Pathological in Situ Reprogramming of Somatic Cells by the Unfolded Protein Response
2013; Elsevier BV; Volume: 183; Issue: 3 Linguagem: Inglês
10.1016/j.ajpath.2013.05.008
ISSN1525-2191
AutoresHisashi Johno, Masanori Kitamura,
Tópico(s)Genetics, Aging, and Longevity in Model Organisms
ResumoIn response to tissue injuries, terminally differentiated cells are reprogrammed to undergo dedifferentiation to gain mitogenic and metabolic properties. The dedifferentiated cells acquire an immature phenotype, proliferate actively, produce abundant extracellular matrix, and recruit circulating leukocytes via secretion of chemokines, contributing to tissue repair and/or fibrosis. However, this remodeling process is self-limiting, and in the later phase, the activated, dedifferentiated cells are reprogrammed to redifferentiate into a mature, quiescent phenotype. Currently, molecular mechanisms underlying this bidirectional pathological reprogramming remain elusive. It is known that the unfolded protein response (UPR) is induced at local tissues under pathological situations and affects cellular fate—survival or death. It is also known that the UPR is involved in cell differentiation and organogenesis during embryonic development. In this review, we describe a hypothesis for regulatory roles of the UPR in the pathological reprogramming of somatic cells (ie, cellular dedifferentiation and redifferentiation at the sites of injury). In response to tissue injuries, terminally differentiated cells are reprogrammed to undergo dedifferentiation to gain mitogenic and metabolic properties. The dedifferentiated cells acquire an immature phenotype, proliferate actively, produce abundant extracellular matrix, and recruit circulating leukocytes via secretion of chemokines, contributing to tissue repair and/or fibrosis. However, this remodeling process is self-limiting, and in the later phase, the activated, dedifferentiated cells are reprogrammed to redifferentiate into a mature, quiescent phenotype. Currently, molecular mechanisms underlying this bidirectional pathological reprogramming remain elusive. It is known that the unfolded protein response (UPR) is induced at local tissues under pathological situations and affects cellular fate—survival or death. It is also known that the UPR is involved in cell differentiation and organogenesis during embryonic development. In this review, we describe a hypothesis for regulatory roles of the UPR in the pathological reprogramming of somatic cells (ie, cellular dedifferentiation and redifferentiation at the sites of injury). CME Accreditation Statement: This activity (“ASIP 2013 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.The ASCP designates this journal-based CME activity (“ASIP 2013 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. CME Accreditation Statement: This activity (“ASIP 2013 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity (“ASIP 2013 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity. CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. The response to injury is a dynamic and complex process and involves a series of coordinated events, including leukocyte infiltration, resident cell proliferation, and accumulation of extracellular matrix (ECM). If this process progresses appropriately, normal tissues are reconstructed. However, the repair process is disturbed by various local factors, including infection, hypoxia, and excess levels of inflammatory cytokines, resulting in abnormal repair, such as fibrosis. In the response to injury, terminally differentiated local cells are reprogrammed to undergo dedifferentiation or transdifferentiation to gain active mitogenic and metabolic properties. One typical example is dedifferentiation of glomerular mesangial cells. Under inflammatory conditions, these cells acquire a myofibroblastic phenotype and contribute not only to normal tissue repair but also to the development of glomerulosclerosis.1Couser W.G. Johnson R.J. Mechanisms of progressive renal disease in glomerulonephritis.Am J Kidney Dis. 1994; 23: 193-198Abstract Full Text PDF PubMed Scopus (126) Google Scholar Another typical example is epithelial-mesenchymal transition (EMT) in which resident epithelial cells gain a phenotype characteristic of fibroblasts. EMT is required during normal embryonic development and wound healing but may also lead to transformation into malignant cells and fibrogenic myofibroblasts.2Cannito S. Novo E. di Bonzo L.V. Busletta C. Colombatto S. Parola M. Epithelial-mesenchymal transition: from molecular mechanisms, redox regulation to implications in human health and disease.Antioxid Redox Signal. 