Scleral hypoxia is a target for myopia control

Worldwide, myopia is the leading cause of visual impairment. It results from inappropriate extension of the ocular axis and concomitant declines in scleral strength and thickness caused by extracellular matrix (ECM) remodeling. However, the identities of the initiators and signaling pathways that induce scleral ECM remodeling in myopia are unknown. Here, we used single-cell RNA-sequencing to identify pathways activated in the sclera during myopia development. We found that the hypoxia-signaling, the eIF2-signaling, and mTOR-signaling pathways were activated in murine myopic sclera. Consistent with the role of hypoxic pathways in mouse model of myopia, nearly one third of human myopia risk genes from the genome-wide association study and linkage analyses interact with genes in the hypoxia-inducible factor-1α (HIF-1α)–signaling pathway. Furthermore, experimental myopia selectively induced HIF-1α up-regulation in the myopic sclera of both mice and guinea pigs. Additionally, hypoxia exposure (5% O2) promoted myofibroblast transdifferentiation with down-regulation of type I collagen in human scleral fibroblasts. Importantly, the antihypoxia drugs salidroside and formononetin down-regulated HIF-1α expression as well as the phosphorylation levels of eIF2α and mTOR, slowing experimental myopia progression without affecting normal ocular growth in guinea pigs. Furthermore, eIF2α phosphorylation inhibition suppressed experimental myopia, whereas mTOR phosphorylation induced myopia in normal mice. Collectively, these findings defined an essential role of hypoxia in scleral ECM remodeling and myopia development, suggesting a therapeutic approach to control myopia by ameliorating hypoxia.

Download Full-text

Molecular Signaling Pathways and Essential Metabolic Elements in Bone Remodeling: An Implication of Therapeutic Targets for Bone Diseases

Current Drug Targets ◽

10.2174/1389450121666200910160404 ◽

2020 ◽

Vol 22 (1) ◽

pp. 77-104

Author(s):

Aditi Sharma ◽

Lalit Sharma ◽

Rohit Goyal

Keyword(s):

Signaling Pathways ◽

Type I Collagen ◽

Bone Cells ◽

Bone Remodelling ◽

Cathepsin K ◽

Bone Diseases ◽

Type I ◽

Molecular Signaling ◽

Bone Homeostasis

: Bone is one of the dynamic tissues in the human body that undergoes continuous remodelling through subsequent actions of bone cells, osteoclasts, and osteoblasts. Several signal transduction pathways are involved in the transition of mesenchymal stem cells into osteoblasts. These primarily include Runx2, ATF4, Wnt signaling and sympathetic signalling. The differentiation of osteoclasts is controlled by M-CSF, RANKL, and costimulatory signalling. It is well known that bone remodelling is regulated through receptor activator of nuclear factor-kappa B ligand followed by the binding to RANK, which eventually induces the differentiation of osteoclasts. The resorbing osteoclasts secrete TRAP, cathepsin K, MMP-9 and gelatinase to digest the proteinaceous matrix of type I collagen and form a saucer-shaped lacuna along with resorption tunnels in the trabecular bone. Osteoblasts secrete a soluble decoy receptor, osteoprotegerin that prevents the binding of RANK/RANKL and thus moderating osteoclastogenesis. Moreover, bone homeostasis is also regulated by several growth factors, cytokines, calciotropic hormones, parathyroid hormone and sex steroids. The current review presents a correlation of the probable molecular targets underlying the regulation of bone mass and the role of essential metabolic elements in bone remodelling. Targeting these signaling pathways may help design newer therapies for treating bone diseases.

Download Full-text

Faculty Opinions recommendation of Pivotal role of connective tissue growth factor in lung fibrosis: MAPK-dependent transcriptional activation of type I collagen.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717970990.793469383 ◽

2013 ◽

Author(s):

Achsah Keegan

Keyword(s):

Growth Factor ◽

Connective Tissue ◽

Connective Tissue Growth Factor ◽

Transcriptional Activation ◽

Lung Fibrosis ◽

Type I Collagen ◽

Tissue Growth ◽

Pivotal Role ◽

Type I

Download Full-text

Hyperactivation of RAP1 and JAK/STAT Signaling Pathways Contributes to Fibrosis during the Formation of Nasal Capsular Contraction

European Surgical Research ◽

10.1159/000513780 ◽

2021 ◽

pp. 1-12

Author(s):

