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American Journal of Physiology. Cell... May 2022Aggrecan (Acan) and versican (Vcan) are large chondroitin sulfate proteoglycans of the extracellular matrix. They share the same structural domains at both N- and... (Review)
Review
Aggrecan (Acan) and versican (Vcan) are large chondroitin sulfate proteoglycans of the extracellular matrix. They share the same structural domains at both N- and C-termini. The N-terminal G1 domain binds hyaluronan (HA), forms an HA-rich matrix, and regulates HA-mediated signaling. The C-terminal G3 domain binds other extracellular matrix molecules and forms a supramolecular structure that stores transforming growth factor β (TGFβ) and bone morphogenetic proteins (BMPs) and regulates their signaling. EGF-like motifs in the G3 domain may directly act like an EGF ligand. Both Acan and Vcan are present in cartilage, intervertebral disc, brain, heart, and aorta. Their localizations are essentially reciprocal. This review describes their structural domains, expression patterns and functions, and regulation of their expression.
Topics: Aggrecans; Epidermal Growth Factor; Extracellular Matrix Proteins; Humans; Hyaluronic Acid; Lectins, C-Type; Siblings; Versicans
PubMed: 35385326
DOI: 10.1152/ajpcell.00081.2022 -
Nature Cardiovascular Research Jan 2022Abnormal hematopoiesis advances cardiovascular disease by generating excess inflammatory leukocytes that attack the arteries and the heart. The bone marrow niche...
Abnormal hematopoiesis advances cardiovascular disease by generating excess inflammatory leukocytes that attack the arteries and the heart. The bone marrow niche regulates hematopoietic stem cell proliferation and hence the systemic leukocyte pool, but whether cardiovascular disease affects the hematopoietic organ's microvasculature is unknown. Here we show that hypertension, atherosclerosis and myocardial infarction (MI) instigate endothelial dysfunction, leakage, vascular fibrosis and angiogenesis in the bone marrow, altogether leading to overproduction of inflammatory myeloid cells and systemic leukocytosis. Limiting angiogenesis with endothelial deletion of (encoding vascular endothelial growth factor (VEGF) receptor 2) curbed emergency hematopoiesis after MI. We noted that bone marrow endothelial cells assumed inflammatory transcriptional phenotypes in all examined stages of cardiovascular disease. Endothelial deletion of or (encoding versican), genes shown to be highly expressed in mice with atherosclerosis or MI, reduced hematopoiesis and systemic myeloid cell numbers in these conditions. Our findings establish that cardiovascular disease remodels the vascular bone marrow niche, stimulating hematopoiesis and production of inflammatory leukocytes.
PubMed: 35747128
DOI: 10.1038/s44161-021-00002-8 -
American Journal of Physiology. Cell... Sep 2022Cancer immunoediting progresses through elimination, equilibrium, and escape. Each of these phases is characterized by breaching, remodeling, and rebuilding tissue... (Review)
Review
Cancer immunoediting progresses through elimination, equilibrium, and escape. Each of these phases is characterized by breaching, remodeling, and rebuilding tissue planes and structural barriers that engage extracellular matrix (ECM) components, in particular matrix proteoglycans. Some of the signals emanating from matrix proteoglycan remodeling are readily co-opted by the growing tumor to sustain an environment of tumor-promoting and immune-suppressive inflammation. Yet other matrix-derived cues can be viewed as part of a homeostatic response by the host, aiming to eliminate the tumor and restore tissue integrity. These latter signals may be harnessed for therapeutic purposes to tip the polarity of the tumor immune milieu toward anticancer immunity. In this review, we attempt to showcase the importance and complexity of matrix proteoglycan signaling in both cancer-restraining and cancer-promoting inflammation. We propose that the era of matrix diagnostics and therapeutics for cancer is fast approaching the clinic.