2010; 12: 1383-1430Crossref PubMed Scopus (208) Google Scholar Transforming growth factor (TGF)-β is a crucial factor that promotes EMT and myofibroblast formation, and its dysregulation is involved in carcinogenesis and fibrosis.2Cannito S. Novo E. di Bonzo L.V. Busletta C. Colombatto S. Parola M. Epithelial-mesenchymal transition: from molecular mechanisms, redox regulation to implications in human health and disease.Antioxid Redox Signal. 2010; 12: 1383-1430Crossref PubMed Scopus (208) Google Scholar The similar story has also been proposed in endothelial-mesenchymal transition in which endothelial cells gain a fibroblastic phenotype.3Piera-Velazquez S. Li Z. Jimenez S.A. Role of endothelial-mesenchymal transition (EndoMT) in the pathogenesis of fibrotic disorders.Am J Pathol. 2011; 179: 1074-1080Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar Once they are dedifferentiated, the cells proliferate actively, produce abundant ECM, and recruit leukocytes via secretion of chemokines, contributing to tissue repair and fibrosis. However, this remodeling process is usually transient, and in the later phase, activated, dedifferentiated cells undergo redifferentiation into a mature, quiescent phenotype. Currently, molecular mechanisms underlying the pathological in situ reprogramming of local cells remain elusive. The endoplasmic reticulum (ER) is an intracellular compartment that provides a unique environment for appropriate folding and maturation of newly synthesized proteins. A number of pathophysiological conditions (eg, hypoxia, nutrient deprivation, infection, alteration of redox state, changes in calcium balance, failure of posttranslational modifications and increased general protein synthesis) lead to accumulation of unfolded proteins in the ER, so-called ER stress.4Lee A.S. The glucose-regulated proteins: stress induction and clinical applications.Trends Biochem Sci. 2001; 26: 504-510Abstract Full Text Full Text PDF PubMed Scopus (939) Google Scholar To alleviate ER stress, cells activate evolutionarily conserved signaling cascades [ie, the unfolded protein response (UPR)]. The UPR comprises three major signaling pathways mediated by protein kinase-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1).5Ron D. Walter P. Signal integration in the endoplasmic reticulum unfolded protein response.Nat Rev Mol Cell Biol. 2007; 8: 519-529Crossref PubMed Scopus (5085) Google Scholar The UPR leads to attenuation of ER stress and restoration of ER function via general translational suppression, induction of ER chaperones, and up-regulation of ER-associated degradation. However, if the stress is beyond the folding capacity of the ER, specific cell death programs (proapoptotic UPR) are activated, leading to apoptotic cell death.6Kaufman R.J. Orchestrating the unfolded protein response in health and disease.J Clin Invest. 2002; 110: 1389-1398Crossref PubMed Scopus (1118) Google Scholar Although the UPR is primarily regarded as cellular defense machinery to cope with protein-folding stress, it also serves a wide range of pathophysiological processes, including lipid metabolism, energy homeostasis, and inflammatory processes.7Rutkowski D.T. Hegde R.S. Regulation of basal cellular physiology by the homeostatic unfolded protein response.J Cell Biol. 2010; 189: 783-794Crossref PubMed Scopus (305) Google Scholar The UPR influences cellular states of activation and differentiation. For example, the UPR induces activation of NF-κB and thereby triggers production of a wide range of inflammatory molecules, leading to initiation of inflammation.8Zhang Z. Kaufman R.J. From endoplasmic-reticulum stress to the inflammatory response.Nature. 