Periostin Gene Research Articles

Manipulating Senescence of Cardiac Fibroblasts In Vivo and In Vitro to Investigate Arrhythmogenic Effect of Senescence

Cellular senescence is a stress response characterized by irreversible cell cycle arrest, secretion of inflammatory cytokines and growth factors termed the “senescence associated secretory phenotype” (SASP), and resistance to apoptosis. Senescence plays beneficial roles in tumor suppression, wound healing, and development in young animals, but is thought to underlie aging‐associated pathology in numerous tissues, mainly via the SASP. Our previous work in the aged rabbit myocardial infarction (MI) model demonstrated an increase and persistence of senescence, which we hypothesize to drive increased risk of arrhythmogenesis with age post‐MI. Here, we investigate the molecular mechanisms by which we believe senescence drives arrhythmogenesis. Specifically, we hypothesize that inflammatory cytokines in the SASP locally produced by senescent myofibroblasts acts on border zone myocytes to disrupt cellular‐level electrophysiology. Concordantly, we hypothesize that genetically or pharmacologically eliminating senescent cells post‐MI will mitigate arrhythmogenesis in vivo and in vitro, and that genetically increasing senescence post‐MI in a mouse Cre‐Lox model will increase arrhythmogenesis.Here, we show that commercially‐available aged human cardiac fibroblasts and primary adult rabbit cardiac fibroblasts can be induced into senescence via treatment with low doses of Etoposide in a time‐dependent manner. Additionally, via a senolytic drug screening, we found that high doses of Dasatinib, Quercetin, and Navitoclax effectively eliminate senescent cells but not non‐senescent cells. However, we found combinations of Dasatinib and Quercetin or Dasatinib and Venetoclax did not perform better than either drug in solo. Additionally, we verify that calcium linescan imaging as well as patch clamp measurements of the IKr current can be measured in primary 3‐week‐old rabbit cardiomyocytes.Using genetically altered mice to conditionally knock out the pro‐senescence p53 gene in myofibroblasts under control of the Periostin gene (p53 CKO mice), we find that p53 CKO mice have significantly less senescence post‐MI compared to littermate controls, and the effect is stronger in females compared to males. We also report that fibroblast‐specific knockout of the MDM2 gene in the same condition is embryonic lethal, as Periostin is expressed in the developing valve leaflets and endocardial cushion cells, where senescence plays a vital role in pruning transient fetal structures.In conclusion, we demonstrate methods to genetically and pharmacologically manipulate senescence in vivo and in vitro, which will allow us to investigate the molecular mechanisms through which senescence might play a role in promoting arrhythmogenesis with age post‐MI.Support or Funding InformationThe authors would like to acknowledge our supporting NIH funding sources, R21 grant 1R21AG049608‐01 and R01 grant R01HL139467

Bone regeneration and mineralisation was promoted during distraction osteogenesis by human periostin gene in rabbit mandibular model

ObjectiveTo study the effect of periostin gene on bone regeneration and mineralisation during distraction osteogenesis (DO) in a rabbit mandibular model. Subjects and methodsA total of 54 New Zealand white rabbits underwent mandibular lengthening and were divided into group A and group B (n=27, each). At the end of the distraction, adenoviruses containing human POSTN/enhanced green fluorescent protein (Ad5-POSTN/EGFP) viruses or Ad5-POSTN viruses were injected into the distraction gaps in the group B or A, respectively. On the 4th and 8th week after distraction, eight samples, randomly selected from each group, were subjected to CT scanning and dual energy X-ray absorptiometry detection. All animals from each group were sacrificed for micro-CT, histology, and three-point bend testing eight weeks after DO. ResultsThe CT images showed that callus in the distraction gap of group B was significantly better than that of group A. On the 4th and 8th weeks, the bone mineral densities (BMD) of the bone tissue in the distraction gap of the group B were 0.163±0.011g/cm2 and 0.239±0.024g/cm2, respectively, while the bone mineral contents (BMC) was 0.099±0.011g and 0.205±0.018g, respectively, which were significantly higher compared with group A. Histological sections showed that the trabecular bone in the distraction gap of group B was more coarse. On the basis of micro-CT images and micro-architecture parameters show that the microstructure of the distraction gap of the group B had more mature characteristics. The biomechanical strength of the distracted gap in the group B was 234.30±30.48N, which was 1.28 times higher than that in the group A (P=0.003). ConclusionLocal transduction with human periostin gene would promote osteogenesis and mineralisation in a rabbit mandibular DO model. Periostin might be considered for clinical use if only there is a safe and effective administration method.

