Hyaluronan Synthase Induction and Hyaluronan Accumulation in Mouse Epidermis Following Skin Injury

Tammi, Raija; Pasonen‐Seppänen, Sanna; Kolehmainen, Elina; Tammi, Markku

doi:10.1111/j.0022-202x.2005.23697.x

Cited by 135 publications

(145 citation statements)

References 36 publications

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“…Detailed information is available on the regulatory pathways of epidermal HA synthesis, 15,35 the function of epidermal HA, 36,37 and the expression of epidermal HA synthases and HA receptors. 12,35 In addition, it has been shown recently that UVA and UVB irradiation decrease epidermal HA and CD44 in mice. 38 In contrast only a few biochemical and histological studies addressed the effect of UV irradiation on HA content of murine and human dermis.…”

Section: Discussionmentioning

confidence: 99%

“…The epidermis of adult mice showed weak HA staining as described earlier. 12 As a specific negative control for the HA staining, hyaluronidase digestion was performed (not shown).…”

Section: Uvb Reduces Dermal Hamentioning

confidence: 99%

“…12 In contrast, in the dermis the regulatory pathways of HA are much less understood. Interestingly, several conditions that accelerate skin aging such as estrogen deficiency 13,14 are associated with loss of HA from the dermis, and treatments that counteract actinic skin aging such as retinoic acid increase dermal HA.…”

mentioning

confidence: 99%

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Chronic Ultraviolet B Irradiation Causes Loss of Hyaluronic Acid from Mouse Dermis Because of Down-Regulation of Hyaluronic Acid Synthases

Dai

Freudenberger

Zipper

et al. 2007

The American Journal of Pathology

142

116

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Remodeling of the dermal extracellular matrix occurs during photoaging. Here, the effect of repetitive UVB irradiation on dermal hyaluronic acid (HA) was examined. C57/BL6 mice were chronically (182 days) irradiated with UVB, and consecutive skin biopsies were collected during the irradiation period and afterward (300 and 400 days of age). UVB caused marked loss of HA from the papillary dermis and down-regulation of HA synthase 1 (HAS1), HAS2, and HAS3 mRNA expression. In contrast, hyaluronidases (HYAL) 1, HYAL2, and HA receptor CD44 were unchanged. Furthermore, transforming growth factor ␤-1 (TGF-␤1) and TGF-␤1-receptor II expression were decreased in UVB-irradiated biopsies, and TGF-␤1 strongly induced HAS1 and HAS2 expression in cultured dermal fibroblasts. Therefore, TGF-␤1 might be one factor involved in UVB-induced down-regulation of HAS enzymes. In addition, total cell number and the percentage of proliferating fibroblasts in the papillary dermis of UVB-irradiated mice were decreased. Down-regulation of HAS2 by lentiviral overexpression of short hairpin RNA in vitro caused inhibition of HA synthesis, DNA synthesis, and migration of dermal fibroblasts. In conclusion, chronic UVB irradiation induces loss of HA from the dermis, thereby contributing to the quiescent phenotype of dermal fibroblasts. 1 Photoaging is the most common form of skin damage caused by chronic, repetitive sun exposure.2 The long-term exposure to solar UV irradiation induces damage to the dermal connective tissue and the extracellular matrix (ECM), which in turn leads to the aged appearance of photodamaged skin. Hallmark of this UV-induced ECM remodeling is the degradation of collagen and elastin through the UVB-induced activation of matrix metalloproteinases and decreased de novo synthesis of collagen. The mechanisms of UVB-induced matrix metalloproteinase activation 3 and inhibition of collagen synthesis have been studied in detail.2 In contrast the effect of UVB on hyaluronic acid (HA), another key component of the dermal ECM, is much less understood, and the underlying mechanisms are primarily unknown. HA is a linear polymer composed of repeating disaccharides (D-glucuronic acid-␤-1,3-N-acetylglucosamine-␤-1,4-) and assembled from the respective activated nucleotide sugars (UDPglucuronic acid, UDP-N-acetylglucosamine) at the inner plasma membrane by HA synthases (HAS). Three different HAS isoforms are known that reside in the plasma membrane and extrude the growing HA polymer into the extracellular space.4 HAS1 and HAS2 produce high molecular mass HA (2 to 4 ϫ 10 6 Da), whereas HAS3 synthesizes smaller HA (0.4 to 2.5 ϫ 10 5 Da). 5 The variation of the MW is the only modification of HA because O-or N-sulfations do not occur. HA is an agonist of CD44 and RHAMM (receptor of HA-mediated motility), which enables HA to initiate specific signaling events.6 This receptor signaling and the formation of pericellular HA coats supports proliferation and migration of a variety of cell types including skin fibroblasts. 7 In addition, antiapoptoti...

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Section: Discussionmentioning

confidence: 99%

“…The epidermis of adult mice showed weak HA staining as described earlier. 12 As a specific negative control for the HA staining, hyaluronidase digestion was performed (not shown).…”

Section: Uvb Reduces Dermal Hamentioning

confidence: 99%

See 1 more Smart Citation

Chronic Ultraviolet B Irradiation Causes Loss of Hyaluronic Acid from Mouse Dermis Because of Down-Regulation of Hyaluronic Acid Synthases

Dai

Freudenberger

Zipper

et al. 2007

The American Journal of Pathology

142

116

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“…Hyaluronan can mediate adhesion between keratinocytes in suspension cultures via bridging CD44 on adjacent cells [103], while in the epidermal tissue hyaluronan accumulation between spinous and granular keratinocytes inhibits the formation of desmosomes, the main cell-cell contacts between keratinocytes [104]. Therefore, all stimuli that activate epidermis, like growth factors, trauma, and inflammation, increase hyaluronan synthesis [105] and influence cell adhesion. Hyaluronan accumulation on keratinocytes enhances the turnover of stable cell-cell contacts, stimulates cell migration and proliferation, and delays the terminal differentiation of the keratinocytes.…”

