The multiple, complex roles of versican and its proteolytic turnover by ADAMTS proteases during embryogenesis

Nandadasa, Sumeda; Foulcer, Simon J.; Apte, Suneel S.

doi:10.1016/j.matbio.2014.01.005

Cited by 152 publications

(141 citation statements)

References 80 publications

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“…Colocalization of ADAMTS5 and versican immunoreactivity during embryonic development in the mouse lung at later stages of embryonic development (E16.5) has also been previously reported (McCullough et al 2009). With quantitative immunohistochemistry at E13.5, there was little DPEAAE accumulation in the lungs, suggesting antagonistic roles of versican deposition and versican proteolysis in promoting and inhibiting cellular growth and migration through a provisional extracellular matrix during development, as has been previously proposed in lung, cardiac and musculoskeletal system development and in lung inflammation (Kern et al 2006;Capehart 2010;Nandadasa et al 2014).…”

Section: Discussionmentioning

confidence: 54%

Correlation of Versican Expression, Accumulation, and Degradation during Embryonic Development by Quantitative Immunohistochemistry

Snyder

Washington

Birkland

et al. 2015

J Histochem Cytochem.

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SummaryVersican, a chondroitin sulfate proteoglycan, is important in embryonic development, and disruption of the versican gene is embryonically lethal in the mouse. Although several studies show that versican is increased in various organs during development, a focused quantitative study on versican expression and distribution during lung and central nervous system development in the mouse has not previously been performed. We tracked changes in versican (Vcan) gene expression and in the accumulation and degradation of versican. Vcan expression and quantitative immunohistochemistry performed from embryonic day (E) 11.5 to E15.5 showed peak Vcan expression at E13.5 in the lungs and brain. Quantitative mRNA analysis and versican immunohistochemistry showed differences in the expression of the versican isoforms in the embryonic lung and head. The expression of Vcan mRNA and accumulation of versican in tissues was complementary. Immunohistochemistry demonstrated co-localization of versican accumulation and degradation, suggesting distinct roles of versican deposition and degradation in embryogenesis. Very little versican mRNA or protein was found in the lungs of 12-to 16-week-old mice but versican accumulation was significantly increased in mice with Pseudomonas aeruginosa lung infection. These data suggest that versican plays an important role in fundamental, overlapping cellular processes in lung development and infection. (J Histochem Cytochem 63:952-967, 2015)

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Section: Discussionmentioning

confidence: 54%

Correlation of Versican Expression, Accumulation, and Degradation during Embryonic Development by Quantitative Immunohistochemistry

Snyder

Washington

Birkland

et al. 2015

J Histochem Cytochem.

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“…Whereas the proinflammatory cytokine TNF-α decreased rapidly, ADAMTS-1, an enzyme known to be associated with inflammation and versican processing, 82 changed minimally. To study versican turnover during the gradual decrease in hepatic inflammation and reversal of fibrosis, we assessed the appearance of versican cleavage products, G1-DPEAAE 441 (recently dubbed versikine 71 ) and G1-DPEAAE 1401 , which are generated by the ADAMTS proteoglycanases. We found that the versican V0 fragment was differentially produced during injury and recovery, but the more commonly described V1 fragment (versikine), changed little, with a significant decrease seen only at the 28 days of recovery time point.…”

Section: Versican In Liver Fibrosismentioning

confidence: 99%

“…70 Recently, the G1-DPEAAE 441 neo-epitope cleavage product of versican V1 has been dubbed 'versikine' to underscore the importance of versican cleavage in general and this versican cleavage product, in particular, in regulating tissue remodeling. 71 Given the known roles of versican in other tissues and the increases in CSPGs in liver remodeling, we hypothesized that versican expression would also play a role in the pathogenesis of hepatic fibrosis.…”

