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Hyaluronan's Role in Fibrosis: A Pathogenic Factor or a Passive Player?

Albeiroti S, Soroosh A, de la Motte CA - Biomed Res Int (2015)

Bottom Line: Excessive deposition of extracellular matrix (ECM) molecules is characteristic of most fibrotic tissues.Aside from its role as a hydrating, space filling polymer, HA regulates different cellular functions and is known to have a role in wound healing and inflammation.Importantly, HA deposition is increased in multiple fibrotic diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiology, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

ABSTRACT
Fibrosis is a debilitating condition that can lead to impairment of the affected organ's function. Excessive deposition of extracellular matrix (ECM) molecules is characteristic of most fibrotic tissues. Fibroblasts activated by cytokines or growth factors differentiate into myofibroblasts that drive fibrosis by depositing ECM molecules, such as collagen, fibronectin, and connective tissue growth factor. Transforming growth factor-β (TGF-β) is one of the major profibrotic cytokines which promotes fibrosis by signaling abnormal ECM regulation. Hyaluronan (HA) is a major ECM glycosaminoglycan that is regulated by TGF-β and whose role in fibrosis is emerging. Aside from its role as a hydrating, space filling polymer, HA regulates different cellular functions and is known to have a role in wound healing and inflammation. Importantly, HA deposition is increased in multiple fibrotic diseases. In this review we highlight studies that link HA to fibrosis and discuss what is known about the role of HA, its receptors, and its anabolic and catabolic enzymes in different fibrotic diseases.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of a currently accepted model for cell-mediated HA degradation. Catabolism of HA starts at the cell surface. CD44 binds HA extracellularly and facilitates its degradation by HYAL2. The degradation products (now in the range of 20-kDa polymers) are internalized into endosomes and then transported into the lysosomes where they get further degraded by HYAL1 into tetrasaccharides. N-acetyl glucosaminidase and glucuronidase enzymes then further degrade HA into monosaccharides. “Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2015. All Rights Reserved”.
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Related In: Results  -  Collection


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fig1: Schematic representation of a currently accepted model for cell-mediated HA degradation. Catabolism of HA starts at the cell surface. CD44 binds HA extracellularly and facilitates its degradation by HYAL2. The degradation products (now in the range of 20-kDa polymers) are internalized into endosomes and then transported into the lysosomes where they get further degraded by HYAL1 into tetrasaccharides. N-acetyl glucosaminidase and glucuronidase enzymes then further degrade HA into monosaccharides. “Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2015. All Rights Reserved”.

Mentions: Under many conditions, HA exists in the body bound to one of its protein partners, such as CD44, versican, and aggrecan [25]. CD44 is ubiquitously expressed glycoprotein present on most mammalian cells and is considered the major cell surface receptor for HA. The interaction between CD44's cytoplasmic tail with many intracellular proteins, including kinases and cytoskeletal components, allows for HA to exert a wide range of different cell regulatory functions [26]. CD44 also has a role in HA catabolism by assisting HA-degrading enzymes. Catabolism of HA in humans occurs by endo-β-N-acetylhexosaminidase enzymes known as hyaluronidases (HYALs). Out of the six discovered HYAL enzymes, HYAL1 and HYAL2 are the only somatically active HA degrading enzymes in humans [27, 28] (Figure 1). HYAL1 was identified as an acid-active enzyme in serum in 1967 by De Salegui et al. and later confirmed to be a lysosomal enzyme [29, 30]. On the other hand, HYAL2, also an acid-active enzyme, is a glycosylphosphatidylinositol- (GPI-) anchored cell-surface protein [31]. The turnover of HA occurs rapidly in the body. HA is present normally in high amounts in multiple tissues and fluids of the body, including the joints, the eye vitreous, the umbilical cord, and amniotic fluid. High levels of HA are also present in proliferating tissues and tissues undergoing repair. As a result, the rapid catabolism of HA, through the activity of HYAL enzymes, represents a major mechanism by which HA levels are regulated in the body [32]. Studies have shown that HA degradation is dependent upon the classical HA binding receptor CD44 and involves mainly HYAL1 and HYAL2 [33, 34]. In addition to the enzymatic processes that cleave HA, HA can be degraded by oxidation reactions; particularly, reactive oxygen species (ROS) and free radicals are known to degrade HA polymers [35].


