Platelet-Derived Hyaluronidase 2 Cleaves Hyaluronan into Fragments that Trigger Monocyte-Mediated Production of Proinflammatory Cytokines

Motte, Carol A. de la; Nigro, Julie; Vasanji, Amit; Rho, Hyunjin; Kessler, Sean P.; Bandyopadhyay, Sudip K.; Danese, Silvio; Fiocchi, Claudio; Stern, Robert

doi:10.2353/ajpath.2009.080831

Cited by 113 publications

(137 citation statements)

References 53 publications

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“…HA is synthesized by three different isoenzymes (HAS1-3) located in the plasma membrane, whereas HA degradation is mediated by a series of hyaluronidases that produce HA fragments that can modulate inflammation and immune responses (8,10). HASes polymerize activated sugars (i.e.…”

mentioning

confidence: 99%

Role of UDP-N-Acetylglucosamine (GlcNAc) and O-GlcNAcylation of Hyaluronan Synthase 2 in the Control of Chondroitin Sulfate and Hyaluronan Synthesis

Vigetti

Deleonibus

Moretto

et al. 2012

Journal of Biological Chemistry

127

107

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Background: UDP-GlcNAc is a precursor of glycoconjugates, including hyaluronan, and induces protein glycosylation to form O-linked GlcNAc (O-GlcNAcylation). Results: UDP-GlcNAc induces hyaluronan synthesis through O-GlcNAcylation of hyaluronan synthase 2, which stabilizes the enzyme and prevents its proteasomal degradation. Conclusion: O-GlcNAcylation of hyaluronan synthase 2 can control synthesis of extracellular matrices with hyaluronan. Significance: UDP-GlcNAc could control cell microenvironments that are altered in many pathologies, including vascular diseases and cancer.

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confidence: 99%

Role of UDP-N-Acetylglucosamine (GlcNAc) and O-GlcNAcylation of Hyaluronan Synthase 2 in the Control of Chondroitin Sulfate and Hyaluronan Synthesis

Vigetti

Deleonibus

Moretto

et al. 2012

Journal of Biological Chemistry

127

107

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“…28,29 Data from our laboratory and others indicate that MKs and platelets contain HA, but little is known about its role in these cells. 30,31 In addition, we found that both mouse and human MKs and platelets contain HYAL2 mRNA and protein with no evidence for HYAL1. 31,32 Recently, it was reported that irradiated wild-type (WT) mice receiving transplants of Hyal-2 KO BM had reduced platelet levels, suggesting a role for intrinsic HA depolymerization by MKs in thrombopoiesis.…”

mentioning

confidence: 85%

“…30,31 In addition, we found that both mouse and human MKs and platelets contain HYAL2 mRNA and protein with no evidence for HYAL1. 31,32 Recently, it was reported that irradiated wild-type (WT) mice receiving transplants of Hyal-2 KO BM had reduced platelet levels, suggesting a role for intrinsic HA depolymerization by MKs in thrombopoiesis. 33 We investigated the role of HYAL2 in MK maturation and platelet formation using Hyal-2 KO mice and by generating a CRISPR-Cas9 construct to disrupt Hyal-2 in the MEG-01 human megakaryoblast cell line.…”

mentioning

confidence: 85%

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Hyaluronan Depolymerization by Megakaryocyte Hyaluronidase-2 Is Required for Thrombopoiesis

Petrey

Obery

Kessler

et al. 2016

The American Journal of Pathology

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Hyaluronan is the predominant glycosaminoglycan component of the extracellular matrix with an emerging role in hematopoiesis. Modulation of hyaluronan polymer size is responsible for its control over cellular functions, and the balance of hyaluronan synthesis and degradation determines its molecular size. Although two active somatic hyaluronidases are expressed in mammals, only deficiency in hyaluronidase-2 (Hyal-2) results in thrombocytopenia of unknown mechanism. Our results reveal that Hyal-2 knockout mice accumulate hyaluronan within their bone marrow and within megakaryocytes, the cells responsible for platelet generation. Proplatelet formation by Hyal-2 knockout megakaryocytes was disrupted because of abnormal formation of the demarcation membrane system, which was dilated and poorly developed. Importantly, peptide-mediated delivery of exogenous hyaluronidase rescued deficient proplatelet formation in murine and human megakaryocytes lacking Hyal-2. Together, our data uncover a previously unsuspected mechanism of how hyaluronan and Hyal-2 control platelet generation.

