Urokinase-induced activation of the gp130/Tyk2/Stat3 pathway mediates a pro-inflammatory effect in human mesangial cells via expression of the anaphylatoxin C5a receptor

Shushakova, Nelli; Tkachuk, Natalia; Dangers, Marc; Tkachuk, Sergey; Park, Joon-Keun; Hashimoto, Kôji; Haller, Hermann; Dumler, Inna

doi:10.1242/jcs.03471

Cited by 11 publications

(19 citation statements)

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“…Our observations are also in line with previous findings from our groups and those of others pointing to uPAR proinflammatory [40] and proatherogenic potential [41]. They also strengthen the previously demonstrated interference of uPAR with the complement cascade controlling C5aR expression and related functional effects [6,7]. We found that C5aR expression in atherosclerotic lesions was significantly impaired in uPAR -/ -/LDLR -/ -mice.…”

Section: Discussionsupporting

confidence: 93%

“…Color images available online at www.liebertpub.com/scd VSMC and in VSMC phenotypic modulations [8,23]. Our previous studies point to uPARs ability to interfere with the complement system and, in particular, to control C5aR expression and to affect by this way C5aR-directed functional effects [6,7]. To examine whether uPAR might control C5aR upregulation in MSC during osteogenic differentiation, uPAR was downregulated in MSC by means of a lentivirusbased interfering RNA (Supplementary Fig.…”

Section: Fig 1 Mesenchymal Stem Cells (Msc) Undergo Differentiationmentioning

confidence: 99%

“…Molecular mechanisms underlying regulated expression of C5aR in these processes remain unclear. We have shown previously that the multifunctional urokinase receptor uPAR is an important mediator of the anaphylatoxin C5a/C5a receptor (C5aR) complement cascade controlling C5aR expression, C5aR-directed signaling, and related functional effects in kidney mesangial cells and in alveolar macrophages in vitro and in vivo [6,7]. Our recent findings revealed one further novel function of uPAR as a regulator of differentiation and mobilization of bone marrow-derived mesenchymal stem cells (MSC) and of their engraftment at the place of injury [8].…”

Section: Introductionmentioning

confidence: 99%

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Urokinase Receptor Mediates Osteogenic Differentiation of Mesenchymal Stem Cells and Vascular Calcification via the Complement C5a Receptor

Anaraki

Patecki²,

Larmann³

et al. 2014

Stem Cells and Development

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Vascular calcification is a severe consequence of several pathological processes with a lack of effective therapy. Recent studies suggest that circulating and resident mesenchymal stem cells (MSC) contribute to the osteogenic program of vascular calcification. Molecular mechanisms underlying MSC osteogenic potential and differentiation remain, however, sparsely explored. We investigated a role for the complement receptor C5aR in these processes. We found that expression of C5aR was upregulated upon differentiation of human MSC to osteoblasts. C5aR inhibition by silencing and specific antagonist impaired osteogenic differentiation. We demonstrate that C5aR expression upon MSC differentiation was regulated by the multifunctional urokinase receptor (uPAR). uPAR targeting by siRNA resulted in complete abrogation of C5aR expression and consequently in the inhibition of MSC-osteoblast differentiation. We elucidated the NFkB pathway as the mechanism utilized by the uPAR-C5aR axis. MSC treatment with the NFkB inhibitor completely blocked the differentiation process. Nuclear translocation of the p65 RelA component of the NFkB complex was induced under osteogenic conditions and impaired by the inhibition of uPAR or C5aR. Dual-luciferase reporter assays demonstrated enhanced NFkB signaling upon MSC differentiation, whereas uPAR and C5aR downregulation lead to inhibition of the NFkB activity. We show involvement of the Erk1/2 kinase in this cascade. In vivo studies in a uPAR/LDLR double knockout mouse model of diet-induced atherosclerosis revealed impaired C5aR expression and calcification in aortic sinus plaques in uPAR -/ -/LDLR -/ -versus uPAR + / + /LDLR -/ -control animals. These results suggest that uPAR-C5aR axis via the underlying NFkB transcriptional program controls osteogenic differentiation with functional impact on vascular calcification in vivo.

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Section: Discussionsupporting

confidence: 93%

Section: Fig 1 Mesenchymal Stem Cells (Msc) Undergo Differentiationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Urokinase Receptor Mediates Osteogenic Differentiation of Mesenchymal Stem Cells and Vascular Calcification via the Complement C5a Receptor

Anaraki

Patecki²,

Larmann³

et al. 2014

Stem Cells and Development

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“…uPAR or uPA overexpression has been reported in many human cancers and shown to predict poorer prognosis in patients with breast, prostate, hepatocellular, and pancreatic cancers. [17][18][19][20] Interaction of uPAR and uPA has also been shown to lead to Stat3 phosphorylation and activation, a critical cell survival transcription activator, [21,22] and Stat3 activation has been associated with resistance to cisplatin-based chemotherapy in lung and ovarian cancers. [22,23] Recently, global gene expression and genetic/ epigenetic analysis of HNSCC tumors and cells have identified a large number of molecular alterations associated with cisplatin resistance.…”