2008; 454: 455-462Crossref PubMed Scopus (1588) Google Scholar Accumulating evidence also suggests that the UPR is involved in cell differentiation during embryogenesis. In the embryonic and postembryonic organ development, the UPR is physiologically activated in a variety of differentiating cells. Analyses of gene-knockout mice revealed divergent roles of the UPR in the development and maintenance of various cell types.9Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond.Nat Rev Mol Cell Biol. 2012; 13: 89-102PubMed Google Scholar On the other hand, it is known that the UPR is induced at local tissues under pathological situations. The UPR may also be involved in the dedifferentiation and redifferentiation of local cells during the process of tissue repair and fibrosis. In this article, we describe hypothetical roles of the UPR in the pathological in situ reprogramming of somatic cells toward dedifferentiation and redifferentiation. Several previous reports indicated a role of the UPR in dedifferentiation of terminally differentiated cells. In this section, we describe effects of the UPR on the dedifferentiation of some cell types, including chondrocytes, alveolar epithelial cells, and thyroid epithelial cells (Table 1).Table 1Induction of Dedifferentiation by the UPRDisease/experimental modelEvidence for UPREvidence for dedifferentiationReferenceChondrocyte Osteoarthritis (human)Grp78 ↑, Bag-1 ↑Aggrecan ↓, collagen II ↓10Nugent A.E. Speicher D.M. Gradisar I. McBurney D.L. Baraga A. Doane K.J. Horton Jr., W.E. Advanced osteoarthritis in humans is associated with altered collagen VI expression and upregulation of ER-stress markers Grp78 and bag-1.J Histochem Cytochem. 2009; 57: 923-931Crossref PubMed Scopus (74) Google Scholar, 11Gao Z.Q. Guo X. Duan C. Ma W. Xu P. Wang W. Chen J.C. Altered aggrecan synthesis and collagen expression profiles in chondrocytes from patients with Kashin-Beck disease and osteoarthritis.J Int Med Res. 2012; 40: 1325-1334Crossref PubMed Scopus (26) Google Scholar Chondrodysplasia (mouse; muColα1X-tg/ki)Grp78 ↑, Chop ↑, Xbp1 ↑, Atf6 ↑Prehypertrophic phenotype12Tsang K.Y. Chan D. Cheslett D. Chan W.C. So C.L. Melhado I.G. Chan T.W. Kwan K.M. Hunziker E.B. Yamada Y. Bateman J.F. Cheung K.M. Cheah K.S. Surviving endoplasmic reticulum stress is coupled to altered chondrocyte differentiation and function.PLoS Biol. 2007; 5: e44Crossref PubMed Scopus (151) Google Scholar ER stress inducer (in vitro; TM, SNAP)Grp78 ↑, Chop ↑Aggrecan ↓, collagen II ↓13Oliver B.L. Cronin C.G. Zhang-Benoit Y. Goldring M.B. Tanzer M.L. Divergent stress responses to IL-1β, nitric oxide, and tunicamycin by chondrocytes.J Cell Physiol. 2005; 204: 45-50Crossref PubMed Scopus (51) Google Scholar ER stress inducer (in vitro; TG, TM, GW)Chop ↑, caspase-12 ↑Aggrecan ↓, collagen II ↓, link protein ↓14Yang L. Carlson S.G. McBurney D. Horton Jr., W.E. Multiple signals induce endoplasmic reticulum stress in both primary and immortalized chondrocytes resulting in loss of differentiation, impaired cell growth, and apoptosis.J Biol Chem. 2005; 280: 31156-31165Crossref PubMed Scopus (90) Google ScholarAlveolar epithelial cell Idiopathic pulmonary fibrosis (human)Chop ↑, Atf4 ↑, Atf6 ↑, Xbp1 ↑EMT15Korfei M. Ruppert C. Mahavadi P. Henneke I. Markart P. Koch M. Lang G. Fink L. Bohle R.M. Seeger W. Weaver T.E. Guenther A. Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2008; 178: 838-846Crossref PubMed Scopus (411) Google Scholar, 16Kage H. Borok Z. EMT and interstitial lung disease: a mysterious relationship.Curr Opin Pulm Med. 2012; 18: 517-523PubMed Google Scholar Bleomycin-induced fibrosis (mouse)Grp78 ↑EMT (histocytochemistry)17Zhong Q. Zhou B. Ann D.K. Minoo P. Liu Y. Banfalvi A. Krishnaveni M.S. Dubourd M. Demaio L. Willis B.C. Kim K.J. duBois R.M. Crandall E.D. Beers M.F. Borok Z. Role of endoplasmic reticulum stress in epithelial-mesenchymal transition of alveolar epithelial cells: effects of misfolded surfactant protein.Am J Respir Cell Mol Biol. 2011; 45: 498-509Crossref PubMed Scopus (160) Google Scholar, 18Tanjore H. Xu X.C. Polosukhin V.V. Degryse A.L. Li B. Han W. Sherrill T.P. Plieth D. Neilson E.G. Blackwell T.S. Lawson W.E. Contribution of epithelial-derived fibroblasts to bleomycin-induced lung fibrosis.Am J Respir Crit Care Med. 2009; 180: 657-665Crossref PubMed Scopus (337) Google Scholar ER stress inducer (in vitro; TM, TG)Grp78 ↑, Xbp1 ↑EMT (E-cadherin ↓, ZO-1 ↓, α-SMA ↑)17Zhong Q. Zhou B. Ann D.K. Minoo P. Liu Y. Banfalvi A. Krishnaveni M.S. Dubourd M. Demaio L. Willis B.C. Kim K.J. duBois R.M. Crandall E.D. Beers M.F. Borok Z. Role of endoplasmic reticulum stress in epithelial-mesenchymal transition of alveolar epithelial cells: effects of misfolded surfactant protein.Am J Respir Cell Mol Biol. 2011; 45: 498-509Crossref PubMed Scopus (160) Google Scholar ER stress inducer (in vitro; TM, mSFTPC)Grp78 ↑, Edem ↑, eIF2α ↑EMT (E-cadherin ↓, ZO-1 ↓, α-SMA ↑, vimentin ↑, N-cadherin ↑, S100A4 ↑)18Tanjore H. Xu X.C. Polosukhin V.V. Degryse A.L. Li B. Han W. Sherrill T.P. Plieth D. Neilson E.G. Blackwell T.S. Lawson W.E. Contribution of epithelial-derived fibroblasts to bleomycin-induced lung fibrosis.Am J Respir Crit Care Med. 2009; 180: 657-665Crossref PubMed Scopus (337) Google ScholarThyroid epithelial cell ER stress inducer (in vitro; TM, TG)Grp78 ↑, Xbp1 ↑, Perk/eIF2α ↑Thyroglobulin ↓, TPO ↓, NIS ↓19Ulianich L. Garbi C. Treglia A.S. Punzi D. Miele C. Raciti G.A. Beguinot F. Consiglio E. Di Jeso B. ER stress is associated with dedifferentiation and an epithelial-to-mesenchymal transition-like phenotype in PC Cl3 thyroid cells.J Cell Sci. 2008; 121: 477-486Crossref PubMed Scopus (103) Google ScholarTTF-1 ↓, TTF-2 ↓, Pax-8 ↓EMT (E-cadherin ↓, vimentin ↑, α-SMA ↑, collagen I ↑)α-SMA, α-smooth muscle actin; Atf6, activating transcription factor 6; Bag-1, bcl-2–associated athanogene 1; Edem, endoplasmic reticulum degradation enhancing α-mannosidase-like protein; eIF2α, eukaryotic translation initiation factor 2α; EMT, epithelial-to-mesenchymal transition; Grp78, 78-kDa glucose-regulated protein; GW glucose withdrawal; mSFTPC, mutant surfactant protein C; muColα1X-tg/ki, mutant collagen α1X-transgenic/knock-in mouse; NIS, sodium/iodide symporter; Perk, protein kinase-like ER kinase; SNAP, S-nitroso-N-acetylpenicillamine; TG, thapsigargin; TM, tunicamycin; TPO, thyroperoxidase; TTF, thyroid transcription factor; Xbp1, X-box–binding protein 1; ZO-1, zonula occludens-1. Open table in a new tab α-SMA, α-smooth muscle actin; Atf6, activating transcription factor 6; Bag-1, bcl-2–associated athanogene 1; Edem, endoplasmic reticulum degradation enhancing α-mannosidase-like protein; eIF2α, eukaryotic translation initiation factor 2α; EMT, epithelial-to-mesenchymal transition; Grp78, 78-kDa glucose-regulated protein; GW glucose withdrawal; mSFTPC, mutant surfactant protein C; muColα1X-tg/ki, mutant collagen α1X-transgenic/knock-in mouse; NIS, sodium/iodide symporter; Perk, protein kinase-like ER kinase; SNAP, S-nitroso-N-acetylpenicillamine; TG, thapsigargin; TM, tunicamycin; TPO, thyroperoxidase; TTF, thyroid transcription factor; Xbp1, X-box–binding protein 1; ZO-1, zonula occludens-1. Bone elongation occurs at regions of specialized cartilage (growth plate) situated at both ends of long bones. During this process, chondrocytes originated from the resting zone of the growth plate undergo a series of phenotypic changes, including proliferating, prehypertrophic, and hypertrophic phenotypes, before reaching a terminally differentiated state.20Wallis G.A. Bone growth: coordinating chondrocyte differentiation.Curr Biol. 1996; 6: 1577-1580Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar Chondrocytes are exposed to various stresses, such as mechanical stress, hypoxic stress, and inflammatory stress, all of which may affect the differentiation state of chondroprogenitors and chondrocytes.21Zuscik M.J. Hilton M.J. Zhang X. Chen D. O’Keefe R.J. Regulation of chondrogenesis and chondrocyte differentiation by stress.J Clin Invest. 