Confounding Patient Factors Affecting the Proper Interpretation of the Periostin Level as a Biomarker in Asthma Development.

IntroductionThe proper use of serum periostin (POSTN) as a biomarker for asthma is hindered by inconsistent performance in different clinical settings.ObjectiveTo explore patient’s factors that may affect POSTN expression locally and systematically and its utility as a biomarker for asthma development.Materials and MethodsHere we used bioinformatics analysis of publicly available transcriptomics data to confirm that POSTN is an asthma specific gene involved in core signaling pathways enriched in the bronchial epithelium during asthma. We then explored a large number of datasets to identify possible confounders that may affect the POSTN gene expression and consequently, its interpretation as a reliable biomarker for asthma. Plasma and saliva levels of POSTN were determined in locally recruited asthmatic patients (mild, moderate and severe) compared to healthy controls to confirm the bioinformatics findings.ResultsOur bioinformatics results confirmed that POSTN was consistently upregulated in the bronchial epithelium in asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) bronchial epithelium. In asthma, its mRNA expression was affected by gender, sample anatomical site and type, steroid therapy, and smoking. In our cohort, plasma POSTN was upregulated in severe and non-severe asthmatic patients. Saliva POSTN was significantly higher in non-severe asthmatic patients compared to healthy and severe asthmatic patients (specifically those who are not on Xolair (omalizumab)). Patients’ BMI, inhaled steroid use and Xolair treatment affected POSTN plasma levels.ConclusionUp to our knowledge, this is the first study examining the level of POSTN in the saliva of asthmatic patients. Both plasma and saliva POSTN levels can aid in early diagnosis of asthma. Saliva POSTN level was more sensitive than plasma POSTN in differentiating between severe and non-severe asthmatics. Patients’ characteristics like BMI, the use of inhaled steroids, or Xolair treatment should be carefully reviewed before any meaningful interpretation of POSTN level in clinical practice.

TGFβ1 single-nucleotide polymorphism C-509T alters mucosal cell function in pediatric eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a chronic Th2 antigen driven disorder associated with tissue remodeling. Inflammation and remodeling lead to esophageal rigidity, strictures, and dysphagia. TGFβ1 drives esophageal remodeling including epithelial barrier dysfunction and subepithelial fibrosis. A functional SNP in the TGFβ1 gene that increases its transcription (C-509T) associates with elevated numbers of esophageal TGFβ1 expressing cells. We utilized esophageal biopsies and fibroblasts from TT genotype EoE children to understand if TGFβ1 influenced fibroblast and epithelial cell function in vivo. Genotype TT EoE esophageal fibroblasts had higher baseline TGFβ1, collagen1α1, periostin, and MMP-2 (p<.05) gene expression and distinct contractile properties compared with CC genotype (n=6 subjects per genotype). In vitro TGFβ1 exposure caused greater induction of target gene expression in genotype CC fibroblasts (p<.05). Esophageal biopsies from TT genotype subjects had significantly less epithelial membrane bound E-cadherin (p<.01) and wider cluster distribution at nanometer resolution. TGFβ1 treatment of stratified primary human esophageal epithelial cells and spheroids disrupted transepithelial resistance (p<.001) and E-cadherin localization (p<.0001). A TGFβ1-receptor-I inhibitor improved TGFβ1-mediated E-cadherin mislocalization. These data suggest that EoE severity can depend on genotypic differences that increase in vivo exposure to TGFβ1. TGFβ1 inhibition may be a useful therapy in subsets of EoE patients.

Periostin expression and characters of human adipose tissue-derived mesenchymal stromal cells were aberrantly affected by in vitro cultivation.

