CD44 knock-down in bovine and human chondrocytes results in release of bound HYAL2

Hida, Daisuke; Danielson, Ben T.; Knudson, Cheryl B.; Knudson, Warren

doi:10.1016/j.matbio.2015.04.002

Cited by 18 publications

(23 citation statements)

References 42 publications

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“…Among the several cell surface receptors involved in HA signaling, CD44 is the most abundant and expressed in almost all tissues and across nearly every cell type including chondrocytes, while binding of HA to CD44 is known to be involved in the initiation of a variety of biological activities . A previous report has demonstrated the expression of CD44 in C28/I2 cells . As shown in Fig.…”

Section: Discussionmentioning

confidence: 52%

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High molecular weight hyaluronic acid regulates MMP13 expression in chondrocytes via DUSP10/MKP5

Furuta

Ariyoshi

Okinaga

et al. 2016

Journal Orthopaedic Research

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To determine the effect of high molecular weight hyaluronic acid (HA) on matrix metalloproteinase 13 (MMP13) expression induced by tumor necrosis factor α (TNF-α) in chondrocytes. Human chondrocytic C28/I2 cells were incubated with TNF-α and HA. In some experiments, the cells were pre-incubated with a CD44 function-blocking monoclonal antibody (CD44 mAb) prior to addition of TNF-α and HA. The expression of MMP13 was determined by real-time reverse-transcription polymerase chain reaction (RT-PCR) and an enzyme linked immunosorbent assay, while the phosphorylation of signaling molecules was measured by western blot analysis. The transcriptional activity of activator protein 1 (AP-1) was analyzed by a reporter assay. To further clarify the molecular mechanisms of HA in MMP13 regulation, the expression level of dual-specificity protein phosphatase 10 (DUSP10)/mitogen-activated protein kinases phosphatase 5 (MKP5) in HA-treated chondrocytes was assessed by real-time RT-PCR, western blotting, and immunofluorescence microscopy. HA decreased MMP13 mRNA and protein expression induced by TNF-α. Blockage of HA-CD44 binding by CD44 mAb suppressed HA-mediated inhibition of MMP13. HA inhibited transient phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-jun NH -terminal kinase (JNK) induced by TNF-α. Reporter assay findings also revealed that pre-treatment with HA inhibited the transcriptional activity of AP-1 mediated by TNF-α. Moreover, HA induced the expression of DUSP10/MKP5, a negative regulator of p38 MAPK and JNK pathways. These results indicate that HA-CD44 interactions downregulate TNF-α-induced MMP13 expression via regulation of DUSP10/MKP5, suggesting that HA plays an important role as a regulatory factor in cartilage degradation. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:331-339, 2017.

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Section: Discussionmentioning

confidence: 52%

“…31 A previous report has demonstrated the expression of CD44 in C28/I2 cells. 32 As shown in Fig. 3, pre-treatment with the CD44 function-blocking monoclonal antibody significantly inhibited the effect of HA on MMP13 expression induced by TNF-a.…”

Section: Discussionmentioning

confidence: 68%

High molecular weight hyaluronic acid regulates MMP13 expression in chondrocytes via DUSP10/MKP5

Furuta

Ariyoshi

Okinaga

et al. 2016

Journal Orthopaedic Research

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“…shedding in bovine chondrocytes increases the release of HYAL2 from the membrane of these cells to the ECM where weak HYAL2 activity has been demonstrated [66]. The activity of a soluble form of HYAL2 has been also reported in human bronchial epithelial cells [68].…”

Section: Hyal2 In Ha Catabolismmentioning

confidence: 89%

“…In vitro studies in an HEK293 cell line stably transfected with HYAL2 demonstrated that HYAL2 acts extracellularly, and its activity depends on a cell surface receptor, CD44 [55]. The interaction and colocalization between HYAL2 and CD44 have been also reported in both vesicles and plasma membrane of chondrocytes from arthritis patients [66]. The activity of HYAL2-mediated HA cleavage depends on an acidic microenvironment [67].…”

Section: Hyal2 In Ha Catabolismmentioning

confidence: 96%

Hyaluronidase 2 (HYAL2) is expressed in endothelial cells, as well as some specialized epithelial cells, and is required for normal hyaluronan catabolism

Chowdhury

Hemming

Faiyaz

et al. 2015

Histochem Cell Biol

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Hyaluronidase 2 (HYAL2) is a membrane-anchored protein that is proposed to initiate the degradation of hyaluronan (HA) in the extracellular matrix. The distribution of HYAL2 in tissues, and of HA in tissues lacking HYAL2, is largely unexplored despite the importance of HA metabolism in several disease processes. Herein, we use immunoblot and histochemical analyses to detect HYAL2 and HA in mouse tissues, as well as agarose gel electrophoresis to examine the size of HA. HYAL2 was detected in all tissues that were examined, including the brain. It was localized to the surface and cytoplasm of endothelial cells, as well as specialized epithelial cells in several tissues, including the skin. Accumulated HA, often of higher molecular mass than that in control tissues, was detected in tissues from Hyal2 (-/-) mice. The accumulating HA was located near to where HYAL2 is normally found, although in some tissues, it was distant from the site of HYAL2 localization. Overall, HYAL2 was highest in tissues that remove HA from the circulation (liver, lymph node and spleen), but the levels of HA accumulation in Hyal2 (-/-) mice were highest in tissues that catabolize locally synthesized HA. Our results support HYAL2's role as an extracellular enzyme that initiates HA breakdown in somatic tissues. However, our findings also suggest that HYAL2 contributes to HA degradation through other routes, perhaps as a soluble or secreted form.

