Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation

Kim, Sun-Hwa; Koga, Tatsuya; Isobe, Miho; Kern, Britt; Yokochi, Taeko; Chinn, Y. Eugene; Karsenty, Gérard; Taniguchi, Tadatsugu; Takayanagi, Hiroshi

doi:10.1101/gad.1119303

Cited by 245 publications

(252 citation statements)

References 49 publications

Supporting

Mentioning

231

Contrasting

Order By: Relevance

“…IFN-b has been reported to activate STAT1 [45], an event mediating signals from IFN receptors. However, in STAT1 knockout mice there has been observed significantly elevated OPN production [46]. Consequently, STAT1 activation by IFN-b can be assumed to inhibit OPN production.…”

Section: Discussionmentioning

confidence: 99%

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS

Chen

Nie

et al. 2009

Eur J Immunol

View full text Add to dashboard Cite

IFN-b currently serves as one of the major treatments for MS. Its anti-inflammatory mechanism has been reported as involving a shift in cytokine balance from Th1 to Th2 in the T-cell response against elements of the myelin sheath. In addition to the Th1 and Th2 groups, two other important pro-inflammatory cytokines, IL-17 and osteopontin (OPN), are believed to play important roles in CNS inflammation in the pathogenesis of MS. In this study, we examined the potential effects of IFN-b on the regulation of OPN and IL-17 in MS patients. We found that IFN-b used in vitro at 0.5-3 ng/mL significantly inhibited the production of OPN in primary T cells derived from PBMC. The inhibition of OPN was determined to occur at the CD4 1 T-cell level. In addition, IFN-b inhibited the production of IL-17 and IL-21 in CD4 1 T cells. It has been described that IFN-b suppresses IL-17 production through the inhibition of a monocytic cytokine, the intracellular translational isoform of OPN. Our further investigation demonstrated that IFN-b also acted directly on the CD4 1 T cells to regulate OPN and IL-17 expression through the type I IFN receptor-mediated activation of STAT1 and suppression of STAT3 activity. Administration of IFN-b to EAE mice ameliorated the disease severity. Furthermore, spinal cord infiltration of OPN 1 and IL-17 1 cells decreased in IFN-b-treated EAE mice along with decreases in serum levels of OPN and IL-21. Importantly, decreased OPN production by IFN-b treatment contributes to the reduced migratory activity of T cells. Taken together, the results from both in vitro and in vivo experiments indicate that IFN-b treatment can down-regulate the OPN and IL-17 production in MS. This study provides new insights into the mechanism of action of IFN-b in the treatment of MS. IntroductionMS is a disease of the CNS characterized by chronic inflammatory and demyelinating processes [1]. CNS inflammation is considered as an important feature in MS pathology, and is directly associated with the disease process in MS [2]. Agents that have anti-inflammatory properties have been shown to suppress the disease activity to various degrees. MS is now commonly treated with an immunomodulatory agent, IFN-b, which has shown significant treatment efficacy and is Ã These authors contributed equally to the work. Eur. J. Immunol. 2009. 39: 2525-2536 Immunomodulation 2525 thought to involve a number of different mechanisms of action [3,4]. However, despite extensive clinical experience in the use of IFN-b, its mechanism of action has not been fully elucidated. Studies into its mechanism of action have revealed that anti-inflammatory properties of IFN-b function through the regulation of Th1 and Th2 cytokines [5,6]. Further, there is an evidence indicating that IFN-b promotes the production of IL-10 and inhibits the action of pro-inflammatory cytokines [7,8].Osteopontin (OPN), also known as early T lymphocyte activation-1, has been recently recognized as a pro-inflammatory cytokine promoting the production of IFN-g and IL-12 in macrophages...

show abstract

Section: Discussionmentioning

confidence: 99%

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS

Chen

Nie

et al. 2009

Eur J Immunol

View full text Add to dashboard Cite

show abstract

“…Bones formed via either endochondral or intramembranous ossification in Stat1 Ϫ/Ϫ mice have an increase in mass and mineral density due to a disruption in the proliferation and differentiation properties of both osteoblasts and osteoclasts (Kim et al, 2003;Xiao et al, 2004), and FGFs have an anti-proliferative effect on chondrocytes that is disrupted by loss of Stat1 (Sahni et al, 1999(Sahni et al, , 2001.…”