Hyaluronan's Role in Fibrosis: A Pathogenic Factor or a Passive Player?

Albeiroti S, Soroosh A, de la Motte CA - Biomed Res Int (2015)

Schematic representation of a currently accepted model for cell-mediated HA degradation. Catabolism of HA starts at the cell surface. CD44 binds HA extracellularly and facilitates its degradation by HYAL2. The degradation products (now in the range of 20-kDa polymers) are internalized into endosomes and then transported into the lysosomes where they get further degraded by HYAL1 into tetrasaccharides. N-acetyl glucosaminidase and glucuronidase enzymes then further degrade HA into monosaccharides. “Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2015. All Rights Reserved”.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4637089&req=5

fig1: Schematic representation of a currently accepted model for cell-mediated HA degradation. Catabolism of HA starts at the cell surface. CD44 binds HA extracellularly and facilitates its degradation by HYAL2. The degradation products (now in the range of 20-kDa polymers) are internalized into endosomes and then transported into the lysosomes where they get further degraded by HYAL1 into tetrasaccharides. N-acetyl glucosaminidase and glucuronidase enzymes then further degrade HA into monosaccharides. “Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2015. All Rights Reserved”.
Mentions: Under many conditions, HA exists in the body bound to one of its protein partners, such as CD44, versican, and aggrecan [25]. CD44 is ubiquitously expressed glycoprotein present on most mammalian cells and is considered the major cell surface receptor for HA. The interaction between CD44's cytoplasmic tail with many intracellular proteins, including kinases and cytoskeletal components, allows for HA to exert a wide range of different cell regulatory functions [26]. CD44 also has a role in HA catabolism by assisting HA-degrading enzymes. Catabolism of HA in humans occurs by endo-β-N-acetylhexosaminidase enzymes known as hyaluronidases (HYALs). Out of the six discovered HYAL enzymes, HYAL1 and HYAL2 are the only somatically active HA degrading enzymes in humans [27, 28] (Figure 1). HYAL1 was identified as an acid-active enzyme in serum in 1967 by De Salegui et al. and later confirmed to be a lysosomal enzyme [29, 30]. On the other hand, HYAL2, also an acid-active enzyme, is a glycosylphosphatidylinositol- (GPI-) anchored cell-surface protein [31]. The turnover of HA occurs rapidly in the body. HA is present normally in high amounts in multiple tissues and fluids of the body, including the joints, the eye vitreous, the umbilical cord, and amniotic fluid. High levels of HA are also present in proliferating tissues and tissues undergoing repair. As a result, the rapid catabolism of HA, through the activity of HYAL enzymes, represents a major mechanism by which HA levels are regulated in the body [32]. Studies have shown that HA degradation is dependent upon the classical HA binding receptor CD44 and involves mainly HYAL1 and HYAL2 [33, 34]. In addition to the enzymatic processes that cleave HA, HA can be degraded by oxidation reactions; particularly, reactive oxygen species (ROS) and free radicals are known to degrade HA polymers [35].

Bottom Line: Excessive deposition of extracellular matrix (ECM) molecules is characteristic of most fibrotic tissues.Aside from its role as a hydrating, space filling polymer, HA regulates different cellular functions and is known to have a role in wound healing and inflammation.Importantly, HA deposition is increased in multiple fibrotic diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiology, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

ABSTRACT
Fibrosis is a debilitating condition that can lead to impairment of the affected organ's function. Excessive deposition of extracellular matrix (ECM) molecules is characteristic of most fibrotic tissues. Fibroblasts activated by cytokines or growth factors differentiate into myofibroblasts that drive fibrosis by depositing ECM molecules, such as collagen, fibronectin, and connective tissue growth factor. Transforming growth factor-β (TGF-β) is one of the major profibrotic cytokines which promotes fibrosis by signaling abnormal ECM regulation. Hyaluronan (HA) is a major ECM glycosaminoglycan that is regulated by TGF-β and whose role in fibrosis is emerging. Aside from its role as a hydrating, space filling polymer, HA regulates different cellular functions and is known to have a role in wound healing and inflammation. Importantly, HA deposition is increased in multiple fibrotic diseases. In this review we highlight studies that link HA to fibrosis and discuss what is known about the role of HA, its receptors, and its anabolic and catabolic enzymes in different fibrotic diseases.

No MeSH data available.


Related in: MedlinePlus