Developmental Regulation of FKBP65

FKBP65 (65-kDa FK506-binding protein) is a member of the highly conserved family of intracellular receptors called immunophilins. All have the property of peptidyl-prolyl cis-trans isomerization, and most have been implicated in folding and trafficking events. In an earlier study, we identified that FKBP65 associates with the extracellular matrix protein tropoelastin during its transport through the cell. In the present study, we have carried out a detailed investigation of the subcellular localization of FKBP65 and its relationship to tropoelastin. Using subcellular fractionation, Triton X-114 phase separation, protease protection assays, and immunofluorescence microscopy (IF), we have identified that FKBP65 is contained within the lumen of the endoplasmic reticulum (ER). Subsequent IF studies colocalized FKBP65 with tropoelastin and showed that the two proteins dissociate before reaching the Golgi apparatus. Immunohistochemical localization of FKBP65 in developing lung showed strong staining of vascular and airway smooth muscle cells. Similar areas stained positive for the presence of elastic fibers in the extracellular matrix. The expression of FKBP65 was investigated during development as tropoelastin is not expressed in adult tissues. Tissue-specific expression of FKBP65 was observed in 12-d old mouse tissues; however, the pattern of expression of FKBP65 was not restricted to those tissues expressing tropoelastin. This suggests that additional ligands for FKBP65 likely exist within the ER. Remarkably, in the adult tissues examined, FKBP65 expression was absent or barely detectable. Taken together, these results support an ER-localized FKBP65-tropoelastin interaction that occurs specifically during growth and development of tissues.

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Matrilin-2 Is a Widely Distributed Extracellular Matrix Protein and a Potential Biomarker in the Early Stage of Osteoarthritis in Articular Cartilage

BioMed Research International ◽

10.1155/2014/986127 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 4

Author(s):

Shukun Zhang ◽

Jinwu Peng ◽

Yan Guo ◽

Sara Javidiparsijani ◽

Guirong Wang ◽

...

Keyword(s):

Extracellular Matrix ◽

Articular Cartilage ◽

Epithelial Cells ◽

Matrix Protein ◽

Early Stage ◽

Extracellular Matrix Protein ◽

Corpus Spongiosum ◽

Tracheal Cartilage ◽

Potential Biomarker ◽

Mouse Tissues

In this study, we first generated and characterized a polyclonal antibody against unique domain of matrlin-2 and then used this specific antibody to assess the expression pattern of matrilin-2 by immunohistochemistry. We found that marilin-2 is widely distributed in the connective tissues of many mouse tissues including heart, colon, penis, esophagus, lung, kidney, tracheal cartilage, developmental bone, and adult bone. The expression level of matrilin-2 was remarkably increased in the tissues of osteoarthritis developmental articular cartilage, compared to normal healthy tissues. Furthermore, we determined matrilin-2 expression in specific epithelial cells in stomach and ductal epithelial cells of salivary gland. In other tissues, the positive signals were mainly located around cardiac muscle cells and Purkinje fibers in the heart; corpus spongiosum in the penis; submucosa in the colon and esophagus; extracellular matrix of cartilage in the tracheal cartilage; and, glomerulus, the basement membrane of distal convoluted tubule and renal matrix in kidney. These observations indicated that the distribution pattern of matrilin-2 is heterogeneous in each tissue. Matrilin-2 may play an important role in the communication of matrix to matrix and matrix to cells and will be used as a potential biomarker in the early stage of osteoarthritis of articular cartilage.

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Efemp1 modulates elastic fiber formation and mechanics of the extrahepatic bile duct

10.1101/2021.12.05.471313 ◽

2021 ◽

Author(s):

Jessica Llewellyn ◽

Emilia Roberts ◽

Chengyang Liu ◽

Ali Naji ◽

Richard K. Assoian ◽

...