Section: Stat Proteins Act Upstream Of Tcfap2amentioning

confidence: 99%

Frontal nasal prominence expression driven by Tcfap2a relies on a conserved binding site for STAT proteins

Donner

Williams

2006

Developmental Dynamics

View full text Add to dashboard Cite

The AP-2 transcription factor family is linked with development of the head and limbs in both vertebrate and invertebrate species. Recent evidence has also implicated this gene family in the evolution of the neural crest in chordates, a critical step that allowed the development and elaboration of the vertebrate craniofacial skeleton. In mice, the inappropriate embryonic expression of one particular AP-2 gene, Tcfap2a, encoding AP-2␣, results in multiple developmental abnormalities, including craniofacial and limb defects. Thus, Tcfap2a provides a valuable genetic resource to analyze the regulatory hierarchy responsible for the evolution and development of the face and limbs. Previous studies have identified a 2-kilobase intronic region of both the mouse and human AP-2␣ locus that directs expression of a linked LacZ transgene to the facial processes and the distal mesenchyme of the limb bud in transgenic mice. Further analysis identified two highly conserved regions of ϳ200 -400 bp within this tissue-specific enhancer. We have now initiated a transgenic and biochemical analysis of the most important of these highly conserved regions. Our analysis indicates that although the sequences regulating face and limb expression have been integrated into a single enhancer, different cis-acting sequences ultimately control these two expression domains. Moreover, these studies demonstrate that a conserved STAT binding site provides a major contribution to the expression of Tcfap2a in the facial prominences. Developmental Dynamics 235: 1358 -1370, 2006.

show abstract

“…Indeed, both Runx2 and Oct-1 have been shown to interact with GR [Ning and Robins, 1999;Prefontaine et al, 1999], suggesting that the Runx2/Oct-1 complex may recruit GR. Furthermore, since Runx2 has been shown to interact with STAT1 [Kim et al, 2003], it might also be able to interact with STAT5, thus providing a link between prolactin signaling and Runx2 activity. As Runx2 is a nuclear matrix-binding protein it is also possible to envisage a role in recruiting the b-casein promoter to transcriptionally active nuclear sub-domains via its interaction with Oct-1.…”

Section: A Role For Runx2 In Normal Mammary Glandmentioning

confidence: 99%

A role for Runx2 in normal mammary gland and breast cancer bone metastasis

Shore

2005

J of Cellular Biochemistry

View full text Add to dashboard Cite

The transcription factor Runx2 is essential for the formation of the skeleton. It has therefore primarily been considered as a specific regulator of bone genes. However, mice containing a LacZ insertion at the Runx2 locus also revealed expression in the nascent mammary epithelium. Reports of Runx2 expression in breast cancer cell lines, combined with the fact that breast cancers preferentially metastasise to bone, have also hinted at a potential role for Runx2 in the formation of bone metastasese. These initial observations have prompted further analysis of Runx2 function in mammary epithelial cells and recent findings have demonstrated that Runx2 does indeed contribute to the ability of metastatic breast cancer cell lines to form osteolytic bone lesions. In addition, evidence is accumulating that Runx2 has a role in the regulation of normal mammary gland gene expression and recent data demonstrate that it regulates transcription of the mammary gland-specific gene, b-casein. In this article I discuss recent advances that link Runx2 with normal mammary epithelial cell function and the development of bone metastasese in breast cancer.

show abstract

Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation

Cited by 245 publications

References 49 publications

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS

Frontal nasal prominence expression driven by Tcfap2a relies on a conserved binding site for STAT proteins

A role for Runx2 in normal mammary gland and breast cancer bone metastasis

Contact Info

Product

Resources

About

Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation

Cited by 245 publications

References 49 publications

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4+ T Cells in MS

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4+ T Cells in MS

Frontal nasal prominence expression driven by Tcfap2a relies on a conserved binding site for STAT proteins

A role for Runx2 in normal mammary gland and breast cancer bone metastasis

Contact Info

Product

Resources

About

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS

Regulatory effects of IFN‐β on production of osteopontin and IL‐17 by CD4⁺ T Cells in MS