The Roles of Tenascins in Cardiovascular, Inflammatory, and Heritable Connective Tissue Diseases.
Matsumoto Ken-Ichi,Aoki Hiroki
Frontiers in immunology
Tenascins are a family of multifunctional extracellular matrix (ECM) glycoproteins with time- and tissue specific expression patterns during development, tissue homeostasis, and diseases. There are four family members (tenascin-C, -R, -X, -W) in vertebrates. Among them, tenascin-X (TNX) and tenascin-C (TNC) play important roles in human pathologies. TNX is expressed widely in loose connective tissues. TNX contributes to the stability and maintenance of the collagen network, and its absence causes classical-like Ehlers-Danlos syndrome (clEDS), a heritable connective tissue disorder. In contrast, TNC is specifically and transiently expressed upon pathological conditions such as inflammation, fibrosis, and cancer. There is growing evidence that TNC is involved in inflammatory processes with proinflammatory or anti-inflammatory activity in a context-dependent manner. In this review, we summarize the roles of these two tenascins, TNX and TNC, in cardiovascular and inflammatory diseases and in clEDS, and we discuss the functional consequences of the expression of these tenascins for tissue homeostasis.
Tenascin-C in Heart Diseases-The Role of Inflammation.
International journal of molecular sciences
Tenascin-C (TNC) is a large extracellular matrix (ECM) glycoprotein and an original member of the matricellular protein family. TNC is transiently expressed in the heart during embryonic development, but is rarely detected in normal adults; however, its expression is strongly up-regulated with inflammation. Although neither TNC-knockout nor -overexpressing mice show a distinct phenotype, disease models using genetically engineered mice combined with in vitro experiments have revealed multiple significant roles for TNC in responses to injury and myocardial repair, particularly in the regulation of inflammation. In most cases, TNC appears to deteriorate adverse ventricular remodeling by aggravating inflammation/fibrosis. Furthermore, accumulating clinical evidence has shown that high TNC levels predict adverse ventricular remodeling and a poor prognosis in patients with various heart diseases. Since the importance of inflammation has attracted attention in the pathophysiology of heart diseases, this review will focus on the roles of TNC in various types of inflammatory reactions, such as myocardial infarction, hypertensive fibrosis, myocarditis caused by viral infection or autoimmunity, and dilated cardiomyopathy. The utility of TNC as a biomarker for the stratification of myocardial disease conditions and the selection of appropriate therapies will also be discussed from a clinical viewpoint.
Tenascin-C in cardiovascular tissue remodeling: from development to inflammation and repair.
Circulation journal : official journal of the Japanese Circulation Society
Tenascin-C (TN-C) is a matricellular protein expressed during embryonic development, as well as in wound healing and cancer invasion in various tissues, and may regulate cell behavior and matrix organization during tissue remodeling. In the cardiovascular system, TN-C is transiently expressed at several important steps of embryonic development, playing important roles in the differentiation of cardiomyocytes and in coronary vasculo/angiogenesis. TN-C is sparse in normal adults, but upregulated under pathological conditions such as myocarditis, myocardial infarction, cardiac fibrosis, atherosclerosis, stenotic neointimal hyperplasia, and aneurysm, and is closely associated with tissue injury and inflammation. In view of its specific expression, TN-C could be a realistic and promising biomarker and a target for molecular imaging for the diagnosis of various cardiovascular diseases. TN-C also has diverse functions, including weakening of cell adhesion, up-regulating the expression and activity of matrix metalloproteinases, modulating inflammatory responses, promoting recruitment of myofibroblasts, and enhancing fibrosis. TN-C could exert both harmful and protective effects and might be a therapeutic target as a key molecule in the control of the balance of beneficial and undesirable cellular responses during tissue remodeling.
Tenascin-C Function in Glioma: Immunomodulation and Beyond.
Yalcin Fatih,Dzaye Omar,Xia Shuli
Advances in experimental medicine and biology
First identified in the 1980s, tenascin-C (TNC) is a multi-domain extracellular matrix glycoprotein abundantly expressed during the development of multicellular organisms. TNC level is undetectable in most adult tissues but rapidly and transiently induced by a handful of pro-inflammatory cytokines in a variety of pathological conditions including infection, inflammation, fibrosis, and wound healing. Persistent TNC expression is associated with chronic inflammation and many malignancies, including glioma. By interacting with its receptor integrin and a myriad of other binding partners, TNC elicits context- and cell type-dependent function to regulate cell adhesion, migration, proliferation, and angiogenesis. TNC operates as an endogenous activator of toll-like receptor 4 and promotes inflammatory response by inducing the expression of multiple pro-inflammatory factors in innate immune cells such as microglia and macrophages. In addition, TNC drives macrophage differentiation and polarization predominantly towards an M1-like phenotype. In contrast, TNC shows immunosuppressive function in T cells. In glioma, TNC is expressed by tumor cells and stromal cells; high expression of TNC is correlated with tumor progression and poor prognosis. Besides promoting glioma invasion and angiogenesis, TNC has been found to affect the morphology and function of tumor-associated microglia/macrophages in glioma. Clinically, TNC can serve as a biomarker for tumor progression; and TNC antibodies have been utilized as an adjuvant agent to deliver anti-tumor drugs to target glioma. A better mechanistic understanding of how TNC impacts innate and adaptive immunity during tumorigenesis and tumor progression will open new therapeutic avenues to treat brain tumors and other malignancies.