Keyword(s):

Extracellular Matrix ◽

Bile Duct ◽

Biliary Atresia ◽

Bile Ducts ◽

Matrix Protein ◽

Extrahepatic Bile Duct ◽

Fiber Formation ◽

Extracellular Matrix Protein ◽

Elastic Fibers ◽

Extrahepatic Bile Ducts

AbstractEGF-Containing Fibulin Extracellular Matrix Protein 1 (EFEMP1, also called fibulin 3) is an extracellular matrix protein linked in a genome-wide association study to biliary atresia, a fibro-inflammatory disease of the neonatal extrahepatic bile duct. EFEMP1 is expressed in most tissues and Efemp1 null mice have decreased elastic fibers in visceral fascia; however, in contrast to other short fibulins (fibulins 4 and 5), EFEMP1 does not have a role in the development of large elastic fibers, and its overall function remains unclear. We demonstrated that EFEMP1 is expressed in the submucosa of both neonatal and adult mouse and human extrahepatic bile ducts and that, in adult Efemp1+/- mice, elastin organization into fibers is decreased. We used pressure myography, a technique developed to study the mechanics of the vasculature, to show that Efemp1+/- extrahepatic bile ducts are more compliant to luminal pressure, leading to increased circumferential stretch. We conclude that EFEMP1 has an important role in the formation of elastic fibers and mechanical properties of the extrahepatic bile duct. These data suggest that altered expression of EFEMP1 in the extrahepatic bile duct leads to an abnormal response to mechanical stress such as obstruction, potentially explaining the role of EFEMP1 in biliary atresia.

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Role of LTBP4 in alveolarization, angiogenesis, and fibrosis in lungs

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00031.2017 ◽

2017 ◽

Vol 313 (4) ◽

pp. L687-L698 ◽

Cited By ~ 8

Author(s):

Insa Bultmann-Mellin ◽

Katharina Dinger ◽

Carolin Debuschewitz ◽

Katharina M. A. Loewe ◽

Yvonne Melcher ◽

...

Keyword(s):

Extracellular Matrix ◽

Matrix Protein ◽

Transforming Growth Factor ◽

Elastic Fiber ◽

Transforming Growth Factor Β ◽

Matrix Proteins ◽

Extracellular Matrix Protein ◽

Elastic Fibers ◽

Fiber Network

Deficiency of the extracellular matrix protein latent transforming growth factor-β (TGF-β)-binding protein-4 (LTBP4) results in lack of intact elastic fibers, which leads to disturbed pulmonary development and lack of normal alveolarization in humans and mice. Formation of alveoli and alveolar septation in pulmonary development requires the concerted interaction of extracellular matrix proteins, growth factors such as TGF-β, fibroblasts, and myofibroblasts to promote elastogenesis as well as vascular formation in the alveolar septae. To investigate the role of LTBP4 in this context, lungs of LTBP4-deficient ( Ltbp4−/−) mice were analyzed in close detail. We elucidate the role of LTBP4 in pulmonary alveolarization and show that three different, interacting mechanisms might contribute to alveolar septation defects in Ltbp4−/− lungs: 1) absence of an intact elastic fiber network, 2) reduced angiogenesis, and 3) upregulation of TGF-β activity resulting in profibrotic processes in the lung.

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Immunohistochemical localization of a tenascin-like extracellular matrix protein in sea urchin embryos

Roux s Archives of Developmental Biology ◽

10.1007/bf01681490 ◽

1990 ◽

Vol 199 (3) ◽

pp. 169-173 ◽

Cited By ~ 6

Author(s):

John A. Anstrom ◽

Eleanor J. Mackie ◽

Richard P. Tucker

Keyword(s):

Extracellular Matrix ◽

Sea Urchin ◽

Matrix Protein ◽

Immunohistochemical Localization ◽

Extracellular Matrix Protein ◽

Sea Urchin Embryos

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TNFSF14, a novel target of miR‐326, facilitates airway remodeling in airway smooth muscle cells via inducing extracellular matrix protein deposition and proliferation

The Kaohsiung Journal of Medical Sciences ◽

10.1002/kjm2.12197 ◽

2020 ◽

Vol 36 (7) ◽

pp. 508-514

Author(s):

Hui Zhang ◽

Huan‐Li Yan ◽

Xiang‐Yu Li ◽

Yi‐Nan Guo

Keyword(s):