Human adipose tissue-derived mesenchymal stromal cells (AD-MSCs) have been under focus in regenerative medicine since their discovery as a suitable source of MSCs. AD-MSCs are heterogeneous cells and exhibit variations in population doubling time, morphology and proliferative capacity. This study investigated if human AD-MSCs are developing, during in vitro long-term cultivation, in an unwanted or aberrant way. This study monitored AD-MSCs during their in vitro culture till the tenth passage investigating proliferation kinetics, DNA index and surface markers expression. Also, periostin gene expression was examined. The proliferation capacity and colony forming unit were decreased after passage 6 and the population doubling time was increased. Flow cytometric analysis revealed that newly cultivated population strongly expressed MSCs markers, furthermore, reduction of CD105 expression appeared in passage 5 onwards, the later was associated with significant increase in expression of CD34 (a hematopoietic cell marker). Also, reduction of CD73 and CD90 expression was observed from passage 8. Furthermore, during the first six passages, periostin expression was significantly unchanged, with significant upregulation in late passages. Long-term cultivation of human AD-MSCs changed their characters in an aberrant way and the first four passages might be the most appropriate passages for therapy. More investigation and understanding of these variations are needed to help in standardizing the expansion of MSCs-based therapies.

Patterns of systemic and local inflammation in patients with asthma hospitalised with influenza.

Patients with asthma are at risk of hospitalisation with influenza, but the reasons for this predisposition are unknown. A prospective observational study of adults with PCR-confirmed influenza in 11 UK hospitals, measuring nasal, nasopharyngeal and systemic immune mediators and whole-blood gene expression. Of 133 admissions, 40 (30%) had previous asthma; these were more often female (70% versus 38.7%, OR 3.69, 95% CI 1.67-8.18; p=0.0012), required less mechanical ventilation (15% versus 37.6%, Chi-squared 6.78; p=0.0338) and had shorter hospital stays (mean 8.3 versus 15.3 days, p=0.0333) than those without. In patients without asthma, severe outcomes were more frequent in those given corticosteroids (OR 2.63, 95% CI 1.02-6.96; p=0.0466) or presenting >4 days after disease onset (OR 5.49, 95% CI 2.28-14.03; p=0.0002). Influenza vaccination in at-risk groups (including asthma) were lower than intended by national policy and the early use of antiviral medications were less than optimal. Mucosal immune responses were equivalent between groups. Those with asthma had higher serum interferon (IFN)-α, but lower serum tumour necrosis factor, interleukin (IL)-5, IL-6, CXCL8, CXCL9, IL-10, IL-17 and CCL2 levels (all p<0.05); both groups had similar serum IL-13, total IgE, periostin and blood eosinophil gene expression levels. Asthma diagnosis was unrelated to viral load, IFN-α, IFN-γ, IL-5 or IL-13 levels. Asthma is common in those hospitalised with influenza, but may not represent classical type 2-driven disease. Those admitted with influenza tend to be female with mild serum inflammatory responses, increased serum IFN-α levels and good clinical outcomes.

Knockdown of periostin attenuates 5/6 nephrectomy-induced intrarenal renin-angiotensin system activation, fibrosis, and inflammation in rats.

To simulate clinical features in human chronic kidney disease (CKD), SD rats were subjected to 5/6 nephrectomy in this study. We found that periostin gene was upregulated in the remnant kidneys using Agilent gene microarrays, and further explored its role via in vivo and in vitro experiments. Intrarenal renin-angiotensin system (RAS) was activated in 5/6 nephrectomized rats and partly deactivated by injection of adenoviruses encoding short hairpin RNA against periostin (sh-periostin). Renal fibrosis in nephrectomized rats and profibrotic transforming growth factor-β-induced epithelial-mesenchymal transition (EMT) and ERK1/2 activation in NRK-52E cells were suppressed by sh-periostin. Moreover, knockdown of periostin decreased the generation of Interleukin 6 (IL6) and tumor necrosis factor-α (TNF-α) and accelerated p62 degradation in the remnant kidneys. Both HK-2 cells treated with recombinant periostin and NRK-52E cells infected with adenoviruses expressing periostin produced more IL6 and TNF-α than control cells and displayed impaired autophagy as evidenced by inhibition of LC3II to LC3I conversion, Beclin 1 expression, and p62 degradation. By treating cells with rapamycin, an inhibitor of mamalian target of rapamycin known to activate autophagy, we noted that periostin-induced inflammation was inhibited. Additionally, HK-2 cells transfected with periostin overexpression plasmid generated more CCL2 and CXCL10, two important chemotactic factors, than untransfected cells. Conditioned medium from HK-2 cells overexpressing periostin augmented chemotaxis of THP-1 macrophages. Collectively, our work demonstrates that knockdown of periostin attenuates 5/6 nephrectomy-induced intrarenal RAS activation, fibrosis, and inflammation in rats. These findings advance our understanding of periostin's role in CKD induced by nephron loss.