Section: Pericellular Matrix Regulation Of Cell Adhesionmentioning

confidence: 99%

Hyaluronan-dependent pericellular matrix☆

Evanko¹,

Tammi²,

Tammi³

et al. 2007

Advanced Drug Delivery Reviews

259

238

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Hyaluronan is a multifunctional glycosaminoglycan that forms the structural basis of the pericellular matrix. Hyaluronan is extruded directly through the plasma membrane by one of three hyaluronan synthases and anchored to the cell surface by the synthase or cell surface receptors such as CD44 or RHAMM. Aggregating proteoglycans and other hyaluronan-binding proteins, contribute to the material and biological properties of the matrix and regulate cell and tissue function. The pericellular matrix plays multiple complex roles in cell adhesion/de-adhesion, and cell shape changes associated with proliferation and locomotion. Time-lapse studies show that pericellular matrix formation facilitates cell detachment and mitotic cell rounding. Hyaluronan crosslinking occurs through various proteins, such as tenascin, TSG-6, inter-alpha-trypsin inhibitor, pentraxin and TSP-1. This creates higher order levels of structured hyaluronan that may regulate inflammation and other biological processes. Microvillous or filopodial membrane protrusions are created by active hyaluronan synthesis, and form the scaffold of hyaluronan coats in certain cells. The importance of the pericellular matrix in cellular mechanotransduction and the response to mechanical strain are also discussed.

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“…Hyaluronan is a high molecular mass linear non-sulfated polysaccharide that is a key component of the vertebrate extracellular matrix and has a variety of functions during (1) and following development (2). The unique physicochemical properties of this glycosaminoglycan and its interactions with specific cell surface receptors provide hyaluronan with a central role in cellular migration, adhesion, and proliferation (3).…”

mentioning

confidence: 99%

Regulation of the Hyaluronan Synthase 2 Gene by Convergence in Cyclic AMP Response Element-binding Protein and Retinoid Acid Receptor Signaling

Makkonen¹,

Pasonen‐Seppänen

Törrönen

et al. 2009

Journal of Biological Chemistry

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The human hyaluronan synthase 2 (HAS2) gene encodes for an enzyme making hyaluronan, altered concentrations of which are associated with many pathological situations including wounding, several inflammatory conditions, and malignant tumors. In this study we showed that HAS2 is a primary target of the cAMP activator forskolin and the nuclear hormone alltrans-retinoic acid (RA). The first 2250 bp of the promoter contain three response elements (REs) for the transcription factor CREB1 as well as two REs for the nuclear receptor RAR. Chromatin immunoprecipitation and re-chromatin immunoprecipitation assays using selected fragments of the promoter containing the putative REs showed that forskolin and all-trans-RA modulate the formation of complexes between CREB1 and RAR with various co-regulators at the predicted sites. Interestingly, CREB1 complexes are regulated by all-trans-RA as are RAR complexes by forskolin. Reporter gene assays using nested promoter fragments supported these findings. Forskolin and alltrans-RA co-stimulation reduced the binding of CREB1, RAR, and the co-repressor nuclear receptor co-repressor 1 (NCoR1), but enhanced the association of co-activators MED1 and CREBbinding protein (CBP). RNA interference experiments suggested that MED1 and NCoR1 are central for the all-trans-RA induction of the HAS2 gene and CBP dominates its forskolin response. In general, our findings suggest a convergence of CREB1 and RAR signaling, and demonstrate the individual character of each RE in terms of co-regulator use.Hyaluronan is a high molecular mass linear non-sulfated polysaccharide that is a key component of the vertebrate extracellular matrix and has a variety of functions during (1) and following development (2). The unique physicochemical properties of this glycosaminoglycan and its interactions with specific cell surface receptors provide hyaluronan with a central role in cellular migration, adhesion, and proliferation (3). Hyaluronan is produced by hyaluronan synthase (HAS), 2 an enzyme that resides at the plasma membrane and delivers the growing polysaccharide directly into the extracellular space (3). Of the three members of the vertebrate HAS gene family, HAS2 is vital, whereas no phenotype has been reported for mice with deletions of HAS1 and HAS3 (1). The expression levels of HAS genes, especially HAS2, undergo large and rapid fluctuations, often controlled by growth factors and external conditions (4 -8). Although post-transcriptional regulation of HAS and its enzymatic activity has been reported (9 -11), the majority of data available suggests that hyaluronan synthesis closely correlates with the expression of HAS. Therefore, detailed information on processes that control HAS2 transription are important for understanding the biological functions of hyaluronan, and also for possible therapeutic interference in the clinical conditions involving hyaluronan.We have characterized human HAS2 as a primary retinoic acid receptor (RAR) target gene in keratinocytes (12). In addition to RARs, the transcription...

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Hyaluronan Synthase Induction and Hyaluronan Accumulation in Mouse Epidermis Following Skin Injury

Cited by 135 publications

References 36 publications

Chronic Ultraviolet B Irradiation Causes Loss of Hyaluronic Acid from Mouse Dermis Because of Down-Regulation of Hyaluronic Acid Synthases

Chronic Ultraviolet B Irradiation Causes Loss of Hyaluronic Acid from Mouse Dermis Because of Down-Regulation of Hyaluronic Acid Synthases

Hyaluronan-dependent pericellular matrix☆

Regulation of the Hyaluronan Synthase 2 Gene by Convergence in Cyclic AMP Response Element-binding Protein and Retinoid Acid Receptor Signaling

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