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Multiple Roles of Tenascins in Homeostasis and Pathophysiology of Aorta

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Multiple Roles of Tenascins in Homeostasis and Pathophysiology of Aorta Ann Vasc Dis Vol. 11, No. 2; 2018; pp 169–180 Online May 16, 2018 doi: 10.3400/avd.ra.17-00118 Review Article Multiple Roles of Tenascins in Homeostasis and Pathophysiology of Aorta Kyoko Imanaka-Yoshida, MD, PhD1,2 and Ken-ichi Matsumoto, PhD3 Tenascins are a family of large extracellular matrix (ECM) Keywords: tenascin-C, tenascin-X, inflammation, aortic glycoproteins. Four family members (tenascin-C, -R, -X, and aneurysm, aortic dissection -W) have been identified to date. Each member consists of the same types of structural domains and exhibits time- and tissue-specific expression patterns, suggesting their specific Introduction roles in embryonic development and tissue remodeling. Among them, the significant involvement of tenascin-C Tenascins are a family of large extracellular matrix (ECM) (TNC) and tenascin-X (TNX) in the progression of vascu- glycoproteins. There are four tenascins in vertebrates: lar diseases has been examined in detail. TNC is strongly tenascin-C (TNC), tenascin-R (TNR), tenascin-X (TNX) up-regulated under pathological conditions, induced by a (known as tenascin-Y in birds), and tenascin-W (TNW, number of inflammatory mediators and mechanical stress. also tenascin-N).1,2) Each of the four tenascin family TNC has diverse functions, particularly in the regulation of members consists of the same types of structural domains, inflammatory responses. Recent studies suggest that TNC including a cysteine-rich segment at the amino terminus, is involved in the pathophysiology of aneurysmal and dis- secting lesions, in part by protecting the vascular wall from epidermal growth factor (EGF)-like repeats, fibronectin destructive mechanical stress. TNX is strongly expressed in type III (FNIII)-like repeats, and a fibrinogen (FG)-like vascular walls, and its distribution is often reciprocal to that domain at the carboxyl terminus. of TNC. TNX is involved in the stability and maintenance TNC is the original “tenascin.” It was discovered inde- of the collagen network and elastin fibers. A deficiency in pendently by several laboratories, given different names, TNX results in a form of Ehlers–Danlos syndrome (EDS). and was shown to be highly expressed in tendons, em- Although their exact roles in vascular diseases have not yet bryos, and cancer stroma. TNR is the second member and been elucidated, TNC and TNX are now being recognized is predominantly expressed in the central and peripheral as promising biomarkers for diagnosis and risk stratification of vascular diseases. nervous systems. TNW is primarily found in pre-osteo- genic areas, the periosteum, kidney, smooth muscle, and most prominently, in cancer stroma. TNX is expressed in 1 Department of Pathology and Matrix Biology, Mie Univer- loose connective tissue such as the dermis, epimysium, and sity Graduate School of Medicine, Tsu, Mie, Japan blood vessels. 2 Mie University Research Center for Matrix Biology, Tsu, Tenascin family members exhibit time- and tissue-spe- Mie, Japan cific expression patterns in the embryo and adult and have 3 Department of Biosignaling and Radioisotope Experiment, been categorized as matricellular proteins, which are Interdisciplinary Center for Science Research, Organization “ ” 3,4) for Research and Academic Information, Shimane University, unique ECM proteins. Although each matricellular pro- Izumo, Shimane, Japan tein is unrelated based on the primary structure, they share a number of characteristics: 1) secreted by diverse types Received: November 15, 2017; Accepted: February 23, 2018 of cells, 2) associated with, but not necessarily a part of Corresponding author: Kyoko Imanaka-Yoshida, MD, PhD. the insoluble/fibrillar ECM, 3) counter-adhesive for cells Department of Pathology and Matrix Biology, Mie University under various conditions, 4) prevalent in areas of tissue Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514- 8507, Japan remodeling associated with normal and pathological pro- Tel: +81-59-231-5009, Fax: +81-59-231-5009 cesses, and 5) featured prominently in embryogenesis.5) E-mail: [email protected] Tenascin-C is an original matricellular protein in addi- tion to thrombospondin-1 (TSP-1) and SPARC.3,6) TNX, ©2018 The Editorial Committee of Annals of Vas- cular Diseases. This article is distributed under the terms of the Creative TSP2, osteopontin, CCN1, and CTGF (CCN2) were Commons Attribution License, which permits use, distribution, and repro- subsequently added.7) The term “matricellular protein” is duction in any medium, provided the credit of the original work, a link to becoming more widely used and new members, such as ga- the license, and indication of any change are properly given, and the origi- 