damage signals and migrate to injured site for tissue repair and regeneration. MMPs and their inhibitors TIMPs affect the differentiation and migration of BMSCs. This article reviews the roles of MMPs in differentiation and migration of BMSCs.
Bone Marrow Cells ; cytology ; Cell Differentiation ; physiology ; Cell Movement ; physiology ; Humans ; Matrix Metalloproteinases ; physiology ; Mesenchymal Stromal Cells ; cytology

OBJECTIVEThis study aimed to investigate the effects of in vitro continuous passaging on the morphological phenotype and differentiation characteristics of mouse hyaline chondrocytes, as well as on the balance of the extracellular matrix (ECM).

METHODSEnzymatic digestion was conducted to isolate mouse hyaline chondrocytes, which expanded over five passages in vitro. Hematoxylin-eosin stain was used to show the changes in chondrocyte morphology. Semi-quantitative polymerase chain reaction was performed to analyze the mRNA changes in the marker genes, routine genes, matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs (TIMPs) in chondrocytes. Zymography was carried out to elucidate changes in gelatinase activities.

RESULTSAfter continuous expansion in vitro, the morphology of round or polygonal chondrocytes changed to elongated and spindled shape. The expression of marker genes significantly decreased (P < 0.05), and it was almost negatively expressed by P5 chondrocytes. By contrast, the down regulation of routine genes was insignificant. The gene expression levels of MMPs and TIMPs both decreased (P < 0.05), but the change in MMP-1 and TIMP-1 was not statistically significant (P > 0.05). Meanwhile, the ratio of MMPs/TIMPs was altered. At the protein level, the activities of gelatinases decreased after passaging, especially for P4 and P5 chondrocytes (P < 0.05).

CONCLUSIONSerially passaged chondrocytes dedifferentiated and lost specific phenotypic characteristics during in vitro expansion culture. Simultaneously, the anabolism and catabolism of the cartilage ECM became uncontrollable and led to the imbalance of ECM homeostasis. When hyaline chondrocytes are applied in research on relevant diseases or cartilage tissue engineering, P0-P2 chondrocytes should be used.

Animals ; Cartilage ; Cell Differentiation ; Cells, Cultured ; Chondrocytes ; physiology ; Cytoskeleton ; Extracellular Matrix ; Gelatinases ; Gene Expression ; Hyalin ; physiology ; Matrix Metalloproteinase 1 ; Matrix Metalloproteinases ; Mice ; RNA, Messenger ; Tissue Engineering ; Tissue Inhibitor of Metalloproteinase-1 ; Tissue Inhibitor of Metalloproteinases

AIMTo investigate the relationship between the expression of MMP-2, MMP-9, TIMP-1 and TIMP-2 and ECM accumulation in rat left ventricle in a mechanical unloaded heart model.

METHODS12-week-old male Lewis rats were subjected to abdominal heterotopic heart transplantation to achieve pressure and volume unloading(mechanical unloading). Age and sex matched in situ heart of Lewis rats were used as control. Collagen volume fraction(CVF) was analyzed by picrosiris-red staining plus polarized microscopy. MMP-2 and -9 gelatinolytic activity were measured by gelatin-zymography. mRNA level of MMP-2, MMP-9, TIMP-1 and TIMP-2 were measured by real-time quantitative PCR. TIMP-1 and TIMP-2 protein level were measured by immunoblotting.

RESULTSMyocardial cross-sectional area of transplanted heart was significantly reduced, and accompanied by excessive ECM deposition (CVF 5.22% +/- 1.6% vs. 2.21% +/- 0.9%, P < 0.05) compared to in situ heart. MMP-2 and MMP-9 activity were significantly increased, as well as mRNA level of MMP-2, MMP-9, TIMP-1 and TIMP-2 compared to in situ heart. TIMP-1 and TIMP-2 protein level in mechanically unloaded heart were significantly upregulated compared to in situ heart, especially for TIMP-1.

CONCLUSIONMechanical unloading of left ventricle may lead to excessive ECM deposition, accompanied by imbalance between MMPs and TIMPs system, especially the upregulation of TIMPs.

Animals ; Extracellular Matrix ; metabolism ; Gelatinases ; metabolism ; Heart Transplantation ; physiology ; Heart-Assist Devices ; Male ; Matrix Metalloproteinases ; metabolism ; RNA, Messenger ; metabolism ; Rats ; Rats, Inbred Lew ; Tissue Inhibitor of Metalloproteinases ; metabolism ; Transplantation, Heterotopic ; physiology ; Ventricular Dysfunction, Left ; metabolism