Extracellular Matrix ◽

Smooth Muscle ◽

Smooth Muscle Cells ◽

Airway Smooth Muscle ◽

Matrix Protein ◽

Airway Remodeling ◽

Extracellular Matrix Protein ◽

Airway Smooth Muscle Cells ◽

Protein Deposition ◽

Novel Target

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Fibroblast-to-myofibroblast transition in bronchial asthma

Cellular and Molecular Life Sciences ◽

10.1007/s00018-018-2899-4 ◽

2018 ◽

Vol 75 (21) ◽

pp. 3943-3961 ◽

Cited By ~ 18

Author(s):

Marta Michalik ◽

Katarzyna Wójcik-Pszczoła ◽

Milena Paw ◽

Dawid Wnuk ◽

Paulina Koczurkiewicz ◽

...

Keyword(s):

Extracellular Matrix ◽

Bronchial Asthma ◽

Significant Role ◽

Matrix Protein ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Chronic Inflammatory Disease ◽

Extracellular Matrix Protein ◽

Airway Smooth Muscle Cells ◽

Factors Affecting

Abstract Bronchial asthma is a chronic inflammatory disease in which bronchial wall remodelling plays a significant role. This phenomenon is related to enhanced proliferation of airway smooth muscle cells, elevated extracellular matrix protein secretion and an increased number of myofibroblasts. Phenotypic fibroblast-to-myofibroblast transition represents one of the primary mechanisms by which myofibroblasts arise in fibrotic lung tissue. Fibroblast-to-myofibroblast transition requires a combination of several types of factors, the most important of which are divided into humoural and mechanical factors, as well as certain extracellular matrix proteins. Despite intensive research on the nature of this process, its underlying mechanisms during bronchial airway wall remodelling in asthma are not yet fully clarified. This review focuses on what is known about the nature of fibroblast-to-myofibroblast transition in asthma. We aim to consider possible mechanisms and conditions that may play an important role in fibroblast-to-myofibroblast transition but have not yet been discussed in this context. Recent studies have shown that some inherent and previously undescribed features of fibroblasts can also play a significant role in fibroblast-to-myofibroblast transition. Differences observed between asthmatic and non-asthmatic bronchial fibroblasts (e.g., response to transforming growth factor β, cell shape, elasticity, and protein expression profile) may have a crucial influence on this phenomenon. An accurate understanding and recognition of all factors affecting fibroblast-to-myofibroblast transition might provide an opportunity to discover efficient methods of counteracting this phenomenon.

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Perinatal Lethality and Endothelial Cell Abnormalities in Several Vessel Compartments of Fibulin-1-Deficient Mice

Molecular and Cellular Biology ◽

10.1128/mcb.21.20.7025-7034.2001 ◽

2001 ◽

Vol 21 (20) ◽

pp. 7025-7034 ◽

Cited By ~ 112

Author(s):

Günter Kostka ◽

Richard Giltay ◽

Wilhelm Bloch ◽

Klaus Addicks ◽

Rupert Timpl ◽

...

Keyword(s):

Extracellular Matrix ◽

Matrix Protein ◽

Early Death ◽

Basement Membranes ◽

Extracellular Matrix Protein ◽

Elastic Fibers ◽

Endothelial Lining ◽

Distinct Component ◽

Lung Inflation ◽

Small Vessels

ABSTRACT The extracellular matrix protein fibulin-1 is a distinct component of vessel walls and can be associated with other ligands present in basement membranes, microfibrils, and elastic fibers. Its biological role was investigated by the targeted inactivation of the fibulin-1 gene in mice. This led to massive hemorrhages in several tissues starting at midgestation, ultimately resulting in the death of almost all homozygous embryos upon birth. Histological analysis demonstrated dilation and ruptures in the endothelial lining of various small vessels but not in that of larger vessels. Kidneys displayed a distinct malformation of glomeruli and disorganization of podocytes. A delayed development of lung alveoli suggested impairment in lung inflation. Immunohistology demonstrated the absence of fibulin-1 in its typical localizations but no aberrant patterns for several other extracellular matrix proteins. Electron microscopy revealed intact basement membranes but very irregular cytoplasmic processes of capillary endothelial cells in the organs that were most severely affected. Absence of fibulin-1 caused considerable blood loss but did not compromise blood clotting. The data indicate a strong but restricted abnormality in some endothelial compartments which, together with some kidney and lung defects, may be responsible for early death.