Meng Wu ◽

Ming Li ◽

Hong-Ju Xie ◽

Hong-Wei Liu

Keyword(s):

Signaling Pathways ◽

Type I Collagen ◽

Ex Vivo ◽

Capsular Contracture ◽

Silicone Implant ◽

Type I ◽

Loss Of Function ◽

Sequencing Data ◽

Functional Changes ◽

Stat Signaling

Silicone implant-based augmentation rhinoplasty or mammoplasty induces capsular contracture, which has been acknowledged as a process that develops an abnormal fibrotic capsule associated with the immune response to allogeneic materials. However, the signaling pathways leading to the nasal fibrosis remain poorly investigated. We aimed to explore the molecular mechanism underlying the pathogenesis of nasal capsular contracture, with a specific research interest in the signaling pathways involved in fibrotic development at the advanced stage of contracture. By examining our recently obtained RNA sequencing data and global gene expression profiling between grade II and grade IV nasal capsular tissues, we found that both the RAP1 and JAK/STAT signaling pathways were hyperactive in the contracted capsules. This was verified on quantitative real-time PCR which demonstrated upregulation of most of the representative component signatures in these pathways. Loss-of-function assays through siRNA-mediated Rap1 silencing and/or small molecule-directed inhibition of JAK/STAT pathway in ex vivo primary nasal fibroblasts caused a series of dramatic behavioral and functional changes, including decreased cell viability, increased apoptosis, reduced secretion of proinflammatory cytokines, and synthesis of type I collagen, compared to control cells, and indicating the essential role of the RAP1 and JAK/STAT signaling pathways in nasal capsular fibrosis. Our results sheds light on targeting downstream signaling pathways for the prevention and therapy of silicone implant-induced nasal capsular contracture.

Download Full-text

The Dynamic Interaction between Extracellular Matrix Remodeling and Breast Tumor Progression

Cells ◽

10.3390/cells10051046 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1046

Author(s):

Jorge Martinez ◽

Patricio C. Smith

Keyword(s):

Extracellular Matrix ◽

Type I Collagen ◽

Cell Metabolism ◽

Breast Tumors ◽

Extracellular Matrix Remodeling ◽

Type I ◽

Matrix Remodeling ◽

Desmoplastic Reaction ◽

The Impact

Desmoplastic tumors correspond to a unique tissue structure characterized by the abnormal deposition of extracellular matrix. Breast tumors are a typical example of this type of lesion, a property that allows its palpation and early detection. Fibrillar type I collagen is a major component of tumor desmoplasia and its accumulation is causally linked to tumor cell survival and metastasis. For many years, the desmoplastic phenomenon was considered to be a reaction and response of the host tissue against tumor cells and, accordingly, designated as “desmoplastic reaction”. This notion has been challenged in the last decades when desmoplastic tissue was detected in breast tissue in the absence of tumor. This finding suggests that desmoplasia is a preexisting condition that stimulates the development of a malignant phenotype. With this perspective, in the present review, we analyze the role of extracellular matrix remodeling in the development of the desmoplastic response. Importantly, during the discussion, we also analyze the impact of obesity and cell metabolism as critical drivers of tissue remodeling during the development of desmoplasia. New knowledge derived from the dynamic remodeling of the extracellular matrix may lead to novel targets of interest for early diagnosis or therapy in the context of breast tumors.

Download Full-text

Type I collagen from sea cucumber (Stichopus japonicus) and the role of matrix metalloproteinase-2 in autolysis

Food Bioscience ◽

10.1016/j.fbio.2021.100959 ◽

2021 ◽

Vol 41 ◽

pp. 100959

Author(s):

Long-Jie Yan ◽

Le-Chang Sun ◽

Kai-Yuan Cao ◽

Yu-Lei Chen ◽

Ling-Jing Zhang ◽

...