The transcriptional regulation of periostin by scleraxis in cardiac myofibroblasts

Extracellular matrix (ECM) remodeling resulting in cardiac fibrosis is a crucial factor in determining the severity of myocardial dysfunction during heart failure. In response to stress or damage, cardiac fibroblasts undergo phenotype conversion to myofibroblasts, the primary cell type responsible for ECM synthesis and remodeling in the heart. Periostin, a marker of the myofibroblast phenotype, is a matricellular secreted protein that contributes to cardiac remodeling. Periostin plays important roles in mediating cell–matrix signal transduction and in promoting pro‐fibrotic TGF‐β signaling via coupling with matrix associated lysyl oxidase; it is highly expressed in myofibroblasts, but is not expressed in fibroblasts. We have shown that the transcription factor scleraxis induces the phenotype conversion of cardiac fibroblasts to myofibroblasts by directly transactivating the expression of proteins highly up‐regulated in myofibroblasts, including collagen 1α2, fibronectin and α‐smooth muscle actin. Here we report that the treatment of primary adult rat cardiac myofibroblasts with angiotensin II significantly increases periostin gene expression in parallel with increased scleraxis expression. Over‐expression of scleraxis in myofibroblasts increased periostin expression nearly 19‐fold at the mRNA level. TGF‐b treatment induced periostin expression in cardiac myofibroblasts isolated from wild type mice, but failed to show a similar effect in cells isolated from scleraxis null mice. Using in silico analysis, we identified putative E‐box sites within the periostin gene promoter to which scleraxis may bind to potentially regulate promoter transactivation. Our data suggests that scleraxis is necessary and sufficient for TGF‐β mediated periostin expression. Our findings are consistent with a potential role for scleraxis in cardiac fibrosis, where periostin and fibrillar collagen gene expression are elevated in parallel with scleraxis.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Structure of the Periostin Gene, Its Transcriptional Control and Alternative Splicing, and Protein Expression.

Although many studies have described the role of periostin in various diseases, the functions of periostin derived from alternative splicing and proteinase cleavage at its C-terminus remain unknown. Further experiments investigating the periostin structures that are relevant to diseases are essential for an in-depth understanding of their functions, which would accelerate their clinical applications by establishing new approaches for curing intractable diseases. Furthermore, this understanding would enhance our knowledge of novel functions of periostin related to stemness and response to mechanical stress .

Differential expression of periostin, sclerostin, receptor activator of nuclear factor-κB, and receptor activator of nuclear factor-κB ligand genes in severe chronic periodontitis.

The aim of the present study was to determine and compare the expression profile of periostin (POSTN), sclerostin (SOST), receptor activator nuclear factor-κB (RANK), and RANK ligand (RANKL) genes in gingival tissue samples collected from healthy gingiva (control) and severe chronic periodontitis sites. Fifty systemically-healthy individuals was enrolled in the present case-control study. Gingival tissue samples were obtained from healthy gingiva (N=25) and sites with severe chronic periodontitis (N=25). Total RNA was isolated from all the tissues. cDNA conversion was then performed using a reverse transcription polymerase chain reaction (PCR) program. Real-time PCR and SYBR green method were used to determine the expression levels of SOST, POSTN, RANK, and RANKL genes. An elevated expression (3.5-4-fold) of SOST, RANK, and RANKL genes, with a concomitant reduced expression of the POSTN gene, was identified in severe chronic periodontitis. The intergroup difference between the mean delta cyclic threshold values showed statistical significance at P<.001. The expression profile of SOST, RANK, RANKL, and POSTN genes observed in gingival tissue samples from sites with severe chronic periodontitis and healthy gingiva suggests that the differential level of the gene expression could serve as an indicator of periodontitis progression/severity.

