ErbB3 Governs Endothelial Dysfunction in Hypoxia-Induced Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension, characterized by vascular remodeling, currently lacks curative therapeutic options. The dysfunction of pulmonary artery endothelial cells plays a pivotal role in the initiation and progression of pulmonary hypertension (PH). ErbB3 (human epidermal growth factor receptor 3), also recognized as HER3, is a member of the ErbB family of receptor tyrosine kinases. METHODS: Microarray, immunofluorescence, and Western blotting analyses were conducted to investigate the pathological role of ErbB3. Blood samples were collected for biomarker examination from healthy donors or patients with hypoxic PH. The pathological functions of ErbB3 were further validated in rodents subjected to chronic hypoxia- and Sugen-induced PH, with or without adeno-associated virus-mediated ErbB3 overexpression, systemic deletion, or endothelial cell-specific ErbB3 knockdown. Primary human pulmonary artery endothelial cells and pulmonary artery smooth muscle cells were used to elucidate the underlying mechanisms. RESULTS: ErbB3 exhibited significant upregulation in the serum, lungs, distal pulmonary arteries, and pulmonary artery endothelial cells isolated from patients with PH compared with those from healthy donors. ErbB3 overexpression stimulated hypoxia-induced endothelial cell proliferation, exacerbated pulmonary artery remodeling, elevated systolic pressure in the right ventricle, and promoted right ventricular hypertrophy in murine models of PH. Conversely, systemic deletion or endothelial cell-specific knockout of ErbB3 yielded opposite effects. Coimmunoprecipitation and proteomic analysis identified YB-1 (Y-box binding protein 1) as a downstream target of ErbB3. ErbB3 induced nuclear translocation of YB-1 and subsequently promoted hypoxia-inducible factor 1/2α transcription. A positive loop involving ErbB3-periostin-hypoxia-inducible factor 1/2α was identified to mediate the progressive development of this disease. MM-121, a human anti-ErbB3 monoclonal antibody, exhibited both preventive and therapeutic effects against hypoxia-induced PH. CONCLUSIONS: Our study reveals, for the first time, that ErbB3 serves as a novel biomarker and a promising target for the treatment of PH.

Wnt Signaling Inhibition Prevents Postnatal Inflammation and Disease Progression in Mouse Congenital Myxomatous Valve Disease.

BACKGROUND: Myxomatous valve disease (MVD) is the most common cause of mitral regurgitation, leading to impaired cardiac function and heart failure. MVD in a mouse model of Marfan syndrome includes valve leaflet thickening and progressive valve degeneration. However, the underlying mechanisms by which the disease progresses remain undefined. METHODS: Mice with Fibrillin 1 gene variant Fbn1C1039G/+ recapitulate histopathologic features of Marfan syndrome, and Wnt (Wingless-related integration site) signaling activity was detected in TCF/Lef-lacZ (T-cell factor/lymphoid enhancer factor-ß-galactosidase) reporter mice. Single-cell RNA sequencing was performed from mitral valves of wild-type and Fbn1C1039G/+ mice at 1 month of age. Inhibition of Wnt signaling was achieved by conditional induction of the secreted Wnt inhibitor Dkk1 (Dickkopf-1) expression in periostin-expressing valve interstitial cells of Periostin-Cre; tetO-Dkk1; R26rtTA; TCF/Lef-lacZ; Fbn1C1039G/+ mice. Dietary doxycycline was administered for 1 month beginning with MVD initiation (1-month-old) or MVD progression (2-month-old). Histological evaluation and immunofluorescence for ECM (extracellular matrix) and immune cells were performed. RESULTS: Wnt signaling is activated early in mitral valve disease progression, before immune cell infiltration in Fbn1C1039G/+ mice. Single-cell transcriptomics revealed similar mitral valve cell heterogeneity between wild-type and Fbn1C1039G/+ mice at 1 month of age. Wnt pathway genes were predominantly expressed in valve interstitial cells and valve endothelial cells of Fbn1C1039G/+ mice. Inhibition of Wnt signaling in Fbn1C1039G/+ mice at 1 month of age prevented the initiation of MVD as indicated by improved ECM remodeling and reduced valve leaflet thickness with decreased infiltrating macrophages. However, later, Wnt inhibition starting at 2 months did not prevent the progression of MVD. CONCLUSIONS: Wnt signaling is involved in the initiation of mitral valve abnormalities and inflammation but is not responsible for later-stage valve disease progression once it has been initiated. Thus, Wnt signaling contributes to MVD progression in a time-dependent manner and provides a promising therapeutic target for the early treatment of congenital MVD in Marfan syndrome.

Long noncoding RNA lncPostn links TGF-ß and p53 signaling pathways to transcriptional regulation of cardiac fibrosis.