mentioning

confidence: 99%

Versican: a novel modulator of hepatic fibrosis

Bukong

Maurice

Chahal

et al. 2016

Laboratory Investigation

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Little is known about the deposition and turnover of proteoglycans in liver fibrosis, despite their abundance in the extracellular matrix. Versican plays diverse roles in modulating cell behavior in other fibroproliferative diseases, but remains poorly described in the liver. Hepatic fibrosis was induced by carbon tetrachloride treatment of C57BL/6 mice over 4 weeks followed by recovery over a 28-day period. Primary mouse hepatic stellate cells (HSCs) were activated in culture and versican was transiently knocked down in human (LX2) and mouse HSCs. Expression of versican, A Disintegrinlike and Metalloproteinase with Thrombospondin-1 motifs (ADAMTS)-1, -4, -5, -8, -9, -15, and -20, and markers of fibrogenesis were studied using immunohistochemistry, real-time quantitative PCR, and western blotting. Immunohistochemistry showed increased expression of versican in cirrhotic human livers and the mouse model of fibrosis. Carbon tetrachloride treatment led to significant increases in versican expression and the proteoglycanases ADAMTS-5, -9, -15, and -20, alongside TNF-α, α-smooth muscle actin (α-SMA), collagen-1, and TGF-β expression. During recovery, expression of many of these genes returned to control levels. However, expression of ADAMTS-5, -8, -9, and -15 showed delayed increases in expression at 28 days of recovery, which corresponded with decreases in versican V0 and V1 cleavage products (G1-DPEAAE 1401 and G1-DPEAAE 441 ). Activation of primary HSCs in vitro significantly increased versican, α-SMA, and collagen-1 expression. Transient knockdown of versican in HSCs led to decreases in markers of fibrogenesis and reduced cell proliferation, without inducing apoptosis. Versican expression increases during HSC activation and liver fibrosis, and proteolytic processing occurs during the resolution of fibrosis. Knockdown studies in vitro suggest a possible role of versican in modulating hepatic fibrogenesis.

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“…2 We and others have previously demonstrated that versican (VCAN), a large, chondroitin-sulfate matrix proteoglycan, accumulates in myeloma lesions and have hypothesized that VCAN may contribute to myeloma niche immunoregulation. 3,4 VCAN has crucial, nonredundant significance in embryonic development 5 and emerging roles in cancer inflammation and metastasis. [6][7][8][9] VCAN promotes tolerogenic polarization of antigen-presenting cells through Toll-like receptor 2 (TLR2).…”

Section: Introductionmentioning

confidence: 99%

Immunoregulatory roles of versican proteolysis in the myeloma microenvironment

Hope

Foulcer

Jagodinsky

et al. 2016

Blood

Self Cite

122

107

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• Interplay between myeloma niche stromal cells and myeloid cells generates versikine, a novel damageassociated molecular pattern.• Versikine may promote antigen-presenting cell maturation and CD8 1 T-cell activation/recruitment to the tumor bed.Myeloma immunosurveillance remains incompletely understood. We have demonstrated proteolytic processing of the matrix proteoglycan, versican (VCAN), in myeloma tumors. Whereas intact VCAN exerts tolerogenic activities through Toll-like receptor 2 (TLR2) binding, the immunoregulatory consequences of VCAN proteolysis remain unknown. Here we show that human myeloma tumors displaying CD81 infiltration/aggregates underwent VCAN proteolysis at a site predicted to generate a glycosaminoglycan-bereft N-terminal fragment, versikine. Myeloma-associated macrophages (MAMs), rather than tumor cells, chiefly produced V1-VCAN, the precursor to versikine, whereas stromal cell-derived ADAMTS1 was the most robustly expressed VCAN-degrading protease. Purified versikine induced early expression of inflammatory cytokines interleukin 1b (IL-1b) and IL-6 by human myeloma marrow-derived MAMs. We show that versikine signals through pathways both dependent and independent of Tpl2 kinase, a key regulator of nuclear factor kB1-mediated MAPK activation in macrophages. Unlike intact VCAN, versikine-induced Il-6 production was partially independent of Tlr2. In a model of macrophage-myeloma cell crosstalk, versikine induced components of "T-cell inflammation," including IRF8-dependent type I interferon transcriptional signatures and T-cell chemoattractant CCL2. Thus the interplay between stromal cells and myeloid cells in the myeloma microenvironment generates versikine, a novel bioactive damage-associated molecular pattern that may facilitate immune sensing of myeloma tumors and modulate the tolerogenic consequences of intact VCAN accumulation. Therapeutic versikine administration may potentiate T-cell-activating immunotherapies. (Blood. 2016;128(5):680-685)

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The multiple, complex roles of versican and its proteolytic turnover by ADAMTS proteases during embryogenesis

Cited by 152 publications

References 80 publications

Correlation of Versican Expression, Accumulation, and Degradation during Embryonic Development by Quantitative Immunohistochemistry

Correlation of Versican Expression, Accumulation, and Degradation during Embryonic Development by Quantitative Immunohistochemistry

Versican: a novel modulator of hepatic fibrosis

Immunoregulatory roles of versican proteolysis in the myeloma microenvironment

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