Tumor suppression effect of targeting periostin with siRNA in a nude mouse model of human laryngeal squamous cell carcinoma

The incidence of laryngeal carcinoma is increasing, however, the mechanism is not fully understood. We aimed to investigate the efficacy of periostin gene silencing by siRNA on tumor inhibition, in a novel nude mouse model of human laryngeal squamous cell carcinoma, and to explore possible inhibitory mechanisms. Tumors were established in nude mice by transplantation of LSCC AMC-HN-8 cell line. Forty-eight nude mice were randomly divided into groups of eight each, and treated with high (1.0 OD) or low (0.5 OD) doses of periostin-siRNA or appropriate control solutions. Tumor growth was observed and used to calculate an inhibition rate (%). Routine pathological and electron microscopic examination were used to determine tumor apoptosis and proliferation. Changes in periostin mRNA and protein levels were analyzed. Tumor growth was significantly inhibited in mice treated by high dose periostin-siRNA compared to untreated and those treated with low dose periostin-siRNA (P<0.05). Pathological examination showed increased tumor necrosis and apoptotic changes in treated mice, which was confirmed by electron microscopy. Periostin mRNA and protein expression were significantly reduced in tumors from mice treated with high dose periostin-siRNA, compared to controls and low-dose periostin-siRNA treatment groups (P<0.05). Periostin silencing was associated with growth inhibition of tumor cells in a nude mouse model of LSCC. The underlying mechanism may be due to receptor-mediated induction of relevant signal transduction pathways that modulate the microenvironment needed for cancer cell survival. Periostin is expected to become a new target for cancer therapy.

Periostin (rs3829365) Gene Polymorphism and Cardiac Function in Psoriasis

Psoriasis considered a chronic inflammatory skin disease characterized by spontaneous remissions and exacerbations. The lesions are characterized by circumscribed, dry, erythematous plaques of various sizes covered by silvery white scales. Periostin gene (POSTN) in human is located in the long arm of chromosome 13 (13q13.3) and spans approximately 36 kb, It has 23 exons and encodes for a protein of 836 amino acids with a molecular weight of 93 kD, it was renamed periostin due to itˈs localized expression in the periosteum and the periodontal ligament.The aim of this study was to reveal the association between periostin (rs3829365) gene polymorphism and psoriasis susceptibility. Blood samples were taken from psoriasis patients and control group for genotyping of Periostin gene using PCR. Regarding periostin gene polymorphism, CG and GG genotypes showed higher distributions among psoriasis patients than control and total polymorphism showed higher distributions when compared to CC genotype frequency and G allele carry a risk factor for psoriasis susceptibility.Periostin genpolymorphism(rs3829365) genotypes frequencies CG,GG and(CG+GG) and G allele might play a role in psoriasis pathogenesis.

Periostin, a signal transduction intermediate in TGF-β-induced EMT in U-87MG human glioblastoma cells, and its inhibition by anthocyanidins.

Periostin is a secreted protein that is highly expressed in glioblastoma cells as compared to normal brain tissue, and is therefore considered as a potential biomarker in therapeutic modalities. Its contribution in the cancer cells invasive phenotype is, however, poorly understood. This work investigates the role of periostin in U-87 MG glioblastoma cell invasion, cell migration and in Transforming Growth Factor β (TGF-β)-induced epithelial-mesenchymal transition (EMT). Periostin gene silencing, using small interfering RNA, decreased TGF-β-induced mesenchymal marker expression of fibronectin and vimentin, partly through reduced Smad2, Akt and Fak phosphorylation as well as U-87 MG cell invasion and migration. The effects of anthocyanidins, the most abundant diet-derived flavonoids, were examined on periostin-mediated downstream signaling pathways. Anthocyanidins were found to decrease periostin expression whether added under pre-, co- or post-treatment conditions along with TGF-β, and altered the Akt and Fak signaling pathways. These effects were similar to Galunisertib (LY2157299), a small molecule inhibitor of the TGF-β receptor I kinase. Taken together, our data demonstrate that periostin acts as a central element in TGF-β-induced EMT, which can be prevented by diet-derived anthocyanidins.

