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      The Effect of Ultraviolet B on Fibrillin-1 and Fibrillin-2 in Human Non-pigmented Ciliary Epithelial Cells In Vitro

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          Abstract

          The ciliary zonules link the lens to the ciliary body in the eye, controlling the thickness of the lens for focusing through their characteristic elasticity. The ciliary zonules are composed of oxytalan fibers. Physiological or pathological damage to the ciliary zonules, including exposure to ultraviolet (UV)-A and UV-B components, can lead to lens dislocation. However, no studies have shown whether UV affects the ciliary zonule. Here, we assessed the effects of UV light on human nonpigmented ciliary epithelial cells (HNPCECs). HNPCECs were cultured for 4 weeks, and expression of fibrillin-1 and fibrillin-2 was confirmed. In control cultures (0 mJ/cm 2), some fibrillin-1-positive fibers were merged with fibrillin-2. After UV-A irradiation, the appearance of both fibrillin-1- and fibrillin-2-positive fibers was unchanged. However, after UV-B irradiation, fibrillin-1-positive fibers became thin at an irradiation level of 100 mJ/cm 2, and the fiber structure became amorphous at 150 mJ/cm 2. Fibrillin-2-positive fibers lost their continuity and disappeared after being exposed to 150 mJ/cm 2 UV-B. UV-B irradiation did not affect cell viability, possibly because of the sensitivity of fibrillin-1 and fibrillin-2 to UV-B. Thus, dislocation of the lens with age may be attributable to cumulative exposure to UV-B.

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          Ultraviolet-B irradiation and matrix metalloproteinases: from induction via signaling to initial events.

          Effects of sunlight have fascinated researchers for decades because nearly every living thing on earth is likely to be exposed to sunlight and the ultraviolet (UV) fraction of it. In addition to detrimental long-term effects such as immunosuppression and skin cancer, premature aging of the skin (photoaging) is a well-documented consequence of exposure to UVA and UVB. Photoaged skin is biochemically characterized by an overgrowth of abnormal elastic fibers in the dermis and by a dramatic decrease of distinct collagen types. Ultraviolet irradiation induces delayed UV-responsive genes, among them matrix metalloproteinases, which degrade macromolecules of the extracellular matrix, a hallmark in carcinogenesis and aging. We are interested in UVB-triggered initial events and in subsequent signaling resulting in enhanced expression of two major members of the matrix metalloproteinase family, the interstitial collagenase (MMP-1) and stromelysin-1 (MMP-3), in human dermal fibroblasts. Especially, these skin cells play a central role in connective tissue breakdown in photoaging and as stromal cells in tumor invasion and metastasis by means of their capability to produce matrix metalloproteinases. In this review, we will focus on UVB-triggered induction of matrix metalloproteinases, the so far identified components of the UVB-modulated signal transduction pathway(s), and the UVB irradiation-associated generation of reactive oxygen species (ROS). Finally, a potentially novel aspect in UVB irradiation-mediated expression of interstitial collagenase and stromelysin-1-namely, the involvement of reactive nitrogen species (RNS)-is discussed.
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            Fibrillin degradation by matrix metalloproteinases: implications for connective tissue remodelling.

            Fibrillin is the principal structural component of the 10-12 nm diameter elastic microfibrils of the extracellular matrix. We have previously shown that both fibrillin molecules and assembled microfibrils are susceptible to degradation by serine proteases. In this study, we have investigated the potential catabolic effects of six matrix metalloproteinases (MMP-2, MMP-3, MMP-9, MMP-12, MMP-13 and MMP-14) on fibrillin molecules and on intact fibrillin-rich microfibrils isolated from ciliary zonules. Using newly synthesized recombinant fibrillin molecules, major cleavage sites within fibrillin-1 were identified. In particular, the six different MMPs generated a major degradation product of approximately 45 kDa from the N-terminal region of the molecule, whereas treatment of truncated, unprocessed and furin-processed C-termini also generated large degradation products. Introduction of a single ectopia lentis-causing amino acid substitution (E2447K; one-letter symbols for amino acids) in a calcium-binding epidermal growth factor-like domain, predicted to disrupt calcium binding, markedly altered the pattern of C-terminal fibrillin-1 degradation. However, the fragmentation pattern of a mutant fibrillin-1 with a comparable E-->K substitution in an upstream calcium-binding epidermal growth factor-like domain was indistinguishable from wild-type molecules. Ultrastructural examination highlighted that fibrillin-rich microfibrils isolated from ciliary zonules were grossly disrupted by MMPs. This is the first demonstration that fibrillin molecules and fibrillin-rich microfibrils are degraded by MMPs and that certain amino acid substitutions change the fragmentation patterns. These studies have important implications for physiological and pathological fibrillin catabolism and for loss of connective tissue elasticity in ageing and disease.
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              Homo- and heterotypic fibrillin-1 and -2 interactions constitute the basis for the assembly of microfibrils.