Keyword(s):

Matrix Metalloproteinase ◽

Sea Cucumber ◽

Type I Collagen ◽

Matrix Metalloproteinase 2 ◽

Type I ◽

Stichopus Japonicus

Download Full-text

Role of the amino-terminal extrahelical region of type I collagen in directing the 4D overlap in fibrillogenesis

Biopolymers ◽

10.1002/bip.1979.360181208 ◽

1979 ◽

Vol 18 (12) ◽

pp. 3005-3014 ◽

Cited By ~ 93

Author(s):

Donald L. Helseth ◽

Joseph H. Lechner ◽

Arthur Veis

Keyword(s):

Type I Collagen ◽

Type I ◽

Amino Terminal

Download Full-text

Carotid intima-media thickness and bone turnover: the role of C-terminal telopeptide of type I collagen

Internal and Emergency Medicine ◽

10.1007/s11739-010-0356-y ◽

2010 ◽

Vol 5 (2) ◽

pp. 127-134 ◽

Cited By ~ 7

Author(s):

Christian Leli ◽

Leonella Pasqualini ◽

Gaetano Vaudo ◽

Stefano Gaggioli ◽

Anna Maria Scarponi ◽

...

Keyword(s):

Bone Turnover ◽

Type I Collagen ◽

Intima Media Thickness ◽

Carotid Intima Media Thickness ◽

Type I ◽

Media Thickness

Download Full-text

Tissue inhibitor of metalloproteinases (TIMP) regulates extracellular type I collagen degradation by chondrocytes and endothelial cells

Journal of Cell Science ◽

10.1242/jcs.87.2.357 ◽

1987 ◽

Vol 87 (2) ◽

pp. 357-362

Author(s):

J. Gavrilovic ◽

R.M. Hembry ◽

J.J. Reynolds ◽

G. Murphy

Keyword(s):

Endothelial Cells ◽

Type I Collagen ◽

Model System ◽

Collagen Degradation ◽

Type I ◽

Tissue Inhibitor Of Metalloproteinases ◽

Regulatory Factor ◽

Tissue Inhibitor ◽

Cells Cultured

A specific antiserum to purified rabbit tissue inhibitor of metalloproteinases (TIMP) was raised in sheep, characterized and used to investigate the role of TIMP in a model system. Chondrocytes and endothelial cells cultured on 14C-labelled type I collagen films and stimulated to produce collagenase were unable to degrade the films unless the anti-TIMP antibody was added. The degradation induced was inhibited by a specific anti-rabbit collagenase antibody. It was concluded that TIMP is a major regulatory factor in cell-mediated collagen degradation.

Download Full-text

Fibrillar type I collagens enhance platelet-dependent thrombin generation via glycoprotein VI with direct support of α2β1 but not αIIbβ3 integrin

Thrombosis and Haemostasis ◽

10.1160/th04-12-0783 ◽

2005 ◽

Vol 94 (07) ◽

pp. 107-114 ◽

Cited By ~ 21

Author(s):

Christelle Lecut ◽

Martine Jandrot-Perrus ◽

Marion A. H. Feijge ◽

Judith M. E. M. Cosemans ◽

Johan W. M. Heemskerk

Keyword(s):

Thrombin Generation ◽

Type I Collagen ◽

Platelet Rich Plasma ◽

Procoagulant Activity ◽

Type I ◽

Platelet Surface ◽

Glycoprotein Vi ◽

Collagen Receptors ◽

Fibrillar Collagens

SummaryThe role of collagens and collagen receptors was investigated in stimulating platelet-dependent thrombin generation. Fibrillar type-I collagens, including collagen from human heart, were most potent in enhancing thrombin generation, in a way dependent on exposure of phosphatidylserine (PS) at the platelet surface. Soluble, non-fibrillar type-I collagen required pre-activation of integrin α2β1 with Mn2+ for enhancement of thrombin generation. With all preparations, blocking of glycoprotein VI (GPVI) with 9O12 antibody abrogated the collagen-enhanced thrombin generation, regardless of the α2β1 activation state. Blockade of α2β1 alone or antagonism of autocrine thromboxane A2 and ADP were less effective. Blockade of αIIbβ3 with abciximab suppressed thrombin generation in platelet-rich plasma, but this did not abolish the enhancing effect of collagens. The high activity of type-I fibrillar collagens in stimulating GPVI-dependent procoagulant activity was confirmed in whole-blood flow studies, showing that these collagens induced relatively high expression of PS. Together, these results indicate that: i) fibrillar type-I collagen greatly enhances thrombin generation, ii) GPVI-induced platelet activation is principally responsible for the procoagulant activity of fibrillar and non-fibrillar collagens, iii) α2β1 and signaling via autocrine mediators facilitate and amplify this GPVI activity, and iv) αIIbβ3 is not directly involved in the collagen effect.

Download Full-text