Periosteum contains skeletal stem cells with high bone regenerative potential controlled by Periostin

Bone regeneration relies on the activation of skeletal stem cells (SSCs) that still remain poorly characterized. Here, we show that periosteum contains SSCs with high bone regenerative potential compared to bone marrow stromal cells/skeletal stem cells (BMSCs) in mice. Although periosteal cells (PCs) and BMSCs are derived from a common embryonic mesenchymal lineage, postnatally PCs exhibit greater clonogenicity, growth and differentiation capacity than BMSCs. During bone repair, PCs can efficiently contribute to cartilage and bone, and integrate long-term after transplantation. Molecular profiling uncovers genes encoding Periostin and other extracellular matrix molecules associated with the enhanced response to injury of PCs. Periostin gene deletion impairs PC functions and fracture consolidation. Periostin-deficient periosteum cannot reconstitute a pool of PCs after injury demonstrating the presence of SSCs within periosteum and the requirement of Periostin in maintaining this pool. Overall our results highlight the importance of analyzing periosteum and PCs to understand bone phenotypes.

A study on periostin involvement in the pathophysiology of canine atopic skin.

Atopic dermatitis (AD) is a chronic, pruritic, and allergic skin disease in humans and animals, particularly dogs. Canine AD (cAD) has received attention as a spontaneous atopic animal model because domesticated dogs inhabit a human environment, and cAD shares several clinicopathological features with human AD (hAD). In hAD, periostin (PO) is suggested to play a critical role in the enhancement and chronicity of allergic skin inflammation; however, PO involvement in the pathogenesis of cAD is unknown. Here we aimed to clarify PO involvement in the pathophysiology of cAD and focused on the inducing factor and function of PO in canine atopic skin. Using double-labeled in situ hybridization (ISH), interleukin (IL)-13 mRNA-positive cells were detected near the keratinocytes and dermal fibroblasts expressing PO mRNA in atopic skin. Using an in vitro assay, IL-13 induced PO gene expression in both canine dermal fibroblasts and keratinocytes. PO enhanced in vitro growth of canine keratinocytes. Moreover, among PO-induced genes in cultured canine keratinocytes detected using a microarray, we identified IL-25 as a possible mediator in canine atopic skin. In addition, real time polymerase chain reaction (PCR) analysis revealed upregulation of IL-25 gene expression in PO-stimulated keratinocytes. These data suggest that IL-13 possibly derived from T helper 2 (Th2) cells stimulates PO production in both keratinocytes and fibroblasts, and then PO may play a critical role in the pathophysiology of cAD, particularly in the enhancement and chronicity of skin lesions via IL-25.

Interaction between LRP5 and periostin gene polymorphisms on serum periostin levels and cortical bone microstructure

The purpose of this study is to investigate the interaction between periostin gene polymorphisms (SNPs) and other genes potentially responsible for modulating serum periostin levels and bone microstructure in a cohort of postmenopausal women. In 648 postmenopausal women from the Geneva Retirees Cohort, we analyzed 6 periostin SNPs and another 149 SNPs in 14 genes, namely BMP2, CTNNB1, ESR1, ESR2, LRP5, LRP6, PTH, SPTBN1, SOST, TGFb1, TNFRSF11A, TNFSF11, TNFRSF11B and WNT16. Volumetric BMD and bone microstructure were measured by high-resolution peripheral quantitative computed tomography at the distal radius and tibia. Serum periostin levels were associated with radial cortical porosity, including after adjustment for age, BMI, and years since menopause (p=0.036). Sixteen SNPs in the ESR1, LRP5, TNFRSF11A, SOST, SPTBN1, TNFRSF11B and TNFSF11 genes were associated with serum periostin levels (p range 0.03-0.001) whereas 26 SNPs in 9 genes were associated with cortical porosity at the radius and/or at the tibia. WNT 16 was the gene with the highest number of SNPs associated with both trabecular and cortical microstructure. The periostin SNP rs9547970 was also associated with cortical porosity (p=0.04). In particular, SNPs in LRP5, ESR1 and near the TNFRSF11A gene were associated with both cortical porosity and serum periostin levels. Eventually, we identified an interaction between LRP5 SNP rs648438 and periostin SNP rs9547970 on serum periostin levels (interaction p=0.01) and on radial cortical porosity (interaction p=0.005). These results suggest that periostin expression is genetically modulated, particularly by polymorphisms in the Wnt pathway, and is thereby implicated in the genetic variation of bone microstructure.

Introductory review: periostin-gene and protein structure.

Although many studies have described the role of periostin in various diseases, the function of the periostin protein structures derived from alternative splicing and proteinase cleavage at the C-terminal remain unknown. Further experiments revealing the protein structures that are highly related to diseases are essential to understand the function of periostin in depth, which would accelerate its clinical application by establishing new approaches for curing intractable diseases. Furthermore, this understanding would enhance our knowledge of novel functions of periostin related to stemness and response to mechanical stress.