              Fibrillin-1 and fibrillin-2 constitute the backbone of extracellular filaments, called microfibrils. Fibrillin assembly involves complex multistep mechanisms to result in a periodical head-to-tail alignment in microfibrils. Impaired assembly potentially plays a role in the molecular pathogenesis of genetic disorders caused by mutations in fibrillin-1 (Marfan syndrome) and fibrillin-2 (congenital contractural arachnodactyly). Presently, the basic molecular interactions involved in fibrillin assembly are obscure. Here, we have generated recombinant full-length human fibrillin-1, and two overlapping recombinant polypeptides spanning the entire human fibrillin-2 in a mammalian expression system. Characterization by gel electrophoresis, electron microscopy after rotary shadowing, and reactivity with antibodies demonstrated correct folding of these recombinant polypeptides. Analyses of homotypic and heterotypic interaction repertoires showed N- to C-terminal binding of fibrillin-1, and of fibrillin-1 with fibrillin-2. The interactions were of high affinity with dissociation constants in the low nanomolar range. However, the N- and C-terminal fibrillin-2 polypeptides did not interact with each other. These results demonstrate that fibrillins can directly interact in an N- to C-terminal fashion to form homotypic fibrillin-1 or heterotypic fibrillin-1/fibrillin-2 microfibrils. This conclusion was further strengthened by double immunofluorescence labeling of microfibrils. In addition, the binding epitopes as well as the entire fibrillin molecules displayed very stable properties.
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                Author and article information

                Journal
                Acta Histochem Cytochem
                Acta Histochem Cytochem
                AHC
                Acta Histochemica et Cytochemica
                JAPAN SOCIETY OF HISTOCHEMISTRY AND CYTOCHEMISTRY
                0044-5991
                1347-5800
                26 June 2017
                14 June 2017
                : 50
                : 3
                : 105-109
                Affiliations
                [1 ] Department of Radiation Science, Graduate School of Health Sciences, Hirosaki University , 66–1 Honcho, Hirosaki, Aomori 036–8564, Japan
                [2 ] Section of Pediatric Dentistry, Department of Oral Growth & Development, Division of Clinical Dentistry, Fukuoka Dental College , 2–15–1 Tamura, Sawara-ku, Fukuoka 814–0193, Japan
                [3 ] Department of Anatomy, Nihon University School of Dentistry , 1–8–13, Kanda-Surugadai, Chiyoda-ku, Tokyo 101–8310, Japan
                Author notes
                Correspondence to: Eichi Tsuruga, Department of Radiation Science, Graduate School of Health Sciences, Hirosaki University, 66–1 Honcho, Hirosaki, Aomori 036–8564, Japan. E-mail: tsuru@ 123456hirosaki.ac.jp
                Article
                JST.JSTAGE/ahc/16036 16036
                10.1267/ahc.16036
                5519489
                fe0ca152-76dc-40fe-9b28-5e7891f57231
                2017 The Japan Society of Histochemistry and Cytochemistry

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 5 December 2016
                : 9 May 2017
                Categories
                Regular Article

                Clinical chemistry
                ciliary zonule,fibrillin,microfibril,ultraviolet
                Clinical chemistry
                ciliary zonule, fibrillin, microfibril, ultraviolet

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