Sprouty2 inhibition promotes proliferation and migration of periodontal ligament cells

Tanaka, Urara; Sanui, Terukazu; Fukuda, Takao; Toyoda, Kyosuke; Taketomi, Takaharu; Atomura, Ryo; Yamamichi, Kensuke; Maeda, Hidefumi; Nishimura, Fusanori

doi:10.1111/odi.12369

Cited by 5 publications

(6 citation statements)

References 39 publications

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“…In addition, previous studies in our laboratory have shown that sequestration of Spry2 induces ERK activation, proliferation, and osteogenesis in osteoblastic cells by basic FGF (bFGF) and epidermal growth factor (EGF) stimulation in vitro while suppressing ERK activation and cell proliferation in gingival epithelial cells 26. In addition, we found that Spry2 knockdown combined with bFGF and EGF stimulation increased periodontal ligament cell proliferation and migration, while it prevented osteoblastic differentiation27. Therefore, combined application of a Spry2 inhibitor, bFGF, and EGF may effectively facilitate the growth of the periodontal ligament and alveolar bone while preventing tooth ankylosis and blocking gingival epithelial down‐growth toward bony defects.…”

Section: Introductionsupporting

confidence: 54%

“…In contrast, suppression of Spry2 expression enhanced ubiquitination and degradation of EGF receptors, resulting in decreased proliferation of gingival epithelial cells [26]. In addition, we also found that Spry2 siRNA promoted lamellipodia formation induced by the stimulation of bFGF and EGF via AKT/PI3K and Rac1 activation in PDL cells, thereby activating cell migration while suppressing osteoblastic differentiation [27]. Thus, Spry2 downregulation could benefit periodontal tissue regeneration by increasing the stimulation of growth factors.…”

Section: Discussionmentioning

confidence: 68%

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Inhibition of Sprouty2 polarizes macrophages toward an M2 phenotype by stimulation with interferon γ andPorphyromonas gingivalislipopolysaccharide

Atomura

Sanui

Fukuda

et al. 2016

Immunity, Inflammation and Disease

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Periodontitis is a chronic inflammatory disorder caused by specific bacteria residing in the biofilm, particularly Porphyromonas gingivalis (Pg). Sprouty2 (Spry2) functions as a negative regulator of the fibroblast growth factor (FGF) signaling pathway. We previously demonstrated that sequestration of Spry2 induced proliferation and osteogenesis in osteoblastic cells by basic FGF (bFGF) and epidermal growth factor (EGF) stimulation in vitro, but diminished cell proliferation in gingival epithelial cells. In addition, Spry2 knockdown in combination with bFGF and EGF stimulation increases periodontal ligament cell proliferation and migration accompanied by prevention of osteoblastic differentiation. In this study, we investigated the mechanisms through which Spry2 depletion by interferon (IFN) γ and Pg lipopolysaccharide (LPS) stimulation affected the physiology of macrophages in vitro. Transfection of macrophages with Spry2 small‐interfering RNA (siRNA) promoted the expression of genes characteristic of M2 alternative activated macrophages, induced interleukin (IL)‐10 expression, and enhanced arginase activity, even in cells stimulated with IFNγ and Pg LPS. In addition, we found that phosphoinositide 3‐kinase (PI3K) and AKT activation by Spry2 downregulation enhanced efferocytosis of apoptotic cells by increasing Rac1 activation and decreasing nuclear factor kappa B (NFκB) p65 phosphorylation but not signal transducer and activator of transcription 1 (STAT1) phosphorylation. Collectively, our results suggested that topical administration of Spry2 inhibitors may efficiently resolve inflammation in periodontal disease as macrophage‐based anti‐inflammatory immunotherapy and may create a suitable environment for periodontal wound healing. These in vitro findings provide a molecular basis for new therapeutic approaches in periodontal tissue regeneration.

