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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

Model for catabolism of pericellular hyaluronan glycocalyx matrices (adapted from [86] with the permission from Dr. Hascall).
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4581578&req=5

fig4: Model for catabolism of pericellular hyaluronan glycocalyx matrices (adapted from [86] with the permission from Dr. Hascall).

Mentions: Most cells synthesize HA at some point during their life cycles implicating its function for fundamental biological processes. Unlike all of the sulfated GAGs, biosynthesis of HA does not require a core protein and is not done in the cell's Golgi networks. HA is naturally synthesized by a class of integral membrane proteins called HA synthases, of which vertebrates have three types: HAS1, HAS2, and HAS3 [86–88]. The expression of various HAS isozymes is likely to be a fine control system critical for the effective mediation of different cell behaviors. While HAS1 and HAS2 are able to produce large-sized HA (up to 2000 kDa), HA produced by HAS3 is of a lower molecular mass (100–1000 kDa) [89–91]. HAS2 is dynamically regulated at several levels. For example, a number of studies have defined the details of transcriptional regulation of the HAS2 gene promoter in response to a variety of cytokines and growth factors that are released as a result of wounding [92, 93]. Some of the most dramatic effects of cytokines on HA regulation occur in epidermal keratinocytes of the skin, in which HA production is boosted many-fold by exposure to a variety of growth factors including EGFR [94, 95]. Interestingly, wounding of keratinocytes releases HB-EGF, which itself has been shown to upregulate HA synthesis in neighboring cells [96, 97], an example of the paracrine effects (cell-cell cross-talk) that now appear to have a central role in mechanisms of fibrosis (discussed more below). HAS2 activity can also be governed by posttranslational pathways, such as regulation of O-GlcNAcylation. Once in circulation, HA is very effectively removed by hepatic endothelial cells. This efficient process recovers the sugars by internalization and transport to lysosomes [98]. Most cells do not have this option but do have a metabolically active pericellular matrix (glycocalyx). (Figure 4) For example, keratinocytes catabolize hyaluronan by a mechanism that involves the CD44 HA receptor [86, 99] and a hyaluronidase, most likely GPI-anchored hyaluronidase 2 [100]. The presence of a protease, such as ADAMTS5 (aggrecanase) is likely also involved in order to remove associated proteoglycans (aggrecan and versican) [47]. CD44 rapidly transports (t1/2 of ~15 min) the fragmented HA (20–30 kDa) with any remaining bound proteins into an endosomal compartment distinct from coated pits and pinocytotic uptake pathways. The fragments are then transported to lysosomes for complete degradation (t1/2 of ~3 h) (Figure 4) [86, 99]. Therefore, distinct sites for biosynthesis and catabolism of HA on the surface of cells could effectively cooperate in controlling its dynamic metabolism. The stability of cytosolic HAS2 is significantly increased when serine 221 on Has2 is O-GlcNAcylated [86, 101]. Recent studies from our laboratory indicate that the matricellular protein periostin regulates HAS2 activation at a serine residue in embryonic heart valve remodelling [102]. It is possible that O-GlcNAcylation of this serine is a key for regulating whether or not HAS2 remains inactivated in response to periostin during development of the heart valve [102], which would allow the enzyme to migrate to the cell surface after its synthesis in the ER. There is increasing evidence that phosphorylation of serine and threonine residues in HAS2 to control hyaluronan synthesis whether or not it is activated [86, 103]. The phosphoserine increases when HA synthesis increases and phosphothreonine increases when HA synthesis decreases, as it is expected from the data discussed by Hascall's group [86].


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)

Model for catabolism of pericellular hyaluronan glycocalyx matrices (adapted from [86] with the permission from Dr. Hascall).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: Model for catabolism of pericellular hyaluronan glycocalyx matrices (adapted from [86] with the permission from Dr. Hascall).
Mentions: Most cells synthesize HA at some point during their life cycles implicating its function for fundamental biological processes. Unlike all of the sulfated GAGs, biosynthesis of HA does not require a core protein and is not done in the cell's Golgi networks. HA is naturally synthesized by a class of integral membrane proteins called HA synthases, of which vertebrates have three types: HAS1, HAS2, and HAS3 [86–88]. The expression of various HAS isozymes is likely to be a fine control system critical for the effective mediation of different cell behaviors. While HAS1 and HAS2 are able to produce large-sized HA (up to 2000 kDa), HA produced by HAS3 is of a lower molecular mass (100–1000 kDa) [89–91]. HAS2 is dynamically regulated at several levels. For example, a number of studies have defined the details of transcriptional regulation of the HAS2 gene promoter in response to a variety of cytokines and growth factors that are released as a result of wounding [92, 93]. Some of the most dramatic effects of cytokines on HA regulation occur in epidermal keratinocytes of the skin, in which HA production is boosted many-fold by exposure to a variety of growth factors including EGFR [94, 95]. Interestingly, wounding of keratinocytes releases HB-EGF, which itself has been shown to upregulate HA synthesis in neighboring cells [96, 97], an example of the paracrine effects (cell-cell cross-talk) that now appear to have a central role in mechanisms of fibrosis (discussed more below). HAS2 activity can also be governed by posttranslational pathways, such as regulation of O-GlcNAcylation. Once in circulation, HA is very effectively removed by hepatic endothelial cells. This efficient process recovers the sugars by internalization and transport to lysosomes [98]. Most cells do not have this option but do have a metabolically active pericellular matrix (glycocalyx). (Figure 4) For example, keratinocytes catabolize hyaluronan by a mechanism that involves the CD44 HA receptor [86, 99] and a hyaluronidase, most likely GPI-anchored hyaluronidase 2 [100]. The presence of a protease, such as ADAMTS5 (aggrecanase) is likely also involved in order to remove associated proteoglycans (aggrecan and versican) [47]. CD44 rapidly transports (t1/2 of ~15 min) the fragmented HA (20–30 kDa) with any remaining bound proteins into an endosomal compartment distinct from coated pits and pinocytotic uptake pathways. The fragments are then transported to lysosomes for complete degradation (t1/2 of ~3 h) (Figure 4) [86, 99]. Therefore, distinct sites for biosynthesis and catabolism of HA on the surface of cells could effectively cooperate in controlling its dynamic metabolism. The stability of cytosolic HAS2 is significantly increased when serine 221 on Has2 is O-GlcNAcylated [86, 101]. Recent studies from our laboratory indicate that the matricellular protein periostin regulates HAS2 activation at a serine residue in embryonic heart valve remodelling [102]. It is possible that O-GlcNAcylation of this serine is a key for regulating whether or not HAS2 remains inactivated in response to periostin during development of the heart valve [102], which would allow the enzyme to migrate to the cell surface after its synthesis in the ER. There is increasing evidence that phosphorylation of serine and threonine residues in HAS2 to control hyaluronan synthesis whether or not it is activated [86, 103]. The phosphoserine increases when HA synthesis increases and phosphothreonine increases when HA synthesis decreases, as it is expected from the data discussed by Hascall's group [86].

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