Cardiac fibroblasts are essential for the homeostasis of the extracellular matrix, whose remodeling in many cardiovascular diseases leads to fibrosis. Long noncoding RNAs (lncRNAs) are associated with cardiac pathologies, but their functions in cardiac fibroblasts and contributions to cardiac fibrosis remain unclear. Here, we aimed to identify fibroblast-enriched lncRNAs essential in myocardial infarction (MI)-induced fibrosis and explore the molecular mechanisms responsible for their functions. Global lncRNA profiling was performed in post-MI mouse heart ventricles and transforming growth factor-ß (TGF-ß)-treated primary cardiac fibroblasts and confirmed in published data sets. We identified the cardiac fibroblast-enriched lncPostn, whose expression is stimulated in cardiac fibrosis induced by MI and the extracellular growth factor TGF-ß. The promoter of lncPostn contains a functional TGF-ß response element, and lncPostn knockdown suppresses TGF-ß-stimulated cardiac fibroblast activation and improves cardiac functions post-MI. LncPostn stabilizes and recruits EP300 to the profibrotic periostin's promoter, representing a major mechanism for its transcriptional activation. Moreover, both MI and TGF-ß enhance lncPostn expression while suppressing the cellular growth gatekeeper p53. TGF-ß and p53 knockdown-induced profibrotic gene expression and fibrosis occur mainly through lncPostn and show additive effects. Finally, levels of serum lncPostn are significantly increased in patients' postacute MI and show a strong correlation with fibrosis markers, revealing a potential biomarker of cardiac fibrosis. Our findings identify the fibroblast-enriched lncPostn as a potent profibrotic factor, providing a transcriptional link between TGF-ß and p53 signaling pathways to regulate fibrosis in cardiac fibroblasts.NEW & NOTEWORTHY Cardiac fibroblasts are essential for the homeostasis of the extracellular matrix, whose remodeling in many cardiovascular diseases leads to fibrosis. Long noncoding RNAs are functional and contribute to the biological processes of cardiovascular development and disorders. Our findings identify the fibroblast-enriched lncPostn as a potent profibrotic factor and demonstrate that serum lncPostn level may serve as a potential biomarker of human cardiac fibrosis postacute myocardial infarction.

UTX inhibition suppresses proliferation and promotes apoptosis in patient-derived glioblastoma stem cells by modulating periostin expression.

Glioblastoma stem cells (GSCs) exert a crucial influence on glioblastoma (GBM) development, progression, resistance to therapy, and recurrence, making them an attractive target for drug discovery. UTX, a histone H3K27 demethylase, participates in regulating multiple cancer types. However, its functional role in GSCs remains insufficiently explored. This study aims to investigate the role and regulatory mechanism of UTX on GSCs. Analysis of TCGA data revealed heightened UTX expression in glioma, inversely correlating with overall survival. Inhibiting UTX suppressed GBM cell growth and induced apoptosis. Subsequently, we cultured primary GSCs from three patients, observing that UTX inhibition suppressed cell proliferation and induced apoptosis. RNA-seq was performed to analyze the gene expression changes after silencing UTX in GSCs. The results indicated that UTX-mediated genes were strongly correlated with GBM progression and regulatory tumor microenvironment. The transwell co-cultured experiment showed that silencing UTX in the transwell chamber GSCs inhibited the well plate cell proliferation. Protein-protein interaction analysis revealed that periostin (POSTN) played a role in the UTX-mediated transcriptional regulatory network. Replenishing POSTN reversed the effects of UTX inhibition on GSC proliferation and apoptosis. Our study demonstrated that UTX inhibition hindered POSTN expression by enhancing the H3K27me2/3 level, eventually resulting in inhibiting proliferation and promoting apoptosis of patient-derived GSCs. Our findings may provide a novel and effective strategy for the treatment of GBM.

The role of periostin in cardiac fibrosis.

Cardiac fibrosis, which is the buildup of proteins in the connective tissues of the heart, can lead to end-stage extracellular matrix (ECM) remodeling and ultimately heart failure. Cardiac remodeling involves changes in gene expression in cardiac cells and ECM, which significantly leads to the morbidity and mortality in heart failure. However, despite extensive research, the elusive intricacies underlying cardiac fibrosis remain unidentified. Periostin, an extracellular matrix (ECM) protein of the fasciclin superfamily, acts as a scaffold for building complex architectures in the ECM, which improves intermolecular interactions and augments the mechanical properties of connective tissues. Recent research has shown that periostin not only contributes to normal ECM homeostasis in a healthy heart but also serves as a potent inducible regulator of cellular reorganization in cardiac fibrosis. Here, we reviewed the constitutive domain of periostin and its interaction with other ECM proteins. We have also discussed the critical pathophysiological functions of periostin in cardiac remodeling mechanisms, including two distinct yet potentially intertwined mechanisms. Furthermore, we will focus on the intrinsic complexities within periostin research, particularly surrounding the contentious issues observed in experimental findings.

