Expression of thymosin beta-4 in human periodontal ligament cells and mouse periodontal tissue and its role in osteoblastic/cementoblastic differentiation

Lee, Sang‐im; Lee, Deok-Won; Yun, Hyung-Mun; Cha, Hee‐Jae; Bae, Cheol-Hyeon; Cho, Eui-Sic; Kim, Eun-Cheol

doi:10.1016/j.diff.2015.08.003

Cited by 13 publications

(11 citation statements)

References 45 publications

(56 reference statements)

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“…Importantly, p38, ERK, and JNK MAPK pathways, as well as NF-κB pathways are involved in Tβ4 treated microglia. The regulation of Tβ4 in the activation of MAPK and NF-κB pathways has been reported in human periodontal ligament cells [7], which was consistent with our observation in microglia cells after ethanol exposure.…”

Section: Discussionsupporting

confidence: 82%

“…Tβ4 is the major G-actin-sequestering molecule with diverse functions related to cell proliferation, migration, angiogenesis, cell survival, and inhibition of inflammation [4][5][6][7]. Multiple studies have indicated that Tβ4 protein may promote tissue regeneration in multiple processes including corneal, epidermal, and cardiac wound healing, and is also effective in inflammatory diseases including severe acute pancreatitis and bleomycininduced lung fibrosis [8].…”

Section: Introductionmentioning

confidence: 99%

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Function of Thymosin Beta-4 in Ethanol-Induced Microglial Activation

Zhang¹,

Wu²,

Zeng³

et al. 2016

Cell Physiol Biochem

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Background/Aims: Neuroinflammation mediated by activated microglia may play a pivotal role in a variety of central nervous system (CNS) pathologic conditions, including ethanolinduced neurotoxicity. The purpose of this study was to investigate the function of Tβ4 in ethanol-induced microglia activation. Methods: Quantitative real-time PCR was conducted to assess the expression of Tβ4 and miR-339-5p. Western blot analysis was used to measure the expression of Tβ4, phosphorylated p38, ERK, JNK, Akt, and NF-κB p65. The concentration of TNF-α and IL-1β was determined using ELISA. NO concentration was measured using a nitric oxide colorimetric BioAssay Kit. Double immunofluorescence was performed to determine Tβ4 expression, in order to assess microglial activation in neonatal mouse FASD model. Results: Increased Tβ4 expression was observed in ethanol treated microglia. Knockdown of Tβ4 enhanced ethanol-induced inflammatory mediators tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and nitric oxide (NO) in BV-2 cells was performed. Exogenous Tβ4 treatment significantly inhibited expression and secretion of these inflammatory mediators. Tβ4 treatment attenuated p38, ERK MAPKs, and nuclear factor-kappa B (NF-κB) pathway activation, and enhanced miR-339-5p expression induced by ethanol exposure in microglia. A neonatal mouse fetal alcohol spectrum disorders (FASD) model showed that Tβ4 expression in the microglia of the hippocampus was markedly enhanced, while Tβ4 treatment effectively blocked the ethanol-induced increase in inflammatory mediators, to the level expressed in vehicle-treated control animals. Conclusion: This study is the first to demonstrate the function of Tβ4 in ethanol-induced microglia activation, thus contributing to a more robust understanding of the role of Tβ4 treatment in CNS disease.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Function of Thymosin Beta-4 in Ethanol-Induced Microglial Activation

Zhang¹,

Wu²,

Zeng³

et al. 2016

Cell Physiol Biochem

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“…CAP was later found to be expressed in PDL cells and alveolar bone cells, and to share homology with some collagen domains [49]. Although CEMP1 and CAP may not be unique cementum markers, we examined these mRNA levels in cementoblasts response to rh-SHH, because they may still be useful in defining cementum matrix versus bone [6,10,47]. Our results demonstrate that cementoblasts exposed to rh-SHH protein show high cell growth, ALP activity, calcified nodule formation, and the expression of mineralization-related genes, including the genes for Runx2, OPN, ON, CAP, and CEMP1, dose-dependently.…”

Section: Discussionmentioning

confidence: 98%

“…Cementoblasts share several molecular characteristics with osteoblasts including the expression of alkaline phosphatase (ALP) and noncollagenous proteins such as osteonectin (ON), osteopontin (OPN), and osteocalcin (OCN) [5]. In vivo animal models to evaluate cementogenesis during toot development, the expression pattern of specific matrix molecules, and in vitro studies about the effects of cementum components on periodontal cells have provided important knowledge on how cementum components can regulate cementum regeneration [6][7][8]. In addition, EMD has been shown to induce cementoblast differentiation and periodontal regeneration in vivo [9].…”