Role and underlying mechanisms of the interstitial protein periostin in the diagnosis and treatment of malignant tumors (Review)

Invasion and metastasis are the major characteristics of malignant tumors and are complex processes involving multiple genes. Gene regulation is a precise, large and complex biological control system, and its underlying mechanisms remain to be elucidated. Mesenchymal-specific genes are expressed primarily by mesenchymal cells, and the expression products of these genes are molecules with various structures and functions, including secreted proteins and extracellular matrix proteins. The periostin gene has been newly identified as a mesenchymal-specific gene and an extracellular-matrix secreted protein. Periostin is able to bind to various subtypes of integrin receptors on the surface of the cell membrane. This triggers relevant signal transduction pathways to alter the microenvironment of cancer cells in order to facilitate their survival, invasion, metastasis and angiogenesis as well as enhance the tolerance to hypoxia and chemicals. Therefore, periostin is associated with the grade of malignancy, level of invasion and prognosis of malignant tumors. The in-depth study of periostin may provide an effective marker for tumor diagnosis and prognosis, as well as a novel treatment target.

RETRACTED: Effects of lentivirus-mediated silencing of Periostin on tumor microenvironment and bone metastasis via the integrin-signaling pathway in lung cancer

The study aims to investigate the effects of Periostin gene silencing on tumor microenvironment and bone metastasis via the integrin-signaling pathway in lung cancer (LC). LC patients were divided into bone metastasis and non-bone metastasis groups; Healthy volunteers were selected as normal group. ELISA was performed to detect serum Periostin levels and plasma calcium ion concentration. SBC-5 cells were assigned into blank group (without transfection), negative control (NC) group (transfected with empty plasmid), si-Periostin group (transfected with si-Periostin plasmid), si-Integrin-αvβ3 group (transfected with Integrin-αvβ3 siRNA plasmid) and si-Periostin+si-Integrin-αvβ3 group (transfected with si-Periostin and si-Integrin-αvβ3 plasmid). qRT-PCR and Western blotting were performed to determine mRNA and protein expression of Periostin, metastasis-associated factors of tumor microenvironment and integrin signaling pathway-related proteins. CCK-8, scratch test and transwell assay were applied to detect cell proliferation, migration and invasion respectively. Nude mouse models of LC bone metastasis were established. TRAP Staining was employed to measure the number of osteoclasts. Bone metastasis group exhibited higher levels of Periostin compared to normal and non-bone metastasis groups. Si-Periostin, si-Integrin-αvβ3 and si-Periostin+si-Integrin-αvβ3 groups showed decreased Periostin expression, proliferation rate, migration distance, invasive cells, and expressions of metastasis-associated factors of tumor microenvironment and integrin signaling pathway-related proteins compared to blank and NC groups. Similarly, number of osteoclasts and expression of integrin signaling pathway-related proteins were decreased, and bone injury and calcium ion concentration were reduced. The study demonstrated that down-regulation of Periostin expression modulated tumor microenvironment and inhibited bone metastasis by blocking integrin-signaling pathway in LC.

Periostin is required for matricellular localization of CCN3 in periodontal ligament of mice.

CCN3 is a matricellular protein that belongs to the CCN family. CCN3 consists of 4 domains: insulin-like growth factor-binding protein-like domain (IGFBP), von Willebrand type C-like domain (VWC), thrombospondin type 1-like domain (TSP1), and the C-terminal domain (CT) having a cysteine knot motif. Periostin is a secretory protein that binds to extracellular matrix proteins such as fibronectin and collagen. In this study, we found that CCN3 interacted with periostin. Immunoprecipitation analysis revealed that the TSP1-CT interacted with the 4 repeats of the Fas 1 domain of periostin. Immunofluorescence analysis showed co-localization of CCN3 and periostin in the periodontal ligament of mice. In addition, targeted disruption of the periostin gene in mice decreased the matricellular localization of CCN3 in the periodontal ligament. Thus, these results indicate that periostin was required for the matricellular localization of CCN3 in the periodontal ligament, suggesting that periostin mediated an interaction between CCN3 and the extracellular matrix.