Smad6 Methylation Represses NFκB Activation and Periodontal Inflammation

Zhang, T.; Wu, Jian; Ungvijanpunya, N.; Jackson‐Weaver, Olan; Gou, Yunjiu; Feng, Jing; Ho, Thach-Vu; Shen, Yudao; Liu, J.; Richard, Stéphane; Jin, Jian; Hajishengallis, George; Chai, Yang; Xu, Jun

doi:10.1177/0022034518755688

Cited by 37 publications

(46 citation statements)

References 29 publications

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“…Consequently, many activities of PRMT1 in development may not be related to TGF-␤ family signaling, and others might involve the methylation of inhibitory SMADs. For example, PRMT1 inactivation in periodontal epithelium aggravates inflammatory responses and periodontal tissue injury, and these effects appear to relate to the role of PRMT1-mediated SMAD6 methylation in repressing TLR-MyD88 -NF-B signaling (34). Whether SMAD7 plays a parallel role needs to be assessed.…”

Section: Smad7 Methylation By Prmt1 Controls Tgf-␤ Signaling and Emtmentioning

confidence: 99%

Arginine methylation of SMAD7 by PRMT1 in TGF-β–induced epithelial–mesenchymal transition and epithelial stem-cell generation

Katsuno

Qin

Oses-Prieto

et al. 2018

Journal of Biological Chemistry

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The epithelial-to-mesenchymal transdifferentiation (EMT) is crucial for tissue differentiation in development and drives essential steps in cancer and fibrosis. EMT is accompanied by reprogramming of gene expression and has been associated with the epithelial stem-cell state in normal and carcinoma cells. The cytokine transforming growth factor β (TGF-β) drives this program in cooperation with other signaling pathways and through TGF-β-activated SMAD3 as the major effector. TGF-β-induced SMAD3 activation is inhibited by SMAD7 and to a lesser extent by SMAD6, and SMAD6 and SMAD7 both inhibit SMAD1 and SMAD5 activation in response to the TGF-β-related bone morphogenetic proteins (BMPs). We previously reported that, in response to BMP, protein arginine methyltransferase 1 (PRMT1) methylates SMAD6 at the BMP receptor complex, thereby promoting its dissociation from the receptors and enabling BMP-induced SMAD1 and SMAD5 activation. We now provide evidence that PRMT1 also facilitates TGF-β signaling by methylating SMAD7, which complements SMAD6 methylation. We found that PRMT1 is required for TGF-β-induced SMAD3 activation, through a mechanism similar to that of BMP-induced SMAD6 methylation, and thus promotes the TGF-β-induced EMT and epithelial stem-cell generation. This critical mechanism positions PRMT1 as an essential mediator of TGF-β signaling that controls the EMT and epithelial cell stemness through SMAD7 methylation.

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Section: Smad7 Methylation By Prmt1 Controls Tgf-␤ Signaling and Emtmentioning

confidence: 99%

Arginine methylation of SMAD7 by PRMT1 in TGF-β–induced epithelial–mesenchymal transition and epithelial stem-cell generation

Katsuno

Qin

Oses-Prieto

et al. 2018

Journal of Biological Chemistry

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“…Ligature-induced periodontitis is a well-established mouse model that recapitulates the pathogenesis of the human periodontal disease, including bacteria lm formation, host immune response stimulation, and alveolar bone loss. Ligand-induced periodontal bone loss was apparent from day ve [18][19][20]. We started treatment on day 8, representing an intervention protocol.…”

Section: Discussionmentioning

confidence: 99%

A New Anabolic compound, LLP2A-Ale, Reserves Periodontal Bone Loss in Mice Through Augmentation of Bone Formation

