Uptake of denatured collagen into hepatic stellate cells: evidence for the involvement of urokinase plasminogen activator receptor-associated protein/Endo180

Mousavi, Seyed Ali; Sato, Mitsuru; Sporstøl, Marita; Smedsrød, B; Berg, Trond; Kojima, Naosuke; Senoo, Haruki

doi:10.1042/bj20040966

Cited by 37 publications

(36 citation statements)

References 47 publications

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“…DDR receptors regulate cell adhesion, migration, proliferation, and remodeling of the extracellular matrix by controlling the expression and activity of MMPs (42,55). Similarly, uPARAP/Endo180 from the mannose receptor family was found to be important for collagen internalization in activated rat HSCs (37) and other cultured cells (12,29,33,37,51). Our study provides evidence that collagen macropinocytosis is an additional communication mechanism between HSCs and extracellular matrix.…”

Section: C628mentioning

confidence: 66%

“…In liver, HSCs are important not only for collagen production that contributes to liver cirrhosis, but also for collagen degradation during cirrhosis resolution. Collagen has been reported to be internalized by macrophages and fibroblasts (1,30) and recently by HSCs (36,37). However, the mechanisms and relevance of this process remain undefined and were the focus of this investigation.…”

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confidence: 99%

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Endocytosis of collagen by hepatic stellate cells regulates extracellular matrix dynamics

Bi¹,

Mukhopadhyay²,

Drinane³

et al. 2014

American Journal of Physiology-Cell Physiology

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Hepatic stellate cells (HSCs) generate matrix, which in turn may also regulate HSCs function during liver fibrosis. We hypothesized that HSCs may endocytose matrix proteins to sense and respond to changes in microenvironment. Primary human HSCs, LX2, or mouse embryonic fibroblasts (MEFs) [wild-type; c-abl−/−; or Yes, Src, and Fyn knockout mice (YSF−/−)] were incubated with fluorescent-labeled collagen or gelatin. Fluorescence-activated cell sorting analysis and confocal microscopy were used for measuring cellular internalization of matrix proteins. Targeted PCR array and quantitative real-time PCR were used to evaluate gene expression changes. HSCs and LX2 cells endocytose collagens in a concentration- and time-dependent manner. Endocytosed collagen colocalized with Dextran 10K, a marker of macropinocytosis, and 5-ethylisopropyl amiloride, an inhibitor of macropinocytosis, reduced collagen internalization by 46%. Cytochalasin D and ML7 blocked collagen internalization by 47% and 45%, respectively, indicating that actin and myosin are critical for collagen endocytosis. Wortmannin and AKT inhibitor blocked collagen internalization by 70% and 89%, respectively, indicating that matrix macropinocytosis requires phosphoinositide-3-kinase (PI3K)/AKT signaling. Overexpression of dominant-negative dynamin-2 K44A blocked matrix internalization by 77%, indicating a role for dynamin-2 in matrix macropinocytosis. Whereas c-abl−/− MEF showed impaired matrix endocytosis, YSF−/− MEF surprisingly showed increased matrix endocytosis. It was also associated with complex gene regulations that related with matrix dynamics, including increased matrix metalloproteinase 9 (MMP-9) mRNA levels and zymographic activity. HSCs endocytose matrix proteins through macropinocytosis that requires a signaling network composed of PI3K/AKT, dynamin-2, and c-abl. Interaction with extracellular matrix regulates matrix dynamics through modulating multiple gene expressions including MMP-9.

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Section: C628mentioning

confidence: 66%

mentioning

confidence: 99%

Endocytosis of collagen by hepatic stellate cells regulates extracellular matrix dynamics

Bi¹,

Mukhopadhyay²,

Drinane³

et al. 2014

American Journal of Physiology-Cell Physiology

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“…A member of the mannose receptor family, uPARAP is expressed on macrophages and mesenchymal cells, including chondrocytes and some fibroblasts (Howard et al 2004;Sheikh et al 2000). Mesenchymal cells that lack uPARAP are unable to internalize collagen (Curino et al 2005;East et al 2003;Engelholm et al 2003;Kjoller et al 2004;Madsen et al 2007;Mousavi et al 2005). In addition to its role in collagen internalization and degradation, uPARAP contributes to the adhesion and migration of collagen in vitro (Engelholm et al 2003).…”

