The forkhead transcription factor Foxc2 promotes osteoblastogenesis via up-regulation of integrin β1 expression

Park, Su Jin; Gadi, Jogeswar; Cho, Kyoung Won; Kim, Kwang Joon; Kim, Se Hwa; Jung, Han Sung; Lim, Sung Kil

doi:10.1016/j.bone.2011.05.012

Cited by 42 publications

(25 citation statements)

References 40 publications

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“…(http://genome.ucsc.edu/cgi-bin/hgGateway). Recently, the forkhead transcription factor FoxC2 was reported to upregulate β1-integrin expression by directly binding FBEs in the integrin β1 promoter22. We detected the role of FoxC2 in the EP1 receptor/NF-κB pathway in Huh-7 cells.…”

Section: Resultsmentioning

confidence: 74%

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Prostaglandin E2 stimulates β1-integrin expression in hepatocellular carcinoma through the EP1 receptor/PKC/NF-κB pathway

Bai

Wang

Guo

et al. 2014

Sci Rep

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Prostaglandin E2 (PGE2) has been implicated in cell invasion in hepatocellular carcinoma (HCC), via increased β1-integrin expression and cell migration; however, the mechanism remains unclear. PGE2 exerts its effects via four subtypes of the E prostanoid receptor (EP receptor 1–4). The present study investigated the effect of EP1 receptor activation on β1-integrin expression and cell migration in HCC. Cell migration increased by 60% in cells treated with 17-PT-PGE2 (EP1 agonist), which was suppressed by pretreatment with a β1-integrin polyclonal antibody. PGE2 increased β1-integrin expression by approximately 2-fold. EP1 receptor transfection or treatment with 17-PT-PGE2 mimicked the effect of PGE2 treatment. EP1 siRNA blocked PGE2-mediated β1-integrin expression. 17-PT-PGE2 treatment induced PKC and NF-κB activation; PKC and NF-κB inhibitors suppressed 17-PT-PGE2-mediated β1-integrin expression. FoxC2, a β1-integrin transcription factor, was also upregulated by 17-PT-PGE2. NF-κB inhibitor suppressed 17-PT-PGE2-mediated FoxC2 upregulation. Immunohistochemistry showed p65, FoxC2, EP1 receptor and β1-integrin were all highly expressed in the HCC cases. This study suggested that PGE2 upregulates β1-integrin expression and cell migration in HCC cells by activating the PKC/NF-κB signaling pathway. Targeting PGE2/EP1/PKC/NF-κB/FoxC2/β1-integrin pathway may represent a new therapeutic strategy for the prevention and treatment of this cancer.

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Section: Resultsmentioning

confidence: 74%

“…Interestingly, there are many FBEs in the promotor of β1-integrin in liver cells. The forkhead transcription factor Foxc2 enhances the expression of β1-integrin in osteoblast cells by direct binding to a FBE in its promoter22.…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin E2 stimulates β1-integrin expression in hepatocellular carcinoma through the EP1 receptor/PKC/NF-κB pathway

Bai

Wang

Guo

et al. 2014

Sci Rep

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“…Thus, lymphedema-dependent and lymphedema-independent effects may influence bone formation in this mouse model. Indeed, both Foxc2 (Park et al, 2011) and Cx37 (Pacheco-Costa et al, 2014) are expressed by osteogenic cells, and mice with separate genetic deletion of these proteins have defects in skeletogenesis and altered structural bone characteristics (Iida et al, 1997; Pacheco-Costa et al, 2014). At present, it is unclear whether Foxc2 and Cx37 share molecular pathways in bone development, but the craniofacial features that are exhibited in mice only when deficiencies in Foxc2 and Cx37 are combined are consistent with this idea.…”

Section: Discussionmentioning

confidence: 99%

Combining Foxc2 and Connexin37 deletions in mice leads to severe defects in lymphatic vascular growth and remodeling