Section: Introductionmentioning

confidence: 99%

“…[17][18][19][20] Interaction of uPAR and uPA has also been shown to lead to Stat3 phosphorylation and activation, a critical cell survival transcription activator, [21,22] and Stat3 activation has been associated with resistance to cisplatin-based chemotherapy in lung and ovarian cancers. [22,23] Recently, global gene expression and genetic/ epigenetic analysis of HNSCC tumors and cells have identified a large number of molecular alterations associated with cisplatin resistance. [24,25] In the current study, to investigate the phenomena of acquired cisplatin resistance in HNSCC, we performed gene expression profiling of cisplatin sensitive and resistant cells isogenic HNSCC cell lines.…”

Section: Introductionmentioning

confidence: 99%

SERPINB2 down‐regulation contributes to chemoresistance in head and neck cancer

Huang

et al. 2013

Molecular Carcinogenesis

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Resistance to cisplatin-based chemotherapy is responsible for the majority of deaths from head and neck squamous cell carcinoma (HNSCC). In this study, using genome-wide gene expression analysis to investigate potential molecular mediators of HNSCC chemoresistance, we identified SERPINB2, a known inhibitor of extracellular serine proteinase urokinase-type plasminogen activator (uPA), as an important candidate. Whereas SERPINB2 is known to function as a suppressor of uPA molecular cascades, many of which play important roles in tumor invasion and metastasis, a role for SERPINB2 in cancer drug resistance has not been examined. By using quantitative real-time PCR and Western blot analysis, we determined that SERPINB2 mRNA and protein levels correlated with chemoresistance in HNSCC cell lines, and significantly lower SERPINB2 expression levels were observed in two cisplatin resistant HNSCC subclones compared to their isogenic drug-sensitive parental lines. Immunohistochemical analysis of HNSCC tumor tissues from patients treated with neoadjuvant cisplatin-based chemotherapy (n = 67 cases) revealed a significant association between SERPINB2 protein levels, tumor differentiation and patient relapse. Moreover, SERPINB2 down-regulation was a strong predictor of reduced overall survival in patients with HNSCC who received cisplatin-based chemotherapy (P = 0.001, log rank test). Studies using either siRNA-mediated down-regulation or forced over-expression of SERPINB2 in HNSCC cell lines confirmed a functional role for SERPINB2 in drug resistance. The findings were further supported using chemical inhibitors of STAT3 activity (a downstream effecter of uPAR signaling pathway), showing that STAT3 suppression altered HNSCC cell line cisplatin sensitivity. This is the first report on a role for SERPINB2 in acquired resistance to cisplatin in patients with HNSCC.

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Urokinase Receptor Mediates Osteoclastogenesis via M-CSF Release From Osteoblasts and the c-Fms/PI3K/Akt/NF-κB Pathway in Osteoclasts

Anaraki

Patecki

Tkachuk

et al. 2014

Journal of Bone and Mineral Research

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Bone remodeling is a dynamic process based on a fine-tuned balance between formation and degradation of bone. Osteoblasts (OBLs) are responsible for bone formation and bone resorption is mediated by osteoclasts (OCLs). The mechanisms regulating the OBL-OCL balance are critical in health and disease; however, they are still far from being understood. We reported recently that the multifunctional urokinase receptor (uPAR) mediates osteogenic differentiation of mesenchymal stem cells (MSCs) to OBLs and vascular calcification in atherosclerosis. Here, we address the question of whether uPAR may also be engaged in regulation of osteoclastogenesis. We show that uPAR mediates this process in a dual fashion. Thus, uPAR affected OBL-OCL interplay. We observed that osteoclastogenesis was significantly impaired in co-culture of monocyte-derived OCLs and in OBLs derived from MSCs lacking uPAR. We show that expression and release, from OBLs, of macrophage colony-stimulating factor (M-CSF), which is indispensable for OCL differentiation, was inhibited by uPAR loss. We further found that uPAR, on the other hand, controlled formation, differentiation, and functional properties of macrophage-derived OCLs. Expression of osteoclastogenic markers, such as tartrate-resistant acid phosphatase (TRAP) and cathepsin K, was impaired in OCLs derived from uPAR-deficient macrophages. The requirement of uPAR for osteoclastogenesis was further confirmed by immunocytochemistry and in bone resorption assay. We provide evidence that the underlying signaling mechanisms involve uPAR association with the M-CSF binding receptor c-Fms followed by c-Fms phosphorylation and activation of the PI3K/Akt/NF-kB pathway in OCLs. We further show that uPAR uses this pathway to regulate a balance between OCL differentiation, apoptosis, and cell proliferation. Our study identified uPAR as an important and multifaceted regulator of OBL-OCL molecular interplay that may serve as an attractive target in bone disease and ectopic calcification.

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Urokinase-induced activation of the gp130/Tyk2/Stat3 pathway mediates a pro-inflammatory effect in human mesangial cells via expression of the anaphylatoxin C5a receptor

Cited by 11 publications

References 0 publications

Urokinase Receptor Mediates Osteogenic Differentiation of Mesenchymal Stem Cells and Vascular Calcification via the Complement C5a Receptor

Urokinase Receptor Mediates Osteogenic Differentiation of Mesenchymal Stem Cells and Vascular Calcification via the Complement C5a Receptor

SERPINB2 down‐regulation contributes to chemoresistance in head and neck cancer

Urokinase Receptor Mediates Osteoclastogenesis via M-CSF Release From Osteoblasts and the c-Fms/PI3K/Akt/NF-κB Pathway in Osteoclasts

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