Topics: Extracellular Matrix; Humans; Inflammation; Neoplasms; Proteoglycans; Signal Transduction
PubMed: 35876288
DOI: 10.1152/ajpcell.00023.2022 -
American Journal of Physiology. Cell... Aug 2022The extracellular matrix (ECM) imparts critical mechanical and biochemical information to cells in the lungs. Proteoglycans are essential constituents of the ECM and... (Review)
Review
The extracellular matrix (ECM) imparts critical mechanical and biochemical information to cells in the lungs. Proteoglycans are essential constituents of the ECM and play a crucial role in controlling numerous biological processes, including regulating cellular phenotype and function. Versican, a chondroitin sulfate proteoglycan required for embryonic development, is almost absent from mature, healthy lungs and is reexpressed and accumulates in acute and chronic lung disease. Studies using genetically engineered mice show that the versican-enriched matrix can be pro- or anti-inflammatory depending on the cellular source or disease process studied. The mechanisms whereby versican develops a contextual ECM remain largely unknown. The primary goal of this review is to provide an overview of the interaction of versican with its many binding partners, the "versican interactome," and how through these interactions, versican is an integrator of complex extracellular information. Hopefully, the information provided in this review will be used to develop future studies to determine how versican and its binding partners can develop contextual ECMs that control select biological processes. Although this review focuses on versican and the lungs, what is described can be extended to other proteoglycans, tissues, and organs.
Topics: Animals; Extracellular Matrix; Lung; Mice; Versicans
PubMed: 35649251
DOI: 10.1152/ajpcell.00162.2022 -
Progress in Retinal and Eye Research Nov 2023Rhegmatogenous retinal detachment (RRD) is a sight threatening condition that warrants immediate surgical intervention. To date, 29 genes have been associated with... (Review)
Review
Rhegmatogenous retinal detachment (RRD) is a sight threatening condition that warrants immediate surgical intervention. To date, 29 genes have been associated with monogenic disorders involving RRD. In addition, RRD can occur as a multifactorial disease through a combined effect of multiple genetic variants and non-genetic risk factors. In this review, we provide a comprehensive overview of the spectrum of hereditary disorders involving RRD. We discuss genotype-phenotype correlations of these monogenic disorders, and describe genetic variants associated with RRD through multifactorial inheritance. Furthermore, we evaluate our current understanding of the molecular disease mechanisms of RRD-associated genetic variants on collagen proteins, proteoglycan versican, and the TGF-β pathway. Finally, we review the role of genetics in patient management and prevention of RRD. We provide recommendations for genetic testing and prophylaxis of at-risk patients, and hypothesize on novel therapeutic approaches beyond surgical intervention.
Topics: Humans; Retinal Detachment; Visual Acuity; Genetic Association Studies
PubMed: 36621380
DOI: 10.1016/j.preteyeres.2022.101158 -
Cells Apr 2021Uterine fibroids represent the most common benign tumors of the uterus. They are considered a typical fibrotic disorder. In fact, the extracellular matrix (ECM)... (Review)
Review
Uterine fibroids represent the most common benign tumors of the uterus. They are considered a typical fibrotic disorder. In fact, the extracellular matrix (ECM) proteins-above all, collagen 1A1, fibronectin and versican-are upregulated in this pathology. The uterine fibroids etiology has not yet been clarified, and this represents an important matter about their resolution. A model has been proposed according to which the formation of an altered ECM could be the result of an excessive wound healing, in turn driven by a dysregulated inflammation process. A lot of molecules act in the complex inflammatory response. Macrophages have a great flexibility since they can assume different phenotypes leading to the tissue repair process. The dysregulation of macrophage proliferation, accumulation and infiltration could lead to an uncontrolled tissue repair and to the consequent pathological fibrosis. In addition, molecules such as monocyte chemoattractant protein-1 (MCP-1), granulocyte macrophage-colony-stimulating factor (GM-CSF), transforming growth factor-beta (TGF-β), activin A and tumor necrosis factor-alfa (TNF-α) were demonstrated to play an important role in the macrophage action within the uncontrolled tissue repair that contributes to the pathological fibrosis that represents a typical feature of the uterine fibroids.