5,8) nal work is not used for commercial purposes. Remixed or transformed lectins, periostin, and fibulin-5, have joined this group. contributions must be distributed under the same license as the original. An increasing number of reviews have described the Annals of Vascular Diseases Vol. 11, No. 2 (2018) 169 Imanaka-Yoshida K and Matsumoto K roles of tenascin family members, particularly TNC, Among the multiple regulatory mechanisms of expres- in cancer invasion and neurological and inflammatory sion, it is important to note that mechanical stress is a diseases.9–18) Therefore, we herein focus on the roles of strong inducer of TNC.30,31) TNC is known to be highly TNC and TNX in development, homeostasis, and aortic expressed at sites subjected to mechanical stress such as diseases. myotendinous and osteotendinous junctions as well as the branching points of arteries.32,33) Chiquet and co-workers reported a mechanism by which a mechano-signal up- TNC regulates TNC expression.34) Mechanical stimuli activate TNC is a large molecule of approximately 220–400 kDa the RhoA/ROCK signaling pathway via integrin β1,35) as an intact monomer and assembles as a hexamer. It which, in turn, induces the assembly of G-actin and stress exists in a number of different isoforms that are created fiber formation. The depletion of the cytoplasmic G-actin by the alternative splicing of FNIII-like repeats and post- pool results in the translocation of megakaryoblastic translational modifications through glycosylation and leukemia 1 (MKL1)/myocardin-related transcription fac- citrullination (reviewed in refs. 16, 18). tor A (MRTFA) into the nucleus, which is predominantly One of the characteristics of TNC is its spatiotem- localized in the cytoplasm through interaction with G- porally and tightly regulated expression. TNC is highly actin. MLK1/MRTFA induces TNC transcription partly and transiently expressed in embryos at restricted sites as a co-activator of serum response factor (SRF).36,37) This often associated with cell migration, epithelial-mesenchy- RhoA-dependent mechanotransduction requires pericel- mal transition (EMT)/mesenchymal-epithelial transition lular fibronectin.38) TNC binds fibronectin and negatively (MET). It is sparsely expressed in normal adults, except affects the activation of RhoA.39) TNC also affects tissue in a few tissues that bear high mechanical stress are the stiffness, modeling the mechanical effects of its microenvi- locations of high cell turnover and are a specific niche for ronment.40,41) Moreover, TNC itself is an elastic molecule immune cells. that may be stretched to several-fold its original size.42,43) However, TNC is strongly up-regulated during injury, Therefore, TNC may modulate tissue elasticity and stiff- inflammation, repair/regeneration, and cancer invasion ness and may protect cells against mechanical stress. (reviewed in refs. 14, 18). Conversely, the prominent de novo expression of TNC in adults is a hallmark of injury Function of TNC and inflammation, which makes TNC applicable to clinical TNC directly affects cell behavior by binding to various diagnoses. An increasing number of studies have reported cell surface receptors including integrins, which are their the utility of the serum level of TNC as a biomarker for as- main receptor.15,44) TNC also indirectly acts by binding to sessing disease activity and predicting the prognosis of pa- other ECM molecules such as fibronectin or proteoglycans tients, for example, with myocardial diseases (reviewed by (reviewed in refs. 16, 18). In vitro, TNC might be effective refs. 19–21), aortic diseases22,23), and coronary aneurysms in cell migration, inhibiting focal adhesion assembly, pro- in Kawasaki disease.24) Furthermore, in vivo inflammatory moting proliferation, playing an inductive or protective lesions in the cardiovascular system have been successfully role in apoptosis, and changing gene expression in a man- imaged using Fab’ or the single chain Fv fragment of a ner that is dependent on the cellular context. In addition monoclonal anti-TNC antibody.25–29) to many other “important genes,” TNC knockout (TNC KO) mice show an almost normal phenotype,45) which Regulation of TNC expression initially suggested that TNC was a superfluous molecule. The specific expression of TNC suggests the existence of However, subsequent investigations on various disease an accurately tuned regulatory system. The promoter of models using TNC KO demonstrated the significant roles the TNC gene (Tnc) contains a TAT A box and a number of TNC, particularly in inflammation, fibrosis, and tissue of signaling pathways and transcription factors, such repair. as Prx1, Notch, and Sox4, might contribute to specific Accumulating evidence has highlighted the promotion expression in embryonic development (reviewed in refs. of inflammation by TNC through its induction of innate
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