4-Methylumbelliferone induces the expression of membrane type 1-matrix metalloproteinase in cultured human skin fibroblasts

Nakamura, Toshiya; Ishikawa, Takashi; Nanashima, Naoki; Miura, Tomisato; Nozaka, Hiroyuki; Nakaoka, Rie; Sato, Tatsusuke

doi:10.1016/s0006-291x(02)02516-0

Cited by 13 publications

(14 citation statements)

References 19 publications

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“…We treated AoSMCs with 4-MU, a well-known inhibitor of HA synthesis already described for other cell types (Nakamura et al 1995(Nakamura et al , 1997(Nakamura et al , 2002(Nakamura et al , 2007Kosaki et al 1999;Sohara et al 2001;Kudo et al 2004;Rilla et al 2004;Morohashi et al 2006). A clear dose-dependent decrease of HA released into the culture medium was confirmed in AoSMCs after 24 h of treatment with 0.5, 1, and 2 mM of 4-MU by means of PAGEFS ( Figure 1A) and HPLC ( Figure 1B) quantification methods.…”

Section: -Mu Inhibits Ha Synthesis Of Aosmcsmentioning

confidence: 53%

“…By degrading a variety of substrates, including basement membranes, MMP2 increases cell migration and, therefore, promotes the development of several vascular pathologies. Because it has been reported that 4-MU induces MMP2 activation in skin fibroblasts (Nakamura et al 2002), we have studied whether such activation could be detected in AoSMCs. We treated the cells with 1 mM 4-MU and, by means of gelatin zymography, visualized the 72 kDa inactive pro-MMP2 as well as the 66 kDa active MMP2 bands.…”

Section: Mmp2 Activity Is Not Affected By 4-mu In Aosmcsmentioning

confidence: 99%

“…The effect of 4-MU on MMPs is complex. It has been reported that 4-MU induces MMP2 activation in human skin fibroblasts (Nakamura et al 2002) whereas it reduces MMP9 activation in human lymphoma cell lines (Nakamura et al 2007).…”

Section: Introductionmentioning

confidence: 99%

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The effects of 4-methylumbelliferone on hyaluronan synthesis, MMP2 activity, proliferation, and motility of human aortic smooth muscle cells

Vigetti¹,

Rizzi²,

Viola³

et al. 2009

Glycobiology

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Extracellular matrix remodeling after proatherosclerotic injury involves an increase in hyaluronan (HA) that is coupled with vascular smooth muscle cell (SMC) migration, proliferation, and with neointima formation. As such events are dependent on HA, in this study we assessed the effects on SMC behavior of 4-methylumbelliferone (4-MU). As previously described in other cell types, 4-MU reduced HA in cultures of primary human aortic SMCs (AoSMCs) as well as the cellular content of the HA precursor UDP-glucuronic acid. We found that SMCs increased UDP-glucuronyl transferase 1 enzymes, which can reduce the cellular content of UDP-glucuronic acid confirming that the availability of the UDP-sugar substrates can regulate HA synthesis. Interestingly, we reported that 4-MU reduced the transcripts coding for the three HA synthases as well as UDP glucose pyrophosphorylase and dehydrogenase. As HA synthase transcript reduction is common to other cell types, the 4-MU effect on gene expression may be considered a mechanism for HA synthesis inhibition. Moreover, we showed that 4-MU strongly inhibits AoSMCs migration, which was restored by the addition of exogenous HA indicating that the rescuing depends on the interaction of HA with its receptor CD44. Besides the decrease in HA synthesis and cell migration, 4-MU reduced AoSMCs proliferation, indicating that 4-MU may exert a vasoprotective effect.

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Section: -Mu Inhibits Ha Synthesis Of Aosmcsmentioning

confidence: 53%

Section: Mmp2 Activity Is Not Affected By 4-mu In Aosmcsmentioning

confidence: 99%

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The effects of 4-methylumbelliferone on hyaluronan synthesis, MMP2 activity, proliferation, and motility of human aortic smooth muscle cells

Vigetti¹,

Rizzi²,

Viola³

et al. 2009

Glycobiology

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“…For example, 4-MU induces the expression of MT1-MMP mRNA, resulting in activation of MMP2 in human skin fibroblasts (67), but in human lymphoma cell lines, 4-MU decreased the level of mRNA for MMP9 (68). In primary human aortic smooth muscle cells 4-MU did not modify the activity of MMP2 but did cause a decrease in cellular migration, migration that could be rescued with the addition of HA (63).…”

Section: Discussionmentioning

confidence: 96%

4-Methylumbelliferone Diminishes Catabolically Activated Articular Chondrocytes and Cartilage Explants via a Mechanism Independent of Hyaluronan Inhibition

