Hyaluronan Synthase 2 Protects Skin Fibroblasts against Apoptosis Induced by Environmental Stress

Wang, Yan; Lauer, Mark E.; Anand, Sanjay; Mack, Judith A.; Maytin, Edward V.

doi:10.1074/jbc.m114.578377

Cited by 54 publications

(68 citation statements)

References 53 publications

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“…The distinct elevated expression of apoptosis genes in Has1 −/− joints (relative to WT) is consistent with an altered stress-induced apoptotic response in fibroblasts from Has1 −/− and Has3 −/− mice 40 . Moreover, Has1 −/− joints showed elevated expression of Il4 (Table 3), a known stimulator of synovial fibrosis and fibroblast-to-myofibroblast transition 41 .…”

Section: Discussionsupporting

confidence: 65%

Deficiency of hyaluronan synthase 1 (Has1) results in chronic joint inflammation and widespread intra-articular fibrosis in a murine model of knee joint cartilage damage

Chan

Xiao

et al. 2015

Osteoarthritis and Cartilage

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Objective Articular cartilage defects commonly result from traumatic injury and predispose to degenerative joint diseases. To test the hypothesis that aberrant healing responses and chronic inflammation lead to osteoarthritis, we examined spatiotemporal changes in joint tissues after cartilage injury in murine knees. Since intra-articular injection of hyaluronan (HA) can attenuate injury-induced osteoarthritis in wild-type (WT) mice, we investigated a role for HA in the response to cartilage injury in mice lacking HA synthase 1 (Has1−/−). Design Femoral groove cartilage of WT and Has1−/− mice was debrided to generate a non-bleeding wound. Macroscopic imaging, histology, and gene expression were used to evaluate naïve, sham-operated, and injured joints. Results Acute responses (1–2 weeks) in injured joints from WT mice included synovial hyperplasia with HA deposition and joint-wide increases in expression of genes associated with inflammation, fibrosis, and extracellular matrix (ECM) production. By 4 weeks, some resurfacing of damaged cartilage occurred, and early cell responses were normalized. Cartilage damage in Has1−/− mice also induced early responses; however, at 4 weeks, inflammation and fibrosis genes remained elevated with widespread cartilage degeneration and fibrotic scarring in the synovium and joint capsule. Conclusions We conclude that the ineffective repair of injured cartilage in Has1−/− joints can be at least partly explained by the markedly enhanced expression of particular genes in pathways linked to ECM turnover, IL-17/IL-6 cytokine signaling, and apoptosis. Notably, Has1 ablation does not alter gross HA content in the ECM, suggesting that HAS1 has a unique function in the metabolism of inflammatory HA matrices.

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Section: Discussionsupporting

confidence: 65%

Deficiency of hyaluronan synthase 1 (Has1) results in chronic joint inflammation and widespread intra-articular fibrosis in a murine model of knee joint cartilage damage

Chan

Xiao

et al. 2015

Osteoarthritis and Cartilage

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“…HMW HA decreases UVB-induced apoptosis and inflammation in human epithelial corneal cells [140]. Has1/3 null skin fibroblasts, with higher levels of Has2 gene expression, are resistant to stress-induced apoptosis, suggesting that HAS2 protects skin fibroblasts against apoptosis induced by environmental stress [34]. For inflammatory cells, HA seems to induce apoptosis.…”

Section: Ha In Biological Processesmentioning

confidence: 99%

“…Wound closure was significantly faster in Has1 and Has3 double null mice [32]. HAS2 protects skin fibroblasts against apoptosis induced by environmental stress such as UV exposure and serum starvation [34]. Furthermore, Has3 deficiency causes reduction in brain extracellular space leading to altered neuronal activity and seizures [35].…”

Section: Introductionmentioning

confidence: 99%

Hyaluronan as a therapeutic target in human diseases

Liang

Jiang

Noble

2016

Advanced Drug Delivery Reviews

167

106

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Accumulation and turnover of extracellular matrix is a hallmark of tissue injury, repair and remodeling in human diseases. Hyaluronan is a major component of the extracellular matrix and plays an important role in regulating tissue injury and repair, and controlling disease outcomes. The function of hyaluronan depends on its size, location, and interactions with binding partners. While fragmented hyaluronan stimulates the expression of an array of genes by a variety of cell types regulating inflammatory responses and tissue repair, cell surface hyaluronan provides protection against tissue damage from the environment and promotes regeneration and repair. The interactions of hyaluronan and its binding proteins participate in the pathogenesis of many human diseases. Thus, targeting hyaluronan and its interactions with cells and proteins may provide new approaches to developing therapeutics for inflammatory and fibrosing diseases. This review focuses on the role of hyaluronan in biological and pathological processes, and as a potential therapeutic target in human diseases.

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“…Furthermore, HAS2 upregulation may enhance the ability of HSF cells to block apoptosis. HAS3 upregulation has been demonstrated to promote the synthesis of a large number of small molecular weight HA, accelerate blood circulation and metabolism, and reduce the damage of reactive oxygen species and other substances to cells (10).…”

Section: Discussionmentioning

confidence: 99%

“…Studies have indicated that UV exposure from the sun causes apoptosis of dermal fibroblasts (photodamage) and contributes to the development of photoaging (9). Hyaluronic acid (HA), an extracellular matrix molecule synthesized by hyaluronic acid synthase enzymes (HAS), serves a role in regulating apoptosis in fibroblasts (10). Injection of HA fillers provides enrichment of one of the primary ECM compounds, deep hydration of the skin and strongly stimulates fibroblasts, which act on specific receptors cluster of differentiation (CD)44, HA-mediated cell motility and intercellular adhesion molecule-1 to synthesize novel scaffold compounds (11,12).…”

Section: Introductionmentioning

confidence: 99%

GSK126 (EZH2 inhibitor) interferes with ultraviolet A radiation‑induced photoaging of human skin fibroblast cells

2018

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Abstract. Polycomb group genes (PcG) encode chromatin modification proteins that are involved in the epigenetic regulation of cell differentiation, proliferation and the aging processes. The key subunit of the PcG complex, enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), has a central role in a variety of mechanisms, such as the formation of chromatin structure, gene expression regulation and DNA damage. In the present study, ultraviolet A (UVA) was used to radiate human dermal fibroblasts in order to construct a photo-aged cell model. Subsequently, the cell viability assay, Hoechst staining, apoptosis detection using flow cytometry, senescence-associated β-galactosidase (SA-β-gal) staining and erythrocyte exclusion experiments were performed. GSK126, a histone methylation enzyme inhibitor of EZH2, was used as an experimental factor. Results suggested that GSK126 downregulated the mRNA expression levels of EZH2 and upregulated the mRNA expression levels of BMI-1. Notably, GSK126 affected the transcription of various photoaging-related genes and thus protected against photoaging induced by UVA radiation.

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Hyaluronan Synthase 2 Protects Skin Fibroblasts against Apoptosis Induced by Environmental Stress

Cited by 54 publications

References 53 publications

Deficiency of hyaluronan synthase 1 (Has1) results in chronic joint inflammation and widespread intra-articular fibrosis in a murine model of knee joint cartilage damage

Deficiency of hyaluronan synthase 1 (Has1) results in chronic joint inflammation and widespread intra-articular fibrosis in a murine model of knee joint cartilage damage

Hyaluronan as a therapeutic target in human diseases

GSK126 (EZH2 inhibitor) interferes with ultraviolet A radiation‑induced photoaging of human skin fibroblast cells

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