Hyaluronidase 3 (HYAL3) knockout mice do not display evidence of hyaluronan accumulation

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Background:The role of hyaluronidase 2 in hyaluronan degradation and cardiopulmonary function is largely uncharacterized. Results: Hyaluronidase 2-deficient mice accumulate extracellular hyaluronan, leading to defective cardiopulmonary function. Conclusion: Hyaluronidase 2 is essential for hyaluronan degradation and normal heart and lung health. Significance: Our studies suggest that hyaluronidase 2 deficiency should be considered as a contributor to cardiac pathologies in humans.

Section: Discussionmentioning

confidence: 82%

“…Surprisingly, no broad-spectrum HA accumulation, including in the heart, was identified during the characterization of Hyal1-, Hyal2-, or Hyal3-deficient mice (15)(16)(17). Previous studies of Hyal2 Ϫ/Ϫ (knock-out (KO)) mice revealed craniofacial abnormalities and chronic anemia, as well as unexplained preweaning lethality (16).…”

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confidence: 98%

Murine Hyaluronidase 2 Deficiency Results in Extracellular Hyaluronan Accumulation and Severe Cardiopulmonary Dysfunction

Chowdhury¹,

Hemming²,

Hombach‐Klonisch

et al. 2013

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“…Furthermore, our data indicating that that NADPH oxidase regulates Hyal3 expression in VSMC treated with thrombin is significant because increased HA during pathological conditions is the sum of its synthesis and catabolism. This is also an interesting observation because Hyal3 Ϫ/Ϫ mice do not exhibit any HA accumulation (57) and cellular overexpression of Hyal3 does not impart intrinsic hyaluronidase activity (58). In contrast, up-regulation of Hyal3 was reported in chondrocytes treated with cytokines (59).…”

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confidence: 87%

NADPH Oxidases Regulate CD44 and Hyaluronic Acid Expression in Thrombin-treated Vascular Smooth Muscle Cells and in Atherosclerosis

Vendrov

Madamanchi

Niu

et al. 2010

Atherosclerosis is a chronic inflammatory disease of the vessel wall in which reactive oxygen species (ROS) 3 -mediated activation of redox-sensitive transcription pathways modulates atherosclerotic plaque progression. Increased adhesion molecule expression and remodeling of extracellular matrix are among the major changes caused by the activation of redoxsensitive signaling pathways. NADPH oxidases are critical determinants of the redox status of the vessel wall and play a critical role in the pathophysiology of atherosclerosis.

“…Mice deficient in each of these genes have recently been described. However, Hyal3 knockout mice do not display a distinct phenotype (5), Hyal1 null animals develop a slowly progressive osteoarthritis without significant elevation of plasma or tissue levels of HA (6), and Hyal2 Ϫ/Ϫ mice show skeletal and hematological anomalies as well as 10-fold increases in plasma HA (7). Some of these apparent anomalies are explained perhaps by the non-enzymatic functions of these proteins.…”

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confidence: 99%

Two Novel Functions of Hyaluronidase-2 (Hyal2) Are Formation of the Glycocalyx and Control of CD44-ERM Interactions

Duterme

Mertens-Strijthagen

Tammi

et al. 2009

It has long been predicted that the members of the hyaluronidase enzyme family have important non-enzymatic functions. However, their nature remains a mystery. The metabolism of hyaluronan (HA), their major enzymatic substrate, is also enigmatic. To examine the function of Hyal2, a glycosylphosphatidylinositol-anchored hyaluronidase with intrinsically weak enzymatic activity, we have compared stably transfected rat fibroblastic BB16 cell lines with various levels of expression of Hyal2. These cell lines continue to express exclusively the standard form (CD44s) of the main HA receptor, CD44. Hyal2, CD44, and one of its main intracellular partners, ezrin-radixin-moesin (ERM), were found to co-immunoprecipitate. Functionally, Hyal2 overexpression was linked to loss of the glycocalyx, the HA-rich pericellular coat. This effect could be mimicked by exposure of BB16 cells either to Streptomyces hyaluronidase, to HA synthesis inhibitors, or to HA oligosaccharides. This led to shedding of CD44, separation of CD44 from ERM, reduction in baseline level of ERM activation, and markedly decreased cell motility (50% reduction in a wound healing assay). The effects of Hyal2 on the pericellular coat and on CD44-ERM interactions were inhibited by treatment with the Na ؉ /H ؉ exchanger-1 inhibitor ethyl-N-isopropylamiloride. We surmise that Hyal2, through direct interactions with CD44 and possibly some pericellular hyaluronidase activity requiring acidic foci, suppresses the formation or the stability of the glycocalyx, modulates ERMrelated cytoskeletal interactions, and diminishes cell motility. These effects may be relevant to the purported in vivo tumorsuppressive activity of Hyal2.