Section: Resultsmentioning

confidence: 99%

uPARAP expression during murine lung development

Smith¹,

Wagner²,

Huizar³

et al. 2008

Gene Expression Patterns

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Lung remodeling requires active collagen deposition and degradation. Urokinase plasminogen activator receptor-associated protein (uPARAP), or Endo 180, is a cell surface receptor for collagens, which leads to collagen internalization and degradation. Thus, uPARAP-mediated collagen degradation is an additional pathway for matrix remodeling in addition to matrix remodeling mediated by matrix metalloproteinases and cathepsins. Using immunohistochemistry, we demonstrate extensive uPARAP expression in the mesenchyme throughout murine lung development. By immunofluorescence, we demonstrate significant overlap of uPARAP expression with collagen IV expression, but minimal overlap with collagen I expression in the developing murine lung. Finally, we compared lung development between wild-type and uPARAP −/− mice, and found no significant histologic differences, indicating the presence of alternative collagen degradation pathways during murine lung development.Keywords lung development; collagen; uPARAP; Endo 180 Results and DiscussionUrokinase plasminogen activator receptor-associated protein (uPARAP), or Endo180, is a newly described cell-surface receptor that binds and internalizes collagens, including types I, IV, and V, targeting them for lysosomal degradation (Behrendt et al. 2000;Engelholm et al. 2003;Engelholm et al. 2001;Kjoller et al. 2004). A member of the mannose receptor family, uPARAP is expressed on macrophages and mesenchymal cells, including chondrocytes and some fibroblasts (Howard et al. 2004;Sheikh et al. 2000). Mesenchymal cells that lack uPARAP are unable to internalize collagen (Curino et al. 2005;East et al. 2003;Engelholm et al. 2003;Kjoller et al. 2004;Madsen et al. 2007;Mousavi et al. 2005). In addition to its role in collagen internalization and degradation, uPARAP contributes to the adhesion and migration of collagen in vitro (Engelholm et al. 2003). uPARAP may also play a role in human gingival re-epithelialization and remodeling after injury (Honardoust et al. 2006). In addition, uPARAP is expressed in tumor stromal cells and has a role in tumor progression (Curino et al. 2005;Sulek et al. 2007). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. During lung development, the matrix undergoes active remodeling during the formation and differentiation of airways, vasculature, and mature alveoli. In particular, during the saccular stage (E17.5 to post-natal day 5 (PN5)) and alveolar stage (PN5-PN30), the lung interstitium undergoes extensive remodeling with a decrease in the interstitial space, maturation and narrowing of the blood-air barrier and t...

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“…One possible explanation for the lack of lung phenotype is use of an alternative pathway for collagen internalization. Although previous work demonstrated that uPARAP was the primary receptor for collagen internalization in dermal fibroblasts and mouse embryonic fibroblasts (3,(7)(8)(9), other studies have implicated integrins (specifically, a2b1) and MMPs for collagen internalization in different cells (10,11). Therefore, we asked whether lung fibroblasts required uPARAP for collagen internalization.…”

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confidence: 99%

Role of Urokinase Plasminogen Activator Receptor–Associated Protein in Mouse Lung

Bundesmann

Wagner

Chow

et al. 2012

Am J Respir Cell Mol Biol

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Urokinase plasminogen activator receptor-associated protein (uPARAP, or Endo180) is a transmembrane endocytic receptor that mediates collagen internalization and degradation. uPARAP may be a novel pathway for collagen turnover and matrix remodeling in the lung. The function of uPARAP in lung injury has not been described. We analyzed the pulmonary mechanics of uPARAP 2/2 and wild-type mice at baseline and examined their response after bleomycin instillation. We compared collagen internalization in primary mouse lung fibroblasts (MLFs) from wild-type and uPARAP 2/2 mice using flow cytometry and fluorescent microscopy, and we examined the role of cytokines in regulating uPARAP expression and collagen internalization. We show that uPARAP is highly expressed in the lung, and that uPARAP 2/2 mice have increased lung elastance at baseline and after injury. uPARAP 2/2 mice are protected from changes in lung permeability after acute lung injury and have increased collagen content after bleomycin injury. uPARAP is the primary pathway for internalization of collagens in MLFs. Furthermore, collagen internalization through uPARAP does not require matrix metalloproteinase digestion and is independent of integrins. Mediators of lung injury, including transforming growth factor-b, TNF-a, and IL-1, down-regulate both uPARAP expression and collagen internalization. uPARAP is highly expressed in the murine lung, and loss of uPARAP leads to differences in lung mechanics, lung permeability, and collagen content after injury. uPARAP is required for collagen internalization by MLFs. Thus, uPARAP is a novel pathway that regulates matrix remodeling in the lung after injury.Keywords: urokinase plasminogen activator receptor-associated protein; Endo180; collagen internalization; lung fibroblasts; matrix remodeling Urokinase plasminogen activator receptor-associated protein (uPARAP, Endo180, or mannose receptor, C type 2) is a 180-kD transmembrane receptor that can bind and internalize both fibrillar and nonfibrillar collagens (1, 2). After internalization, uPARAP targets collagen to the lysosome for degradation and then uPARAP recycles to the plasma membrane (3). uPARAP is expressed in mesenchymal cells, predominantly fibroblasts. In addition, dermal macrophage and human placental endothelial cells express low levels of uPARAP (1,4,5).We previously demonstrated high expression of uPARAP in the mesenchyme throughout lung development (6). Despite the high expression of uPARAP in the developing lung, development proceeds normally in uPARAP 2/2 mice, and is not associated with any differences in matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinases, or collagen expression in the lung (6). uPARAP 2/2 mice appear phenotypically normal in the unchallenged state, and have a normal lifespan. One possible explanation for the lack of lung phenotype is use of an alternative pathway for collagen internalization. Although previous work demonstrated that uPARAP was the primary receptor for collagen internalization in dermal fibroblast...

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Uptake of denatured collagen into hepatic stellate cells: evidence for the involvement of urokinase plasminogen activator receptor-associated protein/Endo180

Cited by 37 publications

References 47 publications

Endocytosis of collagen by hepatic stellate cells regulates extracellular matrix dynamics

Endocytosis of collagen by hepatic stellate cells regulates extracellular matrix dynamics

uPARAP expression during murine lung development

Role of Urokinase Plasminogen Activator Receptor–Associated Protein in Mouse Lung

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