Section: Introductionmentioning

confidence: 99%

Sonic Hedgehog Promotes Cementoblastic Differentiation via Activating the BMP Pathways

et al. 2016

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Although sonic hedgehog (SHH), an essential molecule in embryogenesis and organogenesis, stimulates proliferation of human periodontal ligament (PDL) stem cells, the effects of recombinant human SHH (rh-SHH) on osteoblastic differentiation are unclear. To reveal the role of SHH in periodontal regeneration, expression of SHH in mouse periodontal tissues and its effects on the osteoblastic/cementoblastic differentiation in human cementoblasts were investigated. SHH is immunolocalized to differentiating cementoblasts, PDL cells, and osteoblasts of the developing mouse periodontium. Addition of rh-SHH increased cell growth, ALP activity, and mineralization nodule formation, and upregulated mRNA expression of osteoblastic and cementoblastic markers. The osteoblastic/cementoblastic differentiation of rh-SHH was abolished by the SHH inhibitor cyclopamine (Cy) and the BMP antagonist noggin. rh-SHH increased the expression of BMP-2 and -4 mRNA, as well as levels of phosphorylated Akt, ERK, p38, and JNK, and of MAPK and NF-κB activation, which were reversed by noggin, Cy, and BMP-2 siRNA. Collectively, this study is the first to demonstrate that SHH can promote cell growth and cell osteoblastic/cementoblastic differentiation via BMP pathway. Thus, SHH plays important roles in the development of periodontal tissue, and might represent a new therapeutic target for periodontitis and periodontal regeneration.

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“…Furthermore, Tβ4 promotes differentiation and mineralization of MC3T3-E1 cells, which are an osteoblast precursor derived from mouse calvaria (51). Tβ4 siRNA transfection suppressed osteoblastic differentiation by reducing calcium nodule formation, alkaline phosphatase activity, and mRNA expression of differentiation markers in human periodontal ligament cells, cementoblasts, and osteoblasts (52). Therefore, increases in Tβ4 level in serum and synovial joint fluid in patients with RA can be explained as one of the host defense systems that protect joint bone against activated osteoclastogenesis during inflammation of arthritic joints.…”

Section: Thymosin β4 and Rheumatoid Arthritismentioning

confidence: 99%

Thymosin β4 in rheumatoid arthritis: Friend or foe

Kim

Yang

2017

Biomedical Reports

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Abstract. Rheumatoid arthritis (RA) has characteristic pannus tissues, which show tumor-like growth of the synovium through chronic joint inflammation. The synovium is highly penetrated by various immune cells, and the synovial lining becomes hyperplastic due to increased numbers of macrophage-like and fibroblast-like synoviocytes. Thus, a resultant hypoxic condition stimulates the expression of inflammation-related genes in various cells, in particular, vascular endothelial growth factor. Thymosin β4 (Tβ4), a 5-kDa protein, is known to play a significant role in various biological activities, such as actin sequestering, cell motility, migration, inflammation, and damage repair. Recent studies have provided evidence that Tβ4 may have a role in RA pathogenesis. The Tβ4 level has been shown to increase significantly in the joint fluid and serum of RA patients. However, whether Tβ4 stimulates or inhibits activation of RA immune responses remains to be determined. In the present study, we discuss the logical and clinical justifications for Tβ4 as a potential target for RA therapeutics. IntroductionCytokines control an extensive range of inflammatory progressions that are associated with the pathogenesis of rheumatoid arthritis (RA). In arthritic joints, pro-inflammatory activities lead to the induction of autoimmunity, chronic inflammation, and, ultimately, joint damage (1). A better understanding of these pathogenic mechanisms has enabled the development of therapeutic agents to inhibit cytokine actions, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1, and IL-6, which have greatly contributed to the management of RA patients (2,3). Biological therapies have contributed innovative improvements to RA treatment (4). However, despite these improvements, 30-50% of RA patients who are non-responders to disease-modifying antirheumatic drugs (DMARDs) fail to respond to treatment with biologic agents (5). Furthermore, radiographic joint damage can proceed even when clinical disease reduction is achieved by biologic agents (6).These results indicate that the inhibition of cytokine networks may not be satisfactory to suppress RA progression. Thus, there is a need for new therapeutic agents to target new molecules, which encouraged us to redirect our efforts to screen other therapeutic targets from joint synovial fluids of RA patients. Recently, we observed that the level of thymosin β4 (Tβ4), which has many biological roles, was significantly increased in the serum and joint fluids of RA patients (7,8). This review aims to discuss the current understanding of the potential role of Tβ4 in RA pathogenesis while addressing current knowledge regarding the association between Tβ4 and arthritic joints for RA management. Rheumatoid arthritisRA is an autoimmune inflammatory disease whose pathogenic mechanisms remain elusive. RA pathogenesis is attributed to a complex interaction between genetic and environmental factors (7). The class II major histocompatibility complex molecules HLA-DR1 and HLA-DR4 are regarded as major...

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Expression of thymosin beta-4 in human periodontal ligament cells and mouse periodontal tissue and its role in osteoblastic/cementoblastic differentiation

Cited by 13 publications

References 45 publications

Function of Thymosin Beta-4 in Ethanol-Induced Microglial Activation

Function of Thymosin Beta-4 in Ethanol-Induced Microglial Activation

Sonic Hedgehog Promotes Cementoblastic Differentiation via Activating the BMP Pathways

Thymosin β4 in rheumatoid arthritis: Friend or foe

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