2008; 118: 429-438Crossref PubMed Scopus (192) Google Scholar Mature chondrocytes synthesize matrix proteins, including type II collagen, aggrecan, and link protein (known markers for differentiated chondrocytes). The steady-state levels of these cartilage components are maintained by chondrocytes. However, excessive stress leads chondrocytes to be unable to repair or replace damaged areas of cartilage. Several reports indicated a link between ER stress and chondrocyte dedifferentiation.12Tsang K.Y. Chan D. Cheslett D. Chan W.C. So C.L. Melhado I.G. Chan T.W. Kwan K.M. Hunziker E.B. Yamada Y. Bateman J.F. Cheung K.M. Cheah K.S. Surviving endoplasmic reticulum stress is coupled to altered chondrocyte differentiation and function.PLoS Biol. 2007; 5: e44Crossref PubMed Scopus (151) Google Scholar, 22Rajpar M.H. McDermott B. Kung L. Eardley R. Knowles L. Heeran M. Thornton D.J. Wilson R. Bateman J.F. Poulsom R. Arvan P. Kadler K.E. Briggs M.D. Boot-Handford R.P. Targeted induction of endoplasmic reticulum stress induces cartilage pathology.PLoS Genet. 2009; 5: e1000691Crossref PubMed Scopus (116) Google Scholar In patients with osteoarthritis, both the UPR and cellular dedifferentiation are detectable in chondrocytes.10Nugent A.E. Speicher D.M. Gradisar I. McBurney D.L. Baraga A. Doane K.J. Horton Jr., W.E. Advanced osteoarthritis in humans is associated with altered collagen VI expression and upregulation of ER-stress markers Grp78 and bag-1.J Histochem Cytochem. 2009; 57: 923-931Crossref PubMed Scopus (74) Google Scholar, 11Gao Z.Q. Guo X. Duan C. Ma W. Xu P. Wang W. Chen J.C. Altered aggrecan synthesis and collagen expression profiles in chondrocytes from patients with Kashin-Beck disease and osteoarthritis.J Int Med Res. 2012; 40: 1325-1334Crossref PubMed Scopus (26) Google Scholar Oliver et al13Oliver B.L. Cronin C.G. Zhang-Benoit Y. Goldring M.B. Tanzer M.L. Divergent stress responses to IL-1β, nitric oxide, and tunicamycin by chondrocytes.J Cell Physiol. 2005; 204: 45-50Crossref PubMed Scopus (51) Google Scholar reported that ER stress inducer tunicamycin caused modest suppression of type II collagen and marked inhibition of aggrecan expression in mature chondrocytes. They also found that inflammatory cytokine IL-1β had the similar effect, which was mediated by nitric oxide–induced ER stress. Yang et al14Yang L. Carlson S.G. McBurney D. Horton Jr., W.E. Multiple signals induce endoplasmic reticulum stress in both primary and immortalized chondrocytes resulting in loss of differentiation, impaired cell growth, and apoptosis.J Biol Chem. 2005; 280: 31156-31165Crossref PubMed Scopus (90) Google Scholar found that ER stress triggered by several different stimuli resulted in impaired accumulation of Alcian Blue–positive ECM and type II collagen in chondrocytes. They also found a down-regulation of aggrecan, type II collagen, and link protein mRNAs in ER stress–exposed cells. Tsang et al12Tsang K.Y. Chan D. Cheslett D. Chan W.C. So C.L. Melhado I.G. Chan T.W. Kwan K.M. Hunziker E.B. Yamada Y. Bateman J.F. Cheung K.M. Cheah K.S. Surviving endoplasmic reticulum stress is coupled to altered chondrocyte differentiation and function.PLoS Biol. 2007; 5: e44Crossref PubMed Scopus (151) Google Scholar studied an in vivo effect of ER stress on terminally differentiating hypertrophic chondrocytes during endochondral bone formation. They generated transgenic mice expressing mutant type X collagen that causes ER stress and found the following: i) ER stress is induced in chondrocytes, ii) their terminal differentiation is interrupted, and iii) endochondral bone formation is delayed, producing a chondrodysplasia phenotype. This impaired differentiation of chondrocytes involved cell-cycle reentry and reexpression of genes characteristic of a prehypertrophic phenotype of chondrocytes. Similarly, Rajpar et al22Rajpar M.H. McDermott B. Kung L. Eardley R. Knowles L. Heeran M. Thornton D.J. Wilson R. Bateman J.F. Poulsom R. Arvan P. Kadler K.E. Briggs M.D. Boot-Handford R.P. Targeted induction of endoplasmic reticulum stress induces cartilage pathology.PLoS Genet. 