The matrix metalloproteinases (MMPs) play a key role in the normal physiology of connective tissue during development, morphogenesis, and wound healing. Dysregulation of their activity has been implicated in numerous diseases including encephalopathy and the process of bone loss. Thus, MMPs may play a role in the encephalopathy and post-transplantation bone disease by immunosuppressive drugs such as cyclosporine (CsA) and tacrolimus. Gelatin zymography of MMP-9 and MMP-2 was performed in the glioma cells and osteoblast after CsA or tacrolimus treatment. Glioma cells or rat osteoblast ROS17/2.8 cells were treated with CsA or tacrolimus to make final concentration from 2 to 250 µM. After incubation, gelatin zymography of MMP-9 and MMP-2 was performed. And the density for the MMP bands were measured using luminescent image analyzer system. Both MMP-9 and MMP-2 activities in the osteoblast cells were decreased depending on the concentration of CsA or tacrolimus. MMP-2 activity was increased after CsA or tacrolimus treatment in the glioma cells. However, MMP-9 activities were decreased after CsA or tacrolimus treatment in the glioma cells. These results indicate that dysregulation of MMPs in the osteoblast and in the glioma cells by immunosuppressive drugs may one of the contributing factors in post-transplantation bone disease and in the encephalopathy by tacrolimus or cyclosporine.
Animals ; Bone Diseases ; Connective Tissue ; Cyclosporine ; Gelatin ; Glioma* ; Matrix Metalloproteinases ; Morphogenesis ; Osteoblasts* ; Physiology ; Rats ; Tacrolimus ; Wound Healing

Tenascin-C (TNC) is an extracellular matrix glycoprotein, which is usually highly expressed in embryonic tissues and tumor tissues, but is not expressed or just lowly expressed in mature tissues. TNC is involved in various complex signaling pathways during tumor metastasis, especially through modulating FAK, RhoA, Wnt and Notch pathways by interacting with syndecan-4, integrin α5β1, matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF). As a result, TNC affects epithelial mesenchymal transition, tumor cell adhesion, proliferation and angiogenesis, which eventually enhances the invasion and metastasis ability of many tumors. Further studies have demonstrated that TNC could be used as prognosis or metastasis marker of patients with malignant tumor.
Cell Adhesion ; Humans ; Integrins ; Matrix Metalloproteinases ; Neoplasm Metastasis ; Neoplasms ; Neovascularization, Pathologic ; Signal Transduction ; Tenascin ; physiology ; Vascular Endothelial Growth Factor A

OBJECTIVETo study the expression changes of matrix metalloproteinases (MMPs) in traumatic deep vein thrombosis (TDVT) in a rat model with the aid of gene chip technology and to explore the roles of MMPs in TDVT.

METHODSTotally 150 Sprague Dawley rats were randomly divided into control group (n equal to 10) and model group (n equal to 140). Rat models of TDVT were established by clamping the femoral vein and fixing the bilateral hind limbs. Then fixation of the hip spica with plaster bandage was conducted. According to the observation phases and/or biological situations of the femoral vein thrombosis, the model rats were further divided into 7 groups. Vascular tissues were obtained from each group through noninvasive incision into the femoral vein at corresponding time points. We adopted the Trizol one-step method for total RNA extraction, Affymetrix RAT 230 2.0 array for detection of RNA expressions and fold change (FC) analysis for changes of differential expressions of MMPs in each group. The main outcome parameters measured included expressions of MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14, MMP-16, MMP-23 and MMP-24. Gene array data of these MMPs were analyzed by the Affymetrix Microarray Analysis software (Version 5.0).

RESULTSFC analysis showed differential expressions of MMPs in each group during the course of TDVT. At the initial period of thrombosis, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, and MMP-24 had significantly high expression, while MMP-12, MMP-13, MMP-14, MMP-16 and MMP-23 had relatively low expression. MMPs were all highly expressed at the peak time of thrombosis. In the process of thrombus resolution, MMP-2, MMP-10, MMP-16 and MMP-24 have relatively low expression, while MMP-12, MMP-13, MMP-14, MMP-16 and MMP-23 have significantly high expression.

CONCLUSIONMMPs may affect the process of TDVT through transcription regulation of the fibrinolysis-anti-fibrinolytic system during the course of thrombosis and thrombus resolution.

Animals ; Disease Models, Animal ; Matrix Metalloproteinases ; physiology ; Rats ; Rats, Sprague-Dawley ; Venous Thrombosis ; enzymology ; etiology ; Wounds and Injuries ; complications

Increased arterial stiffness is an independent predictor of cardiovascular disease independent from blood pressure. Recent studies have shed new light on the importance of inflammation on the pathogenesis of arterial stiffness. Arterial stiffness is associated with the increased activity of angiotensin II, which results in increased NADPH oxidase activity, reduced NO bioavailability and increased production of reactive oxygen species. Angiotensin II signaling activates matrix metalloproteinases (MMPs) which degrade TGFbeta precursors to produce active TGFbeta, which then results in increased arterial fibrosis. Angiotensin II signaling also activates cytokines, including monocyte chemoattractant protein-1, TNF-alpha, interleukin-1, interleukin-17 and interleukin-6. There is also ample clinical evidence that demonstrates the association of inflammation with increased arterial stiffness. Recent studies have shown that reductions in inflammation can reduce arterial stiffness. In patients with rheumatoid arthritis, increased aortic pulse wave velocity in patients was significantly reduced by anti tumor necrosis factor-alpha therapy. Among the major classes of anti hypertensive drugs, drugs that block the activation of the RAS system may be more effective in reducing the progression of arterial stiffness. Thus, there is rationale for targeting specific inflammatory pathways involved in arterial stiffness in the development of future drugs. Understanding the role of inflammation in the pathogenesis of arterial stiffness is important to understanding the complex puzzle that is the pathophysiology of arterial stiffening and may be important for future development of novel treatments.
Angiotensin II/metabolism ; Humans ; Inflammation/drug therapy/metabolism/*physiopathology ; Matrix Metalloproteinases/metabolism ; Vascular Stiffness/drug effects/*physiology