Limits...
Roles of Proteoglycans and Glycosaminoglycans in Wound Healing and Fibrosis.

Ghatak S, Maytin EV, Mack JA, Hascall VC, Atanelishvili I, Moreno Rodriguez R, Markwald RR, Misra S - Int J Cell Biol (2015)

Bottom Line: Fibrosis is a process of dysregulated extracellular matrix (ECM) production that leads to a dense and functionally abnormal connective tissue compartment (dermis).Second, we will discuss the role of proteoglycans and hyaluronan in regulating these processes.Finally, approaches that utilize these concepts as potential therapies for fibrosis are discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.

ABSTRACT
A wound is a type of injury that damages living tissues. In this review, we will be referring mainly to healing responses in the organs including skin and the lungs. Fibrosis is a process of dysregulated extracellular matrix (ECM) production that leads to a dense and functionally abnormal connective tissue compartment (dermis). In tissues such as the skin, the repair of the dermis after wounding requires not only the fibroblasts that produce the ECM molecules, but also the overlying epithelial layer (keratinocytes), the endothelial cells, and smooth muscle cells of the blood vessel and white blood cells such as neutrophils and macrophages, which together orchestrate the cytokine-mediated signaling and paracrine interactions that are required to regulate the proper extent and timing of the repair process. This review will focus on the importance of extracellular molecules in the microenvironment, primarily the proteoglycans and glycosaminoglycan hyaluronan, and their roles in wound healing. First, we will briefly summarize the physiological, cellular, and biochemical elements of wound healing, including the importance of cytokine cross-talk between cell types. Second, we will discuss the role of proteoglycans and hyaluronan in regulating these processes. Finally, approaches that utilize these concepts as potential therapies for fibrosis are discussed.

No MeSH data available.


Related in: MedlinePlus

Structure, binding domains, and interactions of CD44 (Adapted from [7]). The ectodomain of CD44 contains HA-binding motifs and can contain chondroitin sulfate or heparan sulfate chains that can affect its HA-binding capacity and enable its interactions with growth factors and growth factor receptors, and its interaction with matrix metalloproteinases (MMPs). Transmembrane and cytoplasmic domains undergo multiple posttranslational modifications, including palmitoylation and phosphorylation on cysteine and serine residues, respectively, promoting the binding of proteins with crucial functions in cytoskeletal organization and signaling. ErbB2: epidermal growth factor receptor-2; ERM: ezrin–radixin–moesin; FGF: fibroblast growth factor; HGF: hepatocyte growth factor; IQGAP1: IQ motif containing GTPase activating protein 1; MAPK: mitogen-activated protein kinase; PDGFR: platelet-derived growth factor receptor; PI3K: phosphoinositide 3-kinase; TGFR: transforming growth factor receptor; VEGF: vascular endothelial growth factor.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4581578&req=5

fig5: Structure, binding domains, and interactions of CD44 (Adapted from [7]). The ectodomain of CD44 contains HA-binding motifs and can contain chondroitin sulfate or heparan sulfate chains that can affect its HA-binding capacity and enable its interactions with growth factors and growth factor receptors, and its interaction with matrix metalloproteinases (MMPs). Transmembrane and cytoplasmic domains undergo multiple posttranslational modifications, including palmitoylation and phosphorylation on cysteine and serine residues, respectively, promoting the binding of proteins with crucial functions in cytoskeletal organization and signaling. ErbB2: epidermal growth factor receptor-2; ERM: ezrin–radixin–moesin; FGF: fibroblast growth factor; HGF: hepatocyte growth factor; IQGAP1: IQ motif containing GTPase activating protein 1; MAPK: mitogen-activated protein kinase; PDGFR: platelet-derived growth factor receptor; PI3K: phosphoinositide 3-kinase; TGFR: transforming growth factor receptor; VEGF: vascular endothelial growth factor.

Mentions: The constitutive expression of CD44 and HA by a wide variety of cells implies that the interaction between these molecules is regulated. CD44 is the best characterized transmembrane HA receptor and because of its wide distribution it is considered to be the major HA receptor on most cell types [169]. CD44 is a structurally variable and multifunctional cell surface glycoprotein encoded by a single gene [175] (Figure 5). The genomic structure of CD44 consists of 21 exons [175] and the CD44 gene expression varies in size due to insertion of alternatively spliced variable exons derived from exon6–exon14 to form CD44v1–CD44v10 that are located in the membrane-proximal extracellular CD44 domains [176], approximately where N-terminal sequence homology between CD44 molecules from different species ends. The standard CD44 (CD44s) has a molecular weight ~90 kDa and exhibits extensive N-linked and O-linked glycosylation of the extracellular region, emphasizing the glycoprotein nature of CD44. CD44 can be induced to bind HA in cells activated with inflammatory stimuli, including cytokines, such as TNF-α, IL-α, IL-1β, IL-3, granulocyte-macrophage colony stimulating factor (GM-CSH), and interferon-γ (IFNγ) [84, 177, 178]. The molecular mechanisms underlying the induction of CD44-mediated HA binding include increased expression, variable glycosylation, receptor clustering, GAG attachment, phosphorylation, and inclusion of variant exons in the receptor [6, 7, 177, 179–184].