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“…HA has a molecular mass ranging between 1-10 000 kDa and the high molecular weight HA (HMW-HA, 500-10 000 kDa) is produced by HAS 1-3 while low molecular weight HA (1-500 kDa) is produced by enzymatic degradation of HMW-HA by hyaluronidases (HYAL) or through oxidative hydrolysis by reactive oxygen species (ROS) of HMW-HA [29,30]. Platelets possess HYAL-2 that, in cooperation with CD44, may cleave HA into small pro-proliferative fragments [31][32][33][34]. Interestingly, we recently found that the platelet/ASMC interaction results in increased ROS-production [3].…”

Section: Discussionmentioning

confidence: 99%

Hyaluronic acid influence on platelet-induced airway smooth muscle cell proliferation

Holm

Bengtsson

Grenegård

et al. 2012

Experimental Cell Research

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Hyaluronic acid (HA) is one of the main components of the extracellular matrix (ECM) and is expressed throughout the body including the lung and mostly in areas surrounding proliferating and migrating cells. Furthermore, platelets have been implicated as important players in the airway remodeling process, e.g. due to their ability to induce airway smooth muscle cell (ASMC) proliferation. The aim of the present study was to investigate the role of HA, the HA-binding surface receptor CD44 and focal adhesion kinase (FAK) in plateletinduced ASMC proliferation. Proliferation of ASMC was measured using the MTS-assay, and we found that the CD44 blocking antibody and the HA synthase inhibitor 4-Methylumbelliferone (4-MU) significantly inhibited platelet-induced ASMC proliferation.The interaction between ASMC and platelets was studied by fluorescent staining of F-actin.In addition, the ability of ASMC to synthesise HA was investigated by fluorescent staining using biotinylated HA-binding protein and a streptavidin conjugate. We observed that ASMC produced HA and that a CD44 blocking antibody and 4-MU significantly inhibited platelet binding to the area surrounding the ASMC. Furthermore, the FAK-inhibitor PF 573228 inhibited platelet-induced ASMC proliferation. Co-culture of ASMC and platelets also resulted in increased phosphorylation of FAK as detected by Western blot analysis. In addition, 4-MU significantly inhibited the increased FAK-phosphorylation. In conclusion, our findings demonstrate that ECM has the ability to influence platelet-induced ASMC proliferation. Specifically, we propose that HA produced by ASMC is recognised by platelet CD44. The platelet/HA interaction is followed by FAK activation and increased proliferation of co-cultured ASMC. We also suggest that the mitogenic effect of platelets represents a potential important and novel mechanism that may contribute to airway remodelling.

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Platelet-Derived Hyaluronidase 2 Cleaves Hyaluronan into Fragments that Trigger Monocyte-Mediated Production of Proinflammatory Cytokines

Cited by 113 publications

References 53 publications

Role of UDP-N-Acetylglucosamine (GlcNAc) and O-GlcNAcylation of Hyaluronan Synthase 2 in the Control of Chondroitin Sulfate and Hyaluronan Synthesis

Role of UDP-N-Acetylglucosamine (GlcNAc) and O-GlcNAcylation of Hyaluronan Synthase 2 in the Control of Chondroitin Sulfate and Hyaluronan Synthesis

Hyaluronan Depolymerization by Megakaryocyte Hyaluronidase-2 Is Required for Thrombopoiesis

Hyaluronic acid influence on platelet-induced airway smooth muscle cell proliferation

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