Kanady

Munger

Witte

et al. 2015

Developmental Biology

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Connexins (Cxs), proteins that are vital for intercellular communication in vertebrates, have recently been shown to play a critical role in lymphatic development. However, our knowledge is currently limited regarding the functional relationships of Cxs with other proteins and signaling pathways. Cell culture studies have shown that Cx37 is necessary for coordinated activation of the transcription factor NFATc1, which cooperates with Foxc2 (another transcription factor) during lymphatic endothelial development. These data suggest that Cxs, Foxc2, and NFATc1 are part of a common developmental pathway. Here, we present a detailed characterization of Foxc2 +/−Cx37 −/− mice, demonstrating that lymphatic network architecture and valve formation rely on the concurrent embryonic expression and function of Foxc2 and Cx37. Foxc2 +/−Cx37−/− mice have lymphedema in utero, exhibit craniofacial abnormalities, show severe dilation of intestinal lymphatics, display abnormal lacteal development, lack lymphatic valves, and typically die perinatally (outcomes not seen in Foxc2 +/− or Cx37−/− mice separately). We provide a rigorous, quantitative documentation of lymphatic vascular network changes that highlight the specific structural alterations that occur in Foxc2+/− Cx37−/− mice. These data provide further evidence suggesting that Foxc2 and Cx37 are elements in a common molecular pathway directing lymphangiogenesis.

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“…Many studies have revealed a multitude of factors such as mechanical stress [24,46], anabolic molecules [47,48], and implant surface topography [49] that can regulate cell osteogenesis through the integrin a5b1 pathway. Our study further demonstrates that the integrin a5b1 signaling cascade is another influencing factor depending on the chemical property of material surfaces.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic Surface Effects of Tantalum and Titanium on Integrin α5β1/ ERK1/2 Pathway-Mediated Osteogenic Differentiation in Rat Bone Mesenchymal Stromal Cells

Zhuang

Tang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Accumulating evidence demonstrates the superior osteoinductivity of tantalum (Ta) to that of titanium (Ti); however, the mechanisms underlying these differences are unclear. Thus, the objective of the present study was to examine the effects of Ta and Ti surfaces on osteogenesis using rat bone mesenchymal stromal cells (rBMSCs) as a model. Methods: Ta and Ti substrates were polished to a mirror finish to minimize the influences of structural factors, and the intrinsic surface effects of the two materials on the integrin α5β1/mitogen-activated protein kinases 3 and 1 (ERK1/2) cascade-mediated osteogenesis of rBMSCs were evaluated. Alkaline phosphatase (ALP) activity, Alizarin Red staining, real-time polymerase chain reaction, and western blot assays of critical osteogenic markers were conducted to evaluate the effects of the two substrates on cell osteogenesis. Moreover, the role of the integrin α5β1/ERK1/2 pathway on the osteoinductive performance of Ta and Ti was assessed by up- and down-regulation of integrin α5 and β1 with RNA interference, as well as through ERK1/2 inhibition with U0126. Results: Osteogenesis of rBMSCs seeded on the Ta surface was superior to that of cells seeded on the Ti surface in terms of ALP activity, extracellular matrix calcification, and the expression of integrin α5, integrin β1, ERK1/2, Runt-related transcription factor 2, osteocalcin, collagen type I, and ALP at both the mRNA and protein levels. Moreover, down-regulation of integrin α5 or integrin β1, or ERK1/2 inhibition severely impaired the osteoblastic differentiation on the Ta surface. By contrast, over-expression of integrin α5 or integrin β1 improved osteogenesis on the Ti substrates, while subsequent ERK1/2 inhibition abrogated this effect. Conclusion: The integrin α5β1/ERK1/2 pathway plays a crucial role in regulating rBMSCs osteogenic differentiation; thus, the greater ability of a Ta surface to trigger integrin α5β1/ERK1/2 signaling may explain its better osteoinductivity. The different effects of Ta and Ti surfaces on rBMSC osteogenesis are considered to be related to the conductive behaviors between integrin α5β1 and the oxides spontaneously formed on the two metals. These results should facilitate the development of engineering strategies with Ta and Ti surfaces for improved osteogenesis in endosteal implants.

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The forkhead transcription factor Foxc2 promotes osteoblastogenesis via up-regulation of integrin β1 expression

Cited by 42 publications

References 40 publications

Prostaglandin E2 stimulates β1-integrin expression in hepatocellular carcinoma through the EP1 receptor/PKC/NF-κB pathway

Prostaglandin E2 stimulates β1-integrin expression in hepatocellular carcinoma through the EP1 receptor/PKC/NF-κB pathway

Combining Foxc2 and Connexin37 deletions in mice leads to severe defects in lymphatic vascular growth and remodeling

Intrinsic Surface Effects of Tantalum and Titanium on Integrin α5β1/ ERK1/2 Pathway-Mediated Osteogenic Differentiation in Rat Bone Mesenchymal Stromal Cells

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