Soluble Periostin is a potential surveillance biomarker for early and long-term response to chemotherapy in advanced breast cancer.

BACKGROUND: Noninvasive biomarkers for the assessment of response to chemotherapy in advanced breast cancer (BCa) are essential for optimized therapeutic decision-making. We evaluated the potential of soluble Periostin (POSTN) in circulation as a novel biomarker for chemotherapy efficacy monitoring. METHODS: Two hundred and thirty-one patients with different stages of BCa were included. Of those patients, 58 patients with inoperable metastatic disease receiving HER2-targeted or non-targeted chemotherapy were enrolled to assess the performances of markers in recapitulating the chemotherapy efficacy assessed by imaging. POSTN, together with CA153 or CEA at different time points (C0, C2, and C4) were determined. RESULTS: POSTN levels were significantly associated with tumor volume (P < 0.0001) and TNM stages (P < 0.0001) of BCa. For early monitoring, dynamics of POSTN could recapitulate the chemotherapy efficacy among all molecular subtypes (Cohen's weighted kappa = 0.638, P < 0.0001), much better than that of carcinoembryonic antigen (CEA) and cancer antigen 153 (CA15-3). For early partial response, superior performance of POSTN was observed (Cohen's weighted kappa = 0.827, P < 0.0001) in cases with baseline levels above 17.19 ng/mL. For long-term monitoring, the POSTN response was observed to be strongly consistent with the course of the disease. Moreover, progression free survival analysis showed that patients experienced a significant early decrease of POSTN tended to obtain more benefits from the treatments. CONCLUSIONS: The current study suggests that soluble POSTN is an informative serum biomarker to complement the current clinical approaches for early and long-term chemotherapy efficacy monitoring in advanced BCa.

Extracellular vesicles produced by irradiated endothelial or Glioblastoma stem cells promote tumor growth and vascularization modulating tumor microenvironment.

BACKGROUND: Glioblastoma (GBM) is the most lethal primary brain tumor in adult, characterized by highly aggressive and infiltrative growth. The current therapeutic management of GBM includes surgical resection followed by ionizing radiations and chemotherapy. Complex and dynamic interplay between tumor cells and tumor microenvironment drives the progression and contributes to therapeutic resistance. Extracellular vesicles (EVs) play a crucial role in the intercellular communication by delivering bioactive molecules in the surrounding milieu modulating tumor microenvironment. METHODS: In this study, we isolated by ultracentrifugation EVs from GBM stem-like cell (GSC) lines and human microvascular endothelial cells (HMVECs) exposed or not to ionizing irradiation. After counting and characterization, we evaluated the effects of exposure of GSCs to EVs isolated from endothelial cells and vice versa. The RNA content of EVs isolated from GSC lines and HMVECs exposed or not to ionizing irradiation, was analyzed by RNA-Seq. Periostin (POSTN) and Filamin-B (FLNB) emerged in gene set enrichment analysis as the most interesting transcripts enriched after irradiation in endothelial cell-derived EVs and GSC-derived EVs, respectively. POSTN and FLNB expression was modulated and the effects were analyzed by in vitro assays. RESULTS: We confirmed that ionizing radiations increased EV secretion by GSCs and normal endothelial cells, affected the contents of and response to cellular secreted EVs. Particularly, GSC-derived EVs decreased radiation-induced senescence and promoted migration in HMVECs whereas, endothelial cell-derived EVs promoted tumorigenic properties and endothelial differentiation of GSCs. RNA-Seq analysis of EV content, identified FLNB and POSTN as transcripts enriched in EVs isolated after irradiation from GSCs and HMVECs, respectively. Assays performed on POSTN overexpressing GSCs confirmed the ability of POSTN to mimic the effects of endothelial cell-derived EVs on GSC migration and clonogenic abilities and transdifferentiation potential. Functional assays performed on HMVECs after silencing of FLNB supported its role as mediator of the effects of GSC-derived EVs on senescence and migration. CONCLUSION: In this study, we identified POSTN and FLNB as potential mediators of the effects of EVs on GSC and HMVEC behavior confirming that EVs play a crucial role in the intercellular communication by delivering bioactive molecules in the surrounding milieu modulating tumor microenvironment.

Bone marrow-derived fibroblast migration via periostin causes irreversible arthrogenic contracture after joint immobilization.