2009; 5: e1000691Crossref PubMed Scopus (116) Google Scholar generated knock-in mice that express mutant type X collagen. The mutant mice exhibited short limbs and an expanded hypertrophic zone. The chondrocytes in the hypertrophic zone exhibited a robust UPR and consequent disruption of normal gene expression. Taken together, these results raise two possibilities. First, the UPR triggered by ER stress induces dedifferentiation of hypertrophic chondrocytes toward immature phenotypes. Second, the UPR may also disturb prehypertrophic chondrocytes to differentiate into the mature, hypertrophic phenotype. Currently, it is not well understood how the UPR induces dedifferentiation of chondrocytes, but Yu et al23Yu S.M. Kim H.A. Kim S.J. 2-Deoxy-D-glucose regulates dedifferentiation through β-catenin pathway in rabbit articular chondrocytes.Exp Mol Med. 2010; 42: 503-513Crossref PubMed Scopus (18) Google Scholar reported that 2-deoxy-d-glucose, an ER stress inducer, caused dedifferentiation of articular chondrocytes through the β-catenin pathway. They found that this effect was ascribed to accumulation of β-catenin via posttranslational modification. Another possibility is alteration in the TGF-β signaling. In the maintenance of differentiated chondrocytes, the TGF-β signal plays an important role.24Baugé C. Duval E. Ollitrault D. Girard N. Leclercq S. Galéra P. Boumédiene K. Type II TGF-β receptor modulates chondrocyte phenotype.Age (Dordr). 2013; 35: 1105-1116Crossref PubMed Scopus (23) Google Scholar In age-related damage of cartilage, dedifferentiation of chondrocytes is observed. Some report provided evidence for down-regulation of TGF-βs and TGF-β receptors in cartilage of old mice.25Blaney Davidson E.N. Scharstuhl A. Vitters E.L. van der Kraan P.M. van den Berg W.B. Reduced transforming growth factor-β signaling in cartilage of old mice: role in impaired repair capacity.Arthritis Res Ther. 2005; 7: R1338-R1347Crossref PubMed Google Scholar Baugé et al24Baugé C. Duval E. Ollitrault D. Girard N. Leclercq S. Galéra P. Boumédiene K. Type II TGF-β receptor modulates chondrocyte phenotype.Age (Dordr). 2013; 35: 1105-1116Crossref PubMed Scopus (23) Google Scholar reported that chondrocyte dedifferentiation in vitro was associated with a decrease in the TGF-β type II receptor level, and overexpression of the receptor in dedifferentiated chondrocytes restored expression of aggrecan and type II collagen. Similarly, Zhang et al26Zhang F. Yao Y. Su K. Pang P.X. Zhou R. Wang Y. Wang D.A. Redifferentiation of dedifferentiated chondrocytes by adenoviral vector-mediated TGF-β3 and collagen-1 silencing shRNA in 3D culture.Ann Biomed Eng. 2011; 39: 3042-3054Crossref PubMed Scopus (14) Google Scholar reported that overexpression of TGF-β3 facilitated redifferentiation of dedifferentiated chondrocytes in vitro. As described later, ER stress has the potential to affect TGF-β signaling either positively or negatively. For example, in mesangial cells, sustained ER stress suppresses TGF-β signaling via down-regulation of Smads.27Johno H. Nakajima S. Kato H. Yao J. Paton A.W. Paton J.C. Katoh R. Shimizu F. Kitamura M. Unfolded protein response causes a phenotypic shift of inflamed glomerular cells towards redifferentiation through dual blockade of Akt and Smad signaling pathways.Am J Pathol. 2012; 181: 1977-1990Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Blockade of the TGF-β signaling might cause dedifferentiation of chondrocytes by the UPR. The pulmonary alveolar wall consists of three major cell types: type I, squamous alveolar epithelial cells that form the primary structure of an alveolar wall; type II, great alveolar epithelial cells that secrete pulmonary surfactant; and type III, macrophages that destroy foreign materials such as bacteria. Previous investigations suggested a role of EMT in the pathogenesis of tissue fibrosis, including lung fibrosis.28Kim K.K. Kugler M.C. Wolters P.J. Robillard L. Galvez M.G. Brumwell A.N. Sheppard D. Chapman H.A. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix.Proc Natl Acad Sci U S A. 2006; 103: 13180-13185Crossref PubMed Scopus (1066) Google Scholar EMT contributes to generation of the fibroblast population in pulmonary fibrosis, and myofibroblasts, the key effector cells, have arisen from alveolar epithelial cells.29Willis B.C. duBois R.M. Borok Z. Epithelial origin of myofibroblasts during fibrosis in the lung.Proc Am Thorac Soc. 2006; 3: 377-382Crossref PubMed Scopus (419) Google Scholar In sporadic idiopathic pulmonary fibrosis, ER stress and EMT are concurrently induced in type II alveolar cells.15Korfei M. Ruppert C. Mahavadi P. Henneke I. Markart P. Koch M. Lang G. Fink L. Bohle R.M. Seeger W. Weaver T.E. Guenther A. Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2008; 178: 838-846Crossref PubMed Scopus (411) Google Scholar, 16Kage H. Borok Z. EMT and interstitial lung disease: a mysterious relationship.Curr Opin Pulm Med. 2012; 18: 517-523PubMed Google Scholar In vivo induction of ER stress and EMT in type II alveolar cells is also reported in bleomycin-induced pulmonary fibrosis.17Zhong Q. Zhou B. Ann D.K. Minoo P. Liu Y. Banfalvi A. Krishnaveni M.S. Dubourd M. Demaio L. Willis B.C. Kim K.J. duBois R.M. Crandall E.D. Beers M.F. Borok Z. Role of endoplasmic reticulum stress in epithelial-mesenchymal transition of alveolar epithelial cells: effects of misfolded surfactant protein.Am J Respir Cell Mol Biol. 2011; 45: 498-509Crossref PubMed Scopus (160) Google Scholar, 18Tanjore H. Xu X.C. Polosukhin V.V. Degryse A.L. Li B. Han W. Sherrill T.P. Plieth D. Neilson E.G. Blackwell T.S. Lawson W.E. Contribution of epithelial-derived fibroblasts to bleomycin-induced lung fibrosis.Am J Respir Crit Care Med. 2009; 180: 657-665Crossref PubMed Scopus (337) Google Scholar Zhong et al17Zhong Q. Zhou B. Ann D.K. Minoo P. Liu Y. Banfalvi A. Krishnaveni M.S. Dubourd M. Demaio L. Willis B.C. Kim K.J. duBois R.M. Crandall E.D. Beers M.F. Borok Z. Role of endoplasmic reticulum stress in epithelial-mesenchymal transition of alveolar epithelial cells: effects of misfolded surfactant protein.Am J Respir Cell Mol Biol. 2011; 45: 498-509Crossref PubMed Scopus (160) Google Scholar have found that ER stress induced by thapsigargin or tunicamycin decreased expression of epithelial markers, E-cadherin, and zonula occludens protein 1 (ZO-1), whereas induced a myofibroblast marker, α-smooth muscle actin (α-SMA), and fibroblast-like morphology in type II alveolar epithelial cells. Similar results were also reported by other investigators. Tanjore et al30Tanjore H. Cheng D.S. Degryse A.L. Zoz D.F. Abdolrasulnia R. Lawson W.E. Blackwell T.S. Alveolar epithelial cells undergo epithelial-to-mesenchymal transition in response to endoplasmic reticulum stress.J Biol Chem. 2011; 286: 30972-30980Crossref PubMed Scopus (190) Google Scholar found that treatment with tunicamycin induced a fibroblast-like appearance in alveolar epithelial cells. During ER stress, expression of epithelial markers E-cadherin and ZO-1 was depressed, whereas expression of mesenchymal markers increased. They also found that after induction of ER stress, activation of Smad and Src pathways was observed, and that combinational inhibition of Smad2/3 and Src kinase blocked EMT, which was evidenced by maintenance of epithelial appearance and epithelial marker expression. These results suggest that the UPR induces EMT, a dedifferentiation process, in lung epithelial cells and that the generated fibroblasts contribute to pulmonary fibrosis. Thyroid epithelial cells (also called follicular cells or principal cells) are cells in the thyroid gland responsible for the production and secretion of thyroid hormones. Differentiation of thyroid epithelial cells is accompanied by synthesis and secretion of thyroglobulin, a thyroid hormone precursor, and expression of major ER chaperones, including GRP78 and GRP94.31Endo T. Shimura H. Saito T. Ikeda M. Ohmori M. Onaya T. Thyrotropin st
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