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Section: Introductionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 68%

Inhibition of Sprouty2 polarizes macrophages toward an M2 phenotype by stimulation with interferon γ andPorphyromonas gingivalislipopolysaccharide

Atomura

Sanui

Fukuda

et al. 2016

Immunity, Inflammation and Disease

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“…; Tanaka et al . ). Six1 expression is known to be regulated by BMP, FGF, and WNT, at least in the pre‐placodal region (Ahrens & Schlosser ; Litsiou et al .…”

Section: Discussionmentioning

confidence: 97%

“…Since human PDLSCs may be a source of MSCs for cell therapy (Zhu & Liang 2015), manipulating the proliferation of PDLSC is required for producing sufficient number of stem cells (Zhu & Liang 2015). For example, applying secreted molecules, such as BMP4, FGF2, WNT3A, and WNT5A, forces DF stem/progenitor cells and PDLSCs to increase proliferation (Liu et al 2013;Xiang et al 2014;Yan et al 2014;Tanaka et al 2015). Six1 expression is known to be regulated by BMP, FGF, and WNT, at least in the pre-placodal region (Ahrens & Schlosser 2005;Litsiou et al 2005).…”

Section: The Role Of Six1 In Regulating Dfc and Pdlc Proliferationmentioning

confidence: 99%

Six1 is required for mouse dental follicle cell and human periodontal ligament‐derived cell proliferation

et al. 2016

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The periodontal ligament (PDL) is a connective tissue that attaches the tooth cementum to the alveolar bone and is derived from dental follicle cells (DFCs). The DFCs form fibroblasts, osteoblasts, cementoblasts, and PDL stem cells (PDLSCs). We previously reported homeobox transcription factor Six1 expression in mouse DFCs. However, the role of Six1 in periodontal tissue development is largely unknown. In this study, we analyzed SIX1 expression in mouse periodontal tissue cells during postnatal development and adulthood. We also addressed the role of SIX1 in mouse periodontium development and in human cultured PDL-derived cells (PDLCs). In mouse development, SIX1 production was abundant in DFCs and PDL cells by 2 weeks, but it was greatly diminished in the PDL at 4 weeks and in adults. Although the SIX1-positive cell distribution was sparse in the adult PDL, SIX1-positive cells were observed with low expression levels. We used 5-ethynyl-2 0 -deoxyuridine (EdU) for cell labeling to reveal numerous EdU/SIX1-double positive cells at 2 weeks; however, a few EdU-positive cells remained at 4 weeks. The proportion of DFCs that incorporated EdU was significantly lower in Six1-deficient mice compared with wild-type mice at E18.5. In human PDLCs, SIX1 was intensely expressed, and SIX1-knockdown using siRNA reduced proliferating PDLCs. Our results suggest that SIX1 is a key proliferation regulator in mouse DFCs and human PDLCs, which provides novel insight into Six family gene function in mammals.

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“…In our recent study entitled "Sprouty2 inhibition promotes proliferation and migration of periodontal ligament cells", we demonstrated that Spry2 depletion by bFGF and EGF stimulation markedly enhanced PDL cell proliferation and migration [24]. Spry2 knockdown increased bFGF and EGF-induced ERK activation and proliferation in PDL cells, and increased cell migration in a scratch wound-healing assay and Boyden chamber migration assay.…”

Section: Introductionmentioning

confidence: 99%

Biological Effects of Sprouty2 Inhibition in Periodontal Ligament Cells

Sanui¹,

Fukuda²,

Tanaka³

et al. 2016

J Cell Signal

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Sprouty2 inhibition promotes proliferation and migration of periodontal ligament cells

Abstract: Spry2 combined with bFGF and EGF stimulation reduced PDL cell migration and proliferation with inducing osteoblastic differentiation. These in vitro findings may provide a molecular basis for novel therapeutic approaches for establishing periodontal tissue regeneration.

Cited by 5 publications

References 39 publications

Inhibition of Sprouty2 polarizes macrophages toward an M2 phenotype by stimulation with interferon γ andPorphyromonas gingivalislipopolysaccharide

Inhibition of Sprouty2 polarizes macrophages toward an M2 phenotype by stimulation with interferon γ andPorphyromonas gingivalislipopolysaccharide

Six1 is required for mouse dental follicle cell and human periodontal ligament‐derived cell proliferation

Biological Effects of Sprouty2 Inhibition in Periodontal Ligament Cells

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