Osteopontin splice variants expressed by breast tumors regulate monocyte activation via MCP-1 and TGF-β1

Sun, Jia; Feng, Alei; Chen, Songyu; Zhang, Yun; Xie, Qi; Yang, Meixiang; Shao, Qianqian; Liu, Jia; Yang, Qifeng; Kong, Beihua; Qu, Xun

doi:10.1038/cmi.2012.67

Cited by 25 publications

(19 citation statements)

References 30 publications

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“…In contrast to our findings, OPN isoforms derived from tumour (MCF-7) cells do not display pro-inflammatory activity (Sun et al 2013). Here, Sun et al observed no effect of OPN isoforms on LPS-mediated IL-8, IL-6 or IL-12 production from primary human monocytes, whereas all isoforms decreased tumour necrosis factor-α and increased IL-10 production.…”

Section: Discussioncontrasting

confidence: 99%

OPN‐a induces muscle inflammation by increasing recruitment and activation of pro‐inflammatory macrophages

Many

Yokosaki

Uaesoontrachoon

et al. 2016

Experimental Physiology

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New Findings What is the central question of this study? What is the functional relevance of OPN isoform expression in muscle pathology? What is the main finding and its importance? The full‐length human OPN‐a isoform is the most pro‐inflammatory isoform in the muscle microenvironment, acting on macrophages and myoblasts in an RGD‐integrin‐dependent manner. OPN‐a upregulates expression of tenascin‐C (TNC), a known Toll‐like receptor 4 (TLR4) agonist. Blocking TLR4 signalling inhibits the pro‐inflammatory effects of OPN‐a, suggesting that a potential mechanism of OPN action is by promoting TNC–TLR4 signalling. Although osteopontin (OPN) is an important mediator of muscle remodelling in health and disease, functional differences in human spliced OPN variants in the muscle microenvironment have not been characterized. We thus sought to define the pro‐inflammatory activities of human OPN isoforms (OPN‐a, OPN‐b and OPN‐c) on cells present in regenerating muscle. OPN transcripts were quantified in normal and dystrophic human and dog muscle. Human macrophages and myoblasts were stimulated with recombinant human OPN protein isoforms, and cytokine mRNA and protein induction was assayed. OPN isoforms were greatly increased in dystrophic human (OPN‐a > OPN‐b > OPN‐c) and dog muscle (OPN‐a = OPN‐c). In healthy human muscle, mechanical loading also upregulated OPN‐a expression (eightfold; P < 0.01), but did not significantly upregulate OPN‐c expression (twofold; P > 0.05). In vitro, OPN‐a displayed the most pronounced pro‐inflammatory activity among isoforms, acting on both macrophages and myoblasts. In vitro and in vivo data revealed that OPN‐a upregulated tenascin‐C (TNC), a known Toll‐like receptor 4 (TLR4) agonist. Inhibition of TLR4 signalling attenuated OPN‐mediated macrophage cytokine production. In summary, OPN‐a is the most abundant and functionally active human spliced isoform in the skeletal muscle microenvironment. Here, OPN‐a promotes pro‐inflammatory signalling in both macrophages and myoblasts, possibly through induction of TNC–TLR4 signalling. Together, our findings suggest that specific targeting of OPN‐a and/or TNC signalling in the damaged muscle microenvironment may be of therapeutic relevance.

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Section: Discussioncontrasting

confidence: 99%

OPN‐a induces muscle inflammation by increasing recruitment and activation of pro‐inflammatory macrophages

Many

Yokosaki

Uaesoontrachoon

et al. 2016

Experimental Physiology

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“…Changes of OPN and TGFβ1 levels were correlated (R = 0.62). From preclinical studies there is good evidence for an OPN mediated TGFβ1 expression [28–30]. This is in agreement with the kinetics observed in this study, peak concentration of TGFβ1 lagged behind.…”