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Mice lacking the extracellular matrix protein MAGP1 display delayed thrombotic occlusion following vessel injury

Blood ◽

10.1182/blood-2007-07-101733 ◽

2008 ◽

Vol 111 (8) ◽

pp. 4137-4144 ◽

Cited By ~ 28

Author(s):

Claudio C. Werneck ◽

Cristina P. Vicente ◽

Justin S. Weinberg ◽

Adrian Shifren ◽

Richard A. Pierce ◽

...

Keyword(s):

Extracellular Matrix ◽

Von Willebrand Factor ◽

Matrix Protein ◽

Extracellular Matrix Protein ◽

Elastic Fibers ◽

Thrombotic Occlusion ◽

Vessel Injury ◽

Normal Occlusion ◽

Von Willebrand ◽

Willebrand Factor

Abstract Mice lacking the extracellular matrix protein microfibril-associated glycoprotein-1 (MAGP1) display delayed thrombotic occlusion of the carotid artery following injury as well as prolonged bleeding from a tail vein incision. Normal occlusion times were restored when recombinant MAGP1 was infused into deficient animals prior to vessel wounding. Blood coagulation was normal in these animals as assessed by activated partial thromboplastin time and prothrombin time. Platelet number was lower in MAGP1-deficient mice, but the platelets showed normal aggregation properties in response to various agonists. MAGP1 was not found in normal platelets or in the plasma of wild-type mice. In ligand blot assays, MAGP1 bound to fibronectin, fibrinogen, and von Willebrand factor, but von Willebrand factor was the only protein of the 3 that bound to MAGP1 in surface plasmon resonance studies. These findings show that MAGP1, a component of microfibrils and vascular elastic fibers, plays a role in hemostasis and thrombosis.

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Rhinovirus infection induces extracellular matrix protein deposition in asthmatic and nonasthmatic airway smooth muscle cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00411.2010 ◽

2011 ◽

Vol 300 (6) ◽

pp. L951-L957 ◽

Cited By ~ 24

Author(s):

Curtis Kuo ◽

Sam Lim ◽

Nicholas J. C. King ◽

Sebastian L. Johnston ◽

Janette K. Burgess ◽

...

Keyword(s):

Extracellular Matrix ◽

Cell Proliferation ◽

Smooth Muscle ◽

Airway Smooth Muscle ◽

Matrix Protein ◽

Viral Infections ◽

Airway Remodeling ◽

Extracellular Matrix Protein ◽

Airway Smooth Muscle Cells ◽

Increased Risk

Airway remodeling, which includes increases in the extracellular matrix (ECM), is a characteristic feature of asthma and is correlated to disease severity. Rhinovirus (RV) infections are associated with increased risk of asthma development in young children and are the most common cause of asthma exacerbations. We examined whether viral infections can increase ECM deposition and whether this increased ECM modulates cell proliferation and migration. RV infection of nonasthmatic airway smooth muscle (ASM) cells significantly increased the deposition of fibronectin (40% increase, n = 12) and perlecan (80% increase, n = 14), while infection of asthmatic ASM cells significantly increased fibronectin (75% increase, n = 9) and collagen IV (15% increase, n = 9). We then treated the ASM cells with the Toll-like receptor (TLR) agonists polyinosinic:polycytidylic acid, imiquimod, and pure RV RNA and were able to show that the mechanism through which RV induced ECM deposition was via the activation of TLR3 and TLR7/8. Finally, we assessed whether the virus-induced ECM was bioactive by measuring the amount of migration and proliferation of virus-naive cells that seeded onto the ECM. Basically, ECM from asthmatic ASM cells induced twofold greater migration of virus-naive ASM cells than ECM from nonasthmatic ASM cells, and these rates of migration were further increased on RV-modulated ECM. Increased migration on the RV-modulated ECM was not due to increased cell proliferation, as RV-modulated ECM decreased the proliferation of virus-naive cells. Our results suggest that viruses may contribute to airway remodeling through increased ECM deposition, which in turn may contribute to increased ASM mass via increased cell migration.

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