Yao¹,

Jiang

Liu

et al. 2020

Preprint

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Aims. Currently, there are no effective medications that reverse periodontal disease (PD)-induced bone loss. The objective of this study was to test a new anabolic compound, LLP2A-Ale, or with the combination treatment of mesenchymal stromal cell (MSC), in the treatment of bone loss secondary to PD. Martials and Methods. PD was induced in mice by placing a ligature around the second right molar. At one week after disease induction, the mice were treated with placebo, LLP2A-Ale, MSCs, or combination of LLP2A-Ale + MSCs, and euthanized at week 4. Results. We found that PD induced alveolar bone loss that was associated with reduced bone formation. LLP2A alone and in combination with MSCs sustained alveolar bone formation and reversed alveolar bone loss. Additionally, PD alone caused systemic inflammation and increased the circulating levels of G-CSF, IP-10, MIP-1a, and MIP2, which were suppressed by LLP2A-Ale +/- MSCs. LLP2A-Ale +/- MSCs increased bone formation at the peripheral skeletal site (distal femur), which was otherwise suppressed by PD. Conclusion. Our findings indicated that LLP2A-Ale treatment rescued alveolar bone loss caused by PD, primarily by increasing bone formation. LLP2A-Ale also attenuated the circulating levels of a series of inflammatory cytokines and reversed the PD-induced suppression of systemic bone formation.

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“…Although SMAD6 functions as a negative regulator of BMP signaling, it also has BMPindependent functions in innate immunity and other cellular processes (Choi et al, 2006;Lee et al, 2015;Zhang et al, 2018), so it may affect endothelial cell flow responses in BMP-independent ways. Alternatively, canonical BMP signaling also affects flow responses in complex ways, so SMAD6 may regulate flow responses downstream of both Notch and BMP inputs, and it will be interesting to determine whether SMAD6 is a critical integrator of these complex pathways under flow.…”

Section: Smad6 Regulates Endothelial Cell Barrier Function and Junctionsmentioning

confidence: 99%

SMAD6 Integrates Endothelial Cell Homeostatic Flow Responses Downstream of Notch

Ruter

Liu²,

Ngo³

et al. 2020

Preprint

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ABSTRACTLaminar shear stress regulates blood vessel morphogenesis and subsequent quiescence, leading to vascular homeostasis. Although important for vessel function, how vascular homeostasis is set up and maintained is poorly understood. SMAD6, a scaffold for several signaling pathways, is expressed in developing arteries and its expression is flow-regulated. We found that SMAD6 is essential for endothelial cell flow-mediated responses downstream of the mechanosensor Notch1. Endothelial cells with reduced SMAD6 levels failed to align under homeostatic laminar shear flow, while forced SMAD6 expression rescued misalignment induced by reduced Notch1 signaling. SMAD6-dependent homeostatic laminar flow responses required the Notch ligand Dll4 and Notch transcriptional activity. Mechanistically, neither the N-terminal nor the C-terminal domain of SMAD6 alone rescued flow alignment upon loss of Notch signaling. Endothelial cells with reduced Smad6 levels had compromised barrier function, and RNA profiling revealed upregulation of proliferation-associated genes and down regulation of junction-associated genes. Among junction-related genes affected by SMAD6 levels, the proto-cadherin PCDH12 was upregulated by homeostatic flow and required for proper flow-mediated endothelial cell alignment. Thus, SMAD6 is a critical integrator of flow-mediated signaling inputs downstream of Notch1, as vessels transition from an angiogenic to a homeostatic phenotype.

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Smad6 Methylation Represses NFκB Activation and Periodontal Inflammation

Cited by 37 publications

References 29 publications

Arginine methylation of SMAD7 by PRMT1 in TGF-β–induced epithelial–mesenchymal transition and epithelial stem-cell generation

Arginine methylation of SMAD7 by PRMT1 in TGF-β–induced epithelial–mesenchymal transition and epithelial stem-cell generation

A New Anabolic compound, LLP2A-Ale, Reserves Periodontal Bone Loss in Mice Through Augmentation of Bone Formation

SMAD6 Integrates Endothelial Cell Homeostatic Flow Responses Downstream of Notch

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