Section: Discussionsupporting

confidence: 91%

Perioperative changes in osteopontin and TGFβ1 plasma levels and their prognostic impact for radiotherapy in head and neck cancer

et al. 2017

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BackgroundIn head and neck cancer little is known about the kinetics of osteopontin (OPN) expression after tumor resection. In this study we evaluated the time course of OPN plasma levels before and after surgery.MethodsBetween 2011 and 2013 41 consecutive head and neck cancer patients were enrolled in a prospective study (group A). At different time points plasma samples were collected: T0) before, T1) 1 day, T2) 1 week and T3) 4 weeks after surgery. Osteopontin and TGFβ1 plasma concentrations were measured with a commercial ELISA system. Data were compared to 131 head and neck cancer patients treated with primary (n = 42) or postoperative radiotherapy (n = 89; group B1 and B2).ResultsA significant OPN increase was seen as early as 1 day after surgery (T0 to T1, p < 0.01). OPN levels decreased to base line 3-4 weeks after surgery. OPN values were correlated with postoperative TGFβ1 expression suggesting a relation to wound healing. Survival analysis showed a significant benefit for patients with lower OPN levels both in the primary and postoperative radiotherapy group (B1: 33 vs 11.5 months, p = 0.017, B2: median not reached vs 33.4, p = 0.031). TGFβ1 was also of prognostic significance in group B1 (33.0 vs 10.7 months, p = 0.003).ConclusionsPatients with head and neck cancer showed an increase in osteopontin plasma levels directly after surgery. Four weeks later OPN concentration decreased to pre-surgery levels. This long lasting increase was presumably associated to wound healing. Both pretherapeutic osteopontin and TGFβ1 had prognostic impact.

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“…Our in vivo data is also supported by the lack of CCL2-induction found in our myofibroblast cell culture. These findings are novel and additive in respect to a study, where osteopontin has been suggested to specifically modulate expression of CCL2 chemokine and thus regulating activity of monocytes in vitro [23]. Therefore, our findings may be also interpreted as a result of osteopontin-deficiency on noncardiomyocytes, that is, macrophages and fibroblasts in the heart.…”

Section: Discussionsupporting

confidence: 60%

Cardioprotective Effects of Osteopontin-1 during Development of Murine Ischemic Cardiomyopathy

Duerr¹,

Mesenholl²,

Heinemann³

et al. 2014

BioMed Research International

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Repetitive brief ischemia and reperfusion (I/R) is associated with ventricular dysfunction in pathogenesis of murine ischemic cardiomyopathy and human hibernating myocardium. We investigated the role of matricellular protein osteopontin-1 (OPN) in murine model of repetitive I/R. One 15-min LAD-occlusion followed by reperfusion was performed daily over 3, 5, and 7 consecutive days in C57/Bl6 wildtype- (WT-) and OPN−/−-mice (n = 8/group). After echocardiography hearts were processed for histological and mRNA-studies. Cardiac fibroblasts were isolated, cultured, and stimulated with TGF-β1. WT-mice showed an early, strong, and cardiomyocyte-specific osteopontin-expression leading to interstitial macrophage infiltration and consecutive fibrosis after 7 days I/R in absence of myocardial infarction. In contrast, OPN−/−-mice showed small, nontransmural infarctions after 3 days I/R associated with significantly worse ventricular dysfunction. OPN−/−-mice had different expression of myocardial contractile elements and antioxidative mediators and a lower expression of chemokines during I/R. OPN−/−-mice showed predominant collagen deposition in macrophage-rich small infarctions. We found lower induction of tenascin-C, MMP-9, MMP-12, and TIMP-1, whereas MMP-13-expression was higher in OPN−/−-mice. Cultured OPN−/−-myofibroblasts confirmed these findings. In conclusion, osteopontin seems to modulate expression of contractile elements, antioxidative mediators, and inflammatory response and subsequently remodel in order to protect cardiomyocytes in murine ischemic cardiomyopathy.

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Osteopontin splice variants expressed by breast tumors regulate monocyte activation via MCP-1 and TGF-β1

Cited by 25 publications

References 30 publications

OPN‐a induces muscle inflammation by increasing recruitment and activation of pro‐inflammatory macrophages

OPN‐a induces muscle inflammation by increasing recruitment and activation of pro‐inflammatory macrophages

Perioperative changes in osteopontin and TGFβ1 plasma levels and their prognostic impact for radiotherapy in head and neck cancer

Cardioprotective Effects of Osteopontin-1 during Development of Murine Ischemic Cardiomyopathy

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