Matrix metalloproteinases (MMPs) are a family of zinc-dependent extracellular matrix (ECM) remodeling endopeptidases that have the capacity to degrade almost every component of the ECM. The degradation of the ECM is of great importance, since it is related to embryonic development and angiogenesis. It is also involved in cell repair and the remodeling of tissues. When the expression of MMPs is altered, it can generate the abnormal degradation of the ECM. This is the initial cause of the development of chronic degenerative diseases and vascular complications generated by diabetes. In addition, this process has an association with neurodegeneration and cancer progression. Within the ECM, the tissue inhibitors of MMPs (TIMPs) inhibit the proteolytic activity of MMPs. TIMPs are important regulators of ECM turnover, tissue remodeling, and cellular behavior. Therefore, TIMPs (similar to MMPs) modulate angiogenesis, cell proliferation, and apoptosis. An interruption in the balance between MMPs and TIMPs has been implicated in the pathophysiology and progression of several diseases. This review focuses on the participation of both MMPs (e.g., MMP-2 and MMP-9) and TIMPs (e.g., TIMP-1 and TIMP-3) in physiological processes and on how their abnormal regulation is associated with human diseases. The inclusion of current strategies and mechanisms of MMP inhibition in the development of new therapies targeting MMPs was also considered.

https://www.mdpi.com/1422-0067/21/24/9739/pdf

The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases.

Although members of the fibroblast growth factor (FGF) family and their receptors have well-established roles in embryogenesis, their contributions to adult physiology remain relatively unexplored. Here, we use real-time quantitative PCR to determine the mRNA expression patterns of all 22 FGFs, the seven principal FGF receptors (FGFRs), and the three members of the Klotho family of coreceptors in 39 different mouse tissues. Unsupervised hierarchical cluster analysis of the mRNA expression data reveals that most FGFs and FGFRs fall into two groups the expression of which is enriched in either the central nervous system or reproductive and gastrointestinal tissues. Interestingly, the FGFs that can act as endocrine hormones, including FGF15/19, FGF21, and FGF23, cluster in a third group that does not include any FGFRs, underscoring their roles in signaling between tissues. We further show that the most recently identified Klotho family member, Lactase-like, is highly and selectively expressed in brown adipose tissue and eye and can function as an additional coreceptor for FGF19. This FGF atlas provides an important resource for guiding future studies to elucidate the physiological functions of FGFs in adult animals.

Research resource: Comprehensive expression atlas of the fibroblast growth factor system in adult mouse.

The ovary and uterus undergo extensive tissue remodeling throughout each reproductive cycle. This remodeling of the extracellular environment is dependent upon the cyclic hormonal changes associated with each estrous or menstrual cycle. In the ovary, tissue remodeling is requisite for growth and expansion of the follicle, breakdown of the follicular wall during the ovulatory process, transformation of the postovulatory follicle into the corpus luteum, as well as the structural dissolution of the corpus luteum during luteal regression. In the uterus, there is extraordinary turnover of the endometrial connective tissue matrix during each menstrual cycle. This turnover encompasses the complete breakdown and loss of this layer, followed by its subsequent regrowth. With implantation, extensive remodeling of the uterus occurs to support placentation. These dynamic changes in the ovarian and uterine extracellular architecture are regulated, in part, by the matrix metalloproteinase (MMP) system. The MMP system acts to control connective tissue remodeling processes throughout the body and is comprised of both a proteolytic component, the MMPs, and a regulatory component, the associated tissue inhibitors of metalloproteinases. The current review will highlight the key features of the MMPs and tissue inhibitors of metalloproteinases, focus on the changes and regulation of the MMP system that take place throughout the estrous and menstrual cycles, and address the impact of the dynamic tissue remodeling processes on ovarian and uterine physiology.

/pdf/the-matrix-metalloproteinase-system-changes-regulation-and-1xfjexv790.pdf

The Matrix Metalloproteinase System: Changes, Regulation, and Impact throughout the Ovarian and Uterine Reproductive Cycle

Ovulation is a complex process that is initiated by the lutenizing hormone surge and is controlled by the temporal and spatial expression of specific genes. This review focuses on recent endocrine, biochemical, and genetic information that has been derived largely from the identification of new genes that are expressed in the ovary, and from knowledge gained by the targeted deletion of genes that appear to impact the ovulation process. Two main areas are described in most detail. First, because mutant mouse models indicate that appropriate formation of the cumulus matrix is essential for successful ovulation, genes expressed in the cumulus cells and those that control cumulus expansion are discussed. Second, because mice null for the progesterone receptor fail to ovulate and are ideal models for dissecting the critical events downstream of progesterone receptor, genes expressed in mural granulosa cells that regulate the expression of novel proteases are described.

Ovulation: new dimensions and new regulators of the inflammatory-like response.