Roles of Proteoglycans and Glycosaminoglycans in Wound Healing and Fibrosis.

Ghatak S, Maytin EV, Mack JA, Hascall VC, Atanelishvili I, Moreno Rodriguez R, Markwald RR, Misra S - Int J Cell Biol (2015)

Structure, binding domains, and interactions of CD44 (Adapted from [7]). The ectodomain of CD44 contains HA-binding motifs and can contain chondroitin sulfate or heparan sulfate chains that can affect its HA-binding capacity and enable its interactions with growth factors and growth factor receptors, and its interaction with matrix metalloproteinases (MMPs). Transmembrane and cytoplasmic domains undergo multiple posttranslational modifications, including palmitoylation and phosphorylation on cysteine and serine residues, respectively, promoting the binding of proteins with crucial functions in cytoskeletal organization and signaling. ErbB2: epidermal growth factor receptor-2; ERM: ezrin–radixin–moesin; FGF: fibroblast growth factor; HGF: hepatocyte growth factor; IQGAP1: IQ motif containing GTPase activating protein 1; MAPK: mitogen-activated protein kinase; PDGFR: platelet-derived growth factor receptor; PI3K: phosphoinositide 3-kinase; TGFR: transforming growth factor receptor; VEGF: vascular endothelial growth factor.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4581578&req=5

fig5: Structure, binding domains, and interactions of CD44 (Adapted from [7]). The ectodomain of CD44 contains HA-binding motifs and can contain chondroitin sulfate or heparan sulfate chains that can affect its HA-binding capacity and enable its interactions with growth factors and growth factor receptors, and its interaction with matrix metalloproteinases (MMPs). Transmembrane and cytoplasmic domains undergo multiple posttranslational modifications, including palmitoylation and phosphorylation on cysteine and serine residues, respectively, promoting the binding of proteins with crucial functions in cytoskeletal organization and signaling. ErbB2: epidermal growth factor receptor-2; ERM: ezrin–radixin–moesin; FGF: fibroblast growth factor; HGF: hepatocyte growth factor; IQGAP1: IQ motif containing GTPase activating protein 1; MAPK: mitogen-activated protein kinase; PDGFR: platelet-derived growth factor receptor; PI3K: phosphoinositide 3-kinase; TGFR: transforming growth factor receptor; VEGF: vascular endothelial growth factor.
Mentions: The constitutive expression of CD44 and HA by a wide variety of cells implies that the interaction between these molecules is regulated. CD44 is the best characterized transmembrane HA receptor and because of its wide distribution it is considered to be the major HA receptor on most cell types [169]. CD44 is a structurally variable and multifunctional cell surface glycoprotein encoded by a single gene [175] (Figure 5). The genomic structure of CD44 consists of 21 exons [175] and the CD44 gene expression varies in size due to insertion of alternatively spliced variable exons derived from exon6–exon14 to form CD44v1–CD44v10 that are located in the membrane-proximal extracellular CD44 domains [176], approximately where N-terminal sequence homology between CD44 molecules from different species ends. The standard CD44 (CD44s) has a molecular weight ~90 kDa and exhibits extensive N-linked and O-linked glycosylation of the extracellular region, emphasizing the glycoprotein nature of CD44. CD44 can be induced to bind HA in cells activated with inflammatory stimuli, including cytokines, such as TNF-α, IL-α, IL-1β, IL-3, granulocyte-macrophage colony stimulating factor (GM-CSH), and interferon-γ (IFNγ) [84, 177, 178]. The molecular mechanisms underlying the induction of CD44-mediated HA binding include increased expression, variable glycosylation, receptor clustering, GAG attachment, phosphorylation, and inclusion of variant exons in the receptor [6, 7, 177, 179–184].

Bottom Line: Fibrosis is a process of dysregulated extracellular matrix (ECM) production that leads to a dense and functionally abnormal connective tissue compartment (dermis).Second, we will discuss the role of proteoglycans and hyaluronan in regulating these processes.Finally, approaches that utilize these concepts as potential therapies for fibrosis are discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.

ABSTRACT
A wound is a type of injury that damages living tissues. In this review, we will be referring mainly to healing responses in the organs including skin and the lungs. Fibrosis is a process of dysregulated extracellular matrix (ECM) production that leads to a dense and functionally abnormal connective tissue compartment (dermis). In tissues such as the skin, the repair of the dermis after wounding requires not only the fibroblasts that produce the ECM molecules, but also the overlying epithelial layer (keratinocytes), the endothelial cells, and smooth muscle cells of the blood vessel and white blood cells such as neutrophils and macrophages, which together orchestrate the cytokine-mediated signaling and paracrine interactions that are required to regulate the proper extent and timing of the repair process. This review will focus on the importance of extracellular molecules in the microenvironment, primarily the proteoglycans and glycosaminoglycan hyaluronan, and their roles in wound healing. First, we will briefly summarize the physiological, cellular, and biochemical elements of wound healing, including the importance of cytokine cross-talk between cell types. Second, we will discuss the role of proteoglycans and hyaluronan in regulating these processes. Finally, approaches that utilize these concepts as potential therapies for fibrosis are discussed.

No MeSH data available.


Related in: MedlinePlus