Ishizuka

Askew

Ishizuka

et al. 2016

Journal of Biological Chemistry

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Depletion of the cartilage proteoglycan aggrecan is one of the earliest events that occurs in association with osteoarthritis. This loss is often accompanied by a coordinate loss in another glycosaminoglycan, hyaluronan. Chondrocytes experimentally depleted of cell-associated hyaluronan respond by switching to a pro-catabolic metabolism that includes enhanced production of endogenous inflammatory mediators and increased synthesis of matrix metalloproteinases. Hyaluronan turnover is also increased. Together, such a response provides for possible establishment of a self-perpetuating spiral of events that maintains or prolongs the pro-catabolic state. Chondrocytes or cartilage can also be activated by treatment with pro-inflammatory cytokines and mediators such as IL-1␤, TNF␣, LPS, fibronectin fragments, and hyaluronan oligosaccharides. To determine the mechanism of chondrocyte activation due to hyaluronan loss, a depletion method was required that did not include degrading the hyaluronan. In recent years, several laboratories have used the coumarin derivative, 4-methylumbelliferone, as a potent inhibitor of hyaluronan biosynthesis, due in part to its ability to sequester intracellular UDP-glucuronic acid and inhibition of hyaluronan synthase transcription. However, contrary to our expectation, although 4-methylumbelliferone was indeed an inhibitor of hyaluronan biosynthesis, this depletion did not give rise to an activation of chondrocytes or cartilage. Rather, 4-methylumbelliferone directly and selectively blocked gene products associated with the pro-catabolic metabolic state of chondrocytes and did so through a mechanism preceding and independent of hyaluronan inhibition. These data suggest that 4-methylumbelliferone has additional useful applications to block pro-inflammatory cell activation events but complicates how it is used for defining functions related to hyaluronan.The pronounced loss of aggrecan from articular cartilage is an early critical event associated with osteoarthritis (OA) 2 (1, 2). Aggrecan turnover within the extracellular matrix occurs due to the enhanced activity of endoproteinases such as a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 4 (3, 4) and 5 (5, 6) as well as other matrix metalloproteinases (MMPs) (7)(8)(9)(10)(11). In addition to aggrecan, a significant loss of hyaluronan (HA) is also observed in human OA cartilage as compared with normal human cartilage (12,13). A marked depletion of HA was also observed in articular cartilage damaged experimentally, such as in the anterior cruciate ligament transection model of OA (14) and a reduced-loading, splint immobilization model (15) in dogs. In our studies, cultured explants of human articular cartilage treated with IL-1␣ displayed a loss of HA within the superficial and upper middle layers of cartilage, the same layers in which aggrecan loss occurred (16). Other studies on cytokine-stimulated cartilage explants suggested that HA is lost from the cartilage (17,18), and other studies revealed that the HA is lost...

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“…The mechanism of the inhibition was not fully understood, but it was suggested that MU depletes cellular UDP-GlcUA by enzymatic conjugation to GlcUA, using UDP-GlcUA as the donor, and thus inhibits synthesis of hyaluronan (11). In addition to its inhibitory effect on hyaluronan synthesis, MU has been reported to have other abilities such as suppression of the expression of some matrix metalloproteinases (17,20) and cell-adhesion molecules (15). These facts indicate the possibility that MU may affect intracellular signal transduction.…”

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confidence: 99%

4-Methylumbelliferone inhibits the phosphorylation of hyaluronan synthase 2 induced by 12-O-tetradecanoyl-phorbol-13-acetate

et al. 2013

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The effect of 4-methylumbelliferone (MU), a hyaluronan synthase-suppressor, on O-linked β-Nacetylglucosaminylation (O-GlcNAcylation) was investigated in cultured human skin fibroblasts, and we found that MU stimulated O-GlcNAcylation of the cellular proteins. Since O-GlcNAcylation affects protein phosphorylation via Ser/Thr kinases, we examined the effect of MU on both the phosphorylation of hyaluronan synthase 2 (HAS2) and hyaluronan production. The cells were cultured in the presence or absence of 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and MU independently or in combination. The protein fraction of each cell culture was extracted and divided into 2 parts-phosphorylated and non-phosphorylated fractions-by immobilized metal-affinity chromatography. The hyaluronan level in the medium was determined by an ELISA-like assay. Addition of MU decreased the level of hyaluronan in the medium and that of HAS2 in the phosphorylated protein fraction. On the contrary, the addition of TPA increased the levels of both of them. Interestingly, the combination of TPA and MU lowered the levels of them in treated cells as compared to those in untreated control cells. These results suggest that TPA activated protein kinase C (PKC), which stimulates the phosphorylation of HAS2, and increased hyaluronan production. Further, MU may inhibit the phosphorylation of HAS2 by PKC through the stimulation of O-GlcNAcylation.

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4-Methylumbelliferone induces the expression of membrane type 1-matrix metalloproteinase in cultured human skin fibroblasts

Cited by 13 publications

References 19 publications

The effects of 4-methylumbelliferone on hyaluronan synthesis, MMP2 activity, proliferation, and motility of human aortic smooth muscle cells

The effects of 4-methylumbelliferone on hyaluronan synthesis, MMP2 activity, proliferation, and motility of human aortic smooth muscle cells

4-Methylumbelliferone Diminishes Catabolically Activated Articular Chondrocytes and Cartilage Explants via a Mechanism Independent of Hyaluronan Inhibition

4-Methylumbelliferone inhibits the phosphorylation of hyaluronan synthase 2 induced by 12-O-tetradecanoyl-phorbol-13-acetate

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