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“…Interestingly, Harada and Takahashi (32) reported that HYAL2, a GPI-anchored molecule that is localized intracellularly when transfected alone into 293T cells, is translocated to the cell surface upon co-transfection of CD44, suggesting the possibility that it may act as a cell-surface hyaluronidase in the presence of CD44. Still, in view of a number of conflicting data regarding its pH optimum (9,(32)(33)(34) and subcellular localization (9,(33)(34)(35)(36), the significance of HYAL2 as a cell-surface hyaluronidase is far from clear. Two other HYAL family molecules, PH-20/SPAM1 and HYAL5, are active in near neutral pH and can degrade HA in the extracellular environment (12,37).…”

Section: Discussionmentioning

confidence: 99%

A mammalian homolog of the zebrafish transmembrane protein 2 (TMEM2) is the long-sought-after cell-surface hyaluronidase

Yamamoto

Tobisawa

Inubushi

et al. 2017

Journal of Biological Chemistry

140

162

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Edited by Amanda J. Fosang Hyaluronan (HA) is an extremely large polysaccharide (glycosaminoglycan) involved in many cellular functions. HA catabolism is thought to involve the initial cleavage of extracellular high-molecular-weight (HMW) HA into intermediate-size HA by an extracellular or cell-surface hyaluronidase, internalization of intermediate-size HA, and complete degradation into monosaccharides in lysosomes. Despite considerable research, the identity of the hyaluronidase responsible for the initial HA cleavage in the extracellular space remains elusive. HYAL1 and HYAL2 have properties more consistent with lysosomal hyaluronidases, whereas CEMIP/KIAA1199, a recently identified HA-binding molecule that has HA-degrading activity, requires the participation of the clathrincoated pit pathway of live cells for HA degradation. Here we show that transmembrane protein 2 (TMEM2), a mammalian homolog of a protein playing a role in zebrafish endocardial cushion development, is a cell-surface hyaluronidase. Live immunostaining and surface biotinylation assays confirmed that mouse TMEM2 is expressed on the cell surface in a type II transmembrane topology. TMEM2 degraded HMW-HA into ϳ5-kDa fragments but did not cleave chondroitin sulfate or dermatan sulfate, indicating its specificity to HA. The hyaluronidase activity of TMEM2 was Ca 2؉ -dependent; the enzyme's pH optimum is around 6 -7, and unlike CEMIP/ KIAA1199, TMEM2 does not require the participation of live cells for its hyaluronidase activity. Moreover, TMEM2-expressing cells could eliminate HA immobilized on a glass surface in a contact-dependent manner. Together, these data suggest that TMEM2 is the long-sought-after hyaluronidase that cleaves extracellular HMW-HA into intermediate-size fragments before internalization and degradation in the lysosome.Hyaluronic acid (HA) 2 is a glycosaminoglycan composed of repeating disaccharide units of glucuronic acid and N-acetylglucosamine. It is a linear polymer of extremely large molecular mass, often exceeding 10 6 Da (1). The sheer size of HA suggests that cells should have very efficient mechanisms for its metabolism. In fact, one-third of the total body HA, which is estimated to be 15 g in a human with a 70-kg body weight, is thought to be turned over daily (2). In skin, the metabolic halflife of HA is 1 to 1.5 days (3). It is believed that high-molecularweight (HMW) HA (10 6 -10 7 Da) is first degraded extracellularly into intermediate-size fragments of 10 -100 kDa. These are then internalized and degraded to monosaccharides by the combined actions of lysosomal hyaluronidase and exoglucosidases (4). Considering the accumulating evidence for the role of HA degradation in tumor invasion and metastasis (5), identifying the molecule(s) that degrade HA on the cell surface is an important biological issue.The HYAL family molecules have been implicated as the major players in HA catabolism. HYAL1 and HYAL2 are expressed widely and postulated to be the key hyaluronidases involved in HA catabolism in somatic tissues. How...

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CD44 knock-down in bovine and human chondrocytes results in release of bound HYAL2

Cited by 18 publications

References 42 publications

High molecular weight hyaluronic acid regulates MMP13 expression in chondrocytes via DUSP10/MKP5

High molecular weight hyaluronic acid regulates MMP13 expression in chondrocytes via DUSP10/MKP5

Hyaluronidase 2 (HYAL2) is expressed in endothelial cells, as well as some specialized epithelial cells, and is required for normal hyaluronan catabolism

A mammalian homolog of the zebrafish transmembrane protein 2 (TMEM2) is the long-sought-after cell-surface hyaluronidase

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