Topics: Animals; Humans; Immunity; Leiomyoma; Macrophages
PubMed: 33922329
DOI: 10.3390/cells10050982 -
Journal of Translational Medicine Jul 2023Bladder cancer is one of the most common malignant tumors of the urinary system and is associated with a poor prognosis once invasion and distant metastases occur....
BACKGROUND
Bladder cancer is one of the most common malignant tumors of the urinary system and is associated with a poor prognosis once invasion and distant metastases occur. Epithelial-mesenchymal transition (EMT) drives metastasis and invasion in bladder cancer. Transforming growth factor β1 (TGF-β1) and stromal fibroblasts, especially cancer-associated fibroblasts (CAFs), are positive regulators of EMT in bladder cancer. However, it remains unclear how TGF-β1 mediates crosstalk between bladder cancer cells and CAFs and how it induces stromal fibroblast-mediated EMT in bladder cancer. We aimed to investigate the mechanism of TGF-β1 regulation of stromal fibroblast-mediated EMT in bladder cancer cells.
METHODS
Primary CAFs with high expression of fibroblast activation protein (FAP) were isolated from bladder cancer tissue samples. Subsequently, different conditioned media were used to stimulate the bladder cancer cell line T24 in a co-culture system. Gene set enrichment analysis, a human cytokine antibody array, and cytological assays were performed to investigate the mechanism of TGF-β1 regulation of stromal fibroblast-mediated EMT in bladder cancer cells.
RESULTS
Among the TGF-β family, TGF-β1 was the most highly expressed factor in bladder cancer tissue and primary stromal fibroblast supernatant. In the tumor microenvironment, TGF-β1 was mainly derived from stromal fibroblasts, especially CAFs. In stimulated bladder cells, stromal fibroblast-derived TGF-β1 promoted bladder cancer cell migration, invasion, and EMT. Furthermore, TGF-β1 promoted the activation of stromal fibroblasts, inducing CAF-like features, by upregulating FAP in primary normal fibroblasts and a normal fibroblast cell line. Stromal fibroblast-mediated EMT was induced in bladder cancer cells by TGF-β1/FAP. Versican (VCAN), a downstream molecule of FAP, plays an essential role in TGF-β1/FAP axis-induced EMT in bladder cancer cells. VCAN may also function through the PI3K/AKT1 signaling pathway.
CONCLUSIONS
TGF-β1 is a critical mediator of crosstalk between stromal fibroblasts and bladder cancer cells. We revealed a new mechanism whereby TGF-β1 dominated stromal fibroblast-mediated EMT of bladder cancer cells via the FAP/VCAN axis and identified potential biomarkers (FAP, VCAN, N-cadherin, and Vimentin) of bladder cancer. These results enhance our understanding of bladder cancer invasion and metastasis and provide potential strategies for diagnosis, treatment, and prognosis.
Topics: Humans; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Fibroblasts; Signal Transduction; Transforming Growth Factor beta1; Tumor Microenvironment; Urinary Bladder; Urinary Bladder Neoplasms; Versicans
PubMed: 37461061
DOI: 10.1186/s12967-023-04303-3 -
International Journal of Experimental... Feb 2020A Disintegrin And Metalloproteinase with ThromboSpondin motif (ADAMTS)-5 was identified in 1999 as one of the enzymes responsible for cleaving aggrecan, the major... (Review)
Review
A Disintegrin And Metalloproteinase with ThromboSpondin motif (ADAMTS)-5 was identified in 1999 as one of the enzymes responsible for cleaving aggrecan, the major proteoglycan in articular cartilage. Studies in vitro, ex vivo and in vivo have validated ADAMTS-5 as a target in osteoarthritis (OA), a disease characterized by extensive degradation of aggrecan. For this reason, it attracted the interest of many research groups aiming to develop a therapeutic treatment for OA patients. However, ADAMTS-5 proteoglycanase activity is not only involved in the dysregulated aggrecan proteolysis, which occurs in OA, but also in the physiological turnover of other related proteoglycans. In particular, versican, a major ADAMTS-5 substrate, plays an important structural role in heart and blood vessels and its proteolytic processing by ADAMTS-5 must be tightly regulated. On the occasion of the 20th anniversary of the discovery of ADAMTS-5, this review looks at the evidence for its detrimental role in OA, as well as its physiological turnover of cardiovascular proteoglycans. Moreover, the other potential functions of this enzyme are highlighted. Finally, challenges and emerging trends in ADAMTS-5 research are discussed.