Epithelial-to-mesenchymal transition (EMT) increases cell migration and invasion, and facilitates metastasis in multiple carcinoma types, but belies epithelial similarities between primary and secondary tumors. This study addresses the importance of mesenchymal-to-epithelial transition (MET) in the formation of clinically significant metastasis. The previously described bladder carcinoma TSU-Pr1 (T24) progression series of cell lines selected in vivo for increasing metastatic ability following systemic seeding was used in this study. It was found that the more metastatic sublines had acquired epithelial characteristics. Epithelial and mesenchymal phenotypes were confirmed in the TSU-Pr1 series by cytoskeletal and morphologic analysis, and by performance in a panel of in vitro assays. Metastatic ability was examined following inoculation at various sites. Epithelial characteristics associated with dramatically increased bone and soft tissue colonization after intracardiac or intratibial injection. In contrast, the more epithelial sublines showed decreased lung metastases following orthotopic inoculation, supporting the concept that EMT is important for the escape of tumor cells from the primary tumor. We confirmed the overexpression of the IIIc subtype of multiple fibroblast growth factor receptors (FGFR) through the TSU-Pr1 series, and targeted abrogation of FGFR2IIIc reversed the MET and associated functionality in this system and increased survival following in vivo inoculation in severe combined immunodeficient mice. This model is the first to specifically model steps of the latter part of the metastatic cascade in isogenic cell lines, and confirms the suspected role of MET in secondary tumor growth.

https://cancerres.aacrjournals.org/content/canres/66/23/11271.full.pdf

Mesenchymal-to-Epithelial Transition Facilitates Bladder Cancer Metastasis: Role of Fibroblast Growth Factor Receptor-2

Cathepsins B, H, K, L and S belong to the family of lysosomal cysteine proteinases and participate in a variety of proteolytic processes, including degradation of the extracellular matrix (ECM). In the present study, we used Northern hybridization to demonstrate the presence of mRNAs for cathepsins B, H, K, L and S in human endometrium during both the proliferative and secretory phases of menstrual cycle. The mRNA levels for cathepsins H and K were significantly lower in secretory phase endometrium in comparison with proliferative phase endometrium. Immunohistochemical localization of the different cathepsins revealed widespread distribution of all cathepsins in both stroma and epithelial cells. The immunoreactivity for cathepsins B, H and K exhibited changes related to endometrial location and/or to the phase of the cycle. The strongest immunoreactivity for cathepsins B, H, L and S was observed in the surface epithelium of the endometrium. The staining for cathepsins was predominantly intracellular, but immunoreactivity was also detected on the surface of small lymphoid cells in the stroma. The findings of the present study suggest that cysteine cathepsins are needed for normal development and function of human endometrium during both the proliferative and secretory phases.

/pdf/expression-patterns-of-cathepsins-b-h-k-l-and-s-in-the-human-2c1xr97qup.pdf

Expression patterns of cathepsins B, H, K, L and S in the human endometrium

Cathepsins B, H, K, L and S belong to a family of lysosomal cysteine proteinases which participate in a variety of proteolytic processes, including degradation of extracellular matrix. Although the presence of cathepsin mRNAs in the ovary has been reported earlier, very little information is available on their temporospatial expression. In the present study, Northern analysis revealed cyclic changes in the mRNA levels for cathepsins B, H, K, L and S during the 4-day oestrous cycle in the mouse ovary. Immunohistochemical localization revealed distinct expression patterns suggesting different functions for the cathepsins studied. Cathepsin B was predominantly seen in the germinal epithelium throughout the oestrous cycle. Upon follicular maturation, an increasing number of granulosa cells became positive for all cathepsins. Strong cathepsin H staining was sharply defined in theca externa which also stained for cathepsins K and S. Corpus luteum was the predominant location of cathepsin L. The distribution of cathepsin S resembled that of cathepsin L. The developing oocyte stained positive for all cathepsins. In-situ hybridization confirmed the differential production of cathepsin mRNAs by granulosa, thecal and luteal cells. These complex temporal and spatial expression patterns at different stages of the oestrous cycle and follicular development suggest divergent functions for specific cathepsins in follicular development, growth and rupture.

/pdf/differential-expression-patterns-of-cathepsins-b-h-k-l-and-s-b4bwr7dhmr.pdf

Differential expression patterns of cathepsins B, H, K, L and S in the mouse ovary.

https://www.fertstert.org/article/S0015-0282(04)03194-2/pdf

Molecular profiling of polycystic ovaries for markers of cell invasion and matrix turnover

Characterization of the murine Timp4 gene, localization within intron 5 of the synapsin 2 gene and tissue distribution of the mRNA.

while mRNA levels of proa1(IV) collagen and TIMP-3 mRNA were significantly lower in polycystic than control ovaries. During the normal menstrual cycle, an increase was observed in MMP-9 gene expression during the luteal phase. In post-menopausal ovaries, mRNA levels for type I, III and IV collagens and osteonectin were reduced, while the MMP, TIMP (excluding TIMP-3) and cathepsins did not reflect this metabolic down-regulation. Immunohistochemical staining for MMP-9 and TIMP-4 suggested differences between polycystic and normally functioning ovaries. These data demonstrate that normal ovarian functions are associated with changes in production and degradation of ECM. The alterations observed in the production and/or distribution of type IV collagen, TIMP-3 and TIMP-4 suggest involvement of basement membranes in the pathogenesis of PCOS.

Differences in connective tissue gene expression between normally functioning, polycystic and post‐menopausal ovaries

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