Joint contracture causes distressing permanent mobility disorder due to trauma, arthritis, and aging, with no effective treatment available. A principal and irreversible cause of joint contracture has been regarded as the development of joint capsule fibrosis. However, the molecular mechanisms underlying contracture remain unclear. We established a mouse model of knee joint contracture, revealing that fibrosis in joint capsules causes irreversible contracture. RNA-sequencing of contracture capsules demonstrated a marked enrichment of the genes involved in the extracellular region, particularly periostin (Postn). Three-dimensional magnetic resonance imaging and immunohistological analysis of contracture patients revealed posterior joint capsule thickening with abundant type I collagen (Col1a2) and POSTN in humans. Col1a2-GFPTG ; Postn-/- mice and chimeric mice with Col1a2-GFPTG ; tdTomatoTG bone marrow showed fibrosis in joint capsules caused by bone marrow-derived fibroblasts, and POSTN promoted the migration of bone marrow-derived fibroblasts, contributing to fibrosis and contracture. Conversely, POSTN-neutralizing antibody attenuated contracture exacerbation. Our findings identified POSTN as a key inducer of fibroblast migration that exacerbates capsule fibrosis, providing a potential therapeutic strategy for joint contracture.

Periostin increased by mechanical stress upregulates interleukin-6 expression in the ligamentum flavum.

Ligamentum flavum (LF) hypertrophy is a major cause of lumbar spinal canal stenosis. Although mechanical stress is thought to be a major factor involved in LF hypertrophy, the exact mechanism by which it causes hypertrophy has not yet been fully elucidated. Here, changes in gene expression due to long-term mechanical stress were analyzed using RNA-seq in a rabbit LF hypertrophy model. In combination with previously reported analysis results, periostin was identified as a molecule whose expression fluctuates due to mechanical stress. The expression and function of periostin were further investigated using human LF tissues and primary LF cell cultures. Periostin was abundantly expressed in human hypertrophied LF tissues, and periostin gene expression was significantly correlated with LF thickness. In vitro, mechanical stress increased gene expressions of periostin, transforming growth factor-ß1, α-smooth muscle actin, collagen type 1 alpha 1, and interleukin-6 (IL-6) in LF cells. Periostin blockade suppressed the mechanical stress-induced gene expression of IL-6 while periostin treatment increased IL-6 gene expression. Our results suggest that periostin is upregulated by mechanical stress and promotes inflammation by upregulating IL-6 expression, which leads to LF degeneration and hypertrophy. Periostin may be a pivotal molecule for LF hypertrophy and a promising therapeutic target for lumbar spinal stenosis.

Periostin in the relation between periodontal disease and atherosclerotic coronary artery disease: A pilot randomized clinical study.

OBJECTIVE: The aim of this study was to analyze the effects of periodontal treatment on markers of atherosclerotic coronary artery disease and circulating levels of periostin. BACKGROUND: Periostin is necessary for periodontal stability, but it is highly present in atherosclerotic plaques. Treatment of periodontal disease, with low levels of local periostin, is thought to reduce systemic levels of periostin. Thus, this may contribute to cardiovascular health. METHODS: A pilot randomized controlled clinical trial was designed to include patients with severe periodontal disease and history of atherosclerotic coronary artery disease. Samples of gingival crevicular fluid (GCF) and serum were collected before and after periodontal treatment by periodontal surgery or non-surgical therapy. The levels of several markers of inflammation and cardiovascular damage were evaluated including CRP, IFN-γ, IL-1ß, IL-10, MIP-1α, periostin, and TNF-α in GCF and CRP, Fibrinogen, IFN-γ, IL-1ß, IL-6, IL-10, L-Selectin, MIP-1α, Periostin, TNF-α, and vWF in serum. RESULTS: A total of 22 patients with an average of 56 years old were recruited for participating in this study. Twenty of them were male. Most of them (82%) had suffered an acute myocardial event and underwent surgery for placing 1, 2, or 3 stents in the coronary arteries more than 6 months ago but less than 1 year. The treatment of periodontal disease resulted in an overall improvement of all periodontal parameters. Regarding the evaluation of GCF and serum, a significant increase of periostin in the GCF was observed after periodontal surgery. In contrast, although other markers in GCF and serum improved, no significant correlations were found. CONCLUSION: Treatment of periodontal disease through periodontal surgery induces a local and transient increase in the levels of periostin in the gingival crevicular fluid. The effects on systemic markers of inflammation and cardiovascular function have not been confirmed.

Biomarkers in asthma, potential for therapeutic intervention.

Asthma is a heterogeneous disease characterized by multiple phenotypes with varying risk factors and therapeutic responses. This Commentary describes research on biomarkers for T2-"high" and T2-"low" inflammation, a hallmark of the disease. Patients with asthma who exhibit an increase in airway T2 inflammation are classified as having T2-high asthma. In this endotype, Type 2 cytokines interleukins (IL)-4, IL-5, and IL-13, plus other inflammatory mediators, lead to increased eosinophilic inflammation and elevated fractional exhaled nitric oxide (FeNO). In contrast, T2-low asthma has no clear definition. Biomarkers are considered valuable tools as they can help identify various phenotypes and endotypes, as well as treatment response to standard treatment or potential therapeutic targets, particularly for biologics. As our knowledge