Topics: ADAMTS5 Protein; Aggrecans; Animals; Cardiovascular Diseases; Cardiovascular System; Cartilage, Articular; Humans; Osteoarthritis; Protease Inhibitors; Proteolysis; Substrate Specificity; Vascular Remodeling; Versicans
PubMed: 32219922
DOI: 10.1111/iep.12344 -
International Journal of Dentistry 2022Ameloblastoma is a benign but locally invasive odontogenic epithelial tumor, associated with a high recurrence rate after treatment. The action of enzymes of the...
BACKGROUND
Ameloblastoma is a benign but locally invasive odontogenic epithelial tumor, associated with a high recurrence rate after treatment. The action of enzymes of the metalloproteinase family is important to the degraded extracellular matrix, contributing to invasion. Thus, this study aimed to investigate the gene and protein expression of ADAMTS-1 and versican in ameloblastoma.
MATERIALS AND METHODS
Twenty cases of ameloblastoma ( = 20) and ten dental follicles (DF) ( = 10) were used as a source for immunochemistry and quantitative RT-PCR for determining the protein and mRNA expressions of the concerned genes, respectively. Moreover, western blot and indirect immunofluorescence analysis were performed in AME cells.
RESULTS
ADAMTS-1 and versican were overexpressed in DF than ameloblastoma by RT-PCR. However, in the immunolocalization analysis, ADAMTS-1 was expressed in ameloblastoma more than in DF and versican immunostaining obtained a similar pattern between ameloblastoma and DF. Indirect immunofluorescence detected the ADAMTS-1 and versican expression in cell lines derived from ameloblastoma. Western blot from cell lysate and conditioned medium detected ADAMTS-1 bands representing full-length and different processed forms. Monensin treatment confined ADAMTS-1 in the cell cytoplasm. Versican fragments also were detected in different compartments, intracellular and conditioned medium, allowing the versican process by ADAMTS-1.
CONCLUSION
This study showed a distinct expression of ADAMTS-1 and versican in ameloblastoma and DF, with ADAMTS-1 protein higher expression observed in ameloblastoma and possibly cleaved versican. These findings suggested that ADAMTS-1 may participate in tumor invasion, especially for the degradation of substrates (versican) in the ECM.
PubMed: 36338393
DOI: 10.1155/2022/5235376 -
The Journal of Histochemistry and... Nov 2020Versican is a large chondroitin sulfate/dermatan sulfate proteoglycan belonging to the aggrecan/lectican family. In adults, this proteoglycan serves as a structural... (Review)
Review
Versican is a large chondroitin sulfate/dermatan sulfate proteoglycan belonging to the aggrecan/lectican family. In adults, this proteoglycan serves as a structural macromolecule of the extracellular matrix in the brain and large blood vessels. In contrast, versican is transiently expressed at high levels during development and under pathological conditions when the extracellular matrix dramatically changes, including in the inflammation and repair process. There are many reports showing the upregulation of versican in cancer, which correlates with cancer aggressiveness. Versican has four classical splice variants, and all the variants contain G1 and G3 domains at N- and C-termini, respectively. There are two glycosaminoglycan attachment domains CSα and CSβ. The largest V0 variant contains both CSα and CSβ, V1 contains CSβ, V2 contains CSα, and the shortest G3 variant has neither of them. Versican degradation is initiated by cleavage at a site in the CSβ domain by ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) proteinases. The N-terminal fragment containing the G1 domain has been reported to exert various biological functions, although its mechanisms of action have not yet been elucidated. In this review, we describe the role of versican in inflammation and cancer and also address the biological function of versikine.
Topics: Animals; Extracellular Matrix; Humans; Inflammation; Neoplasms; Versicans
PubMed: 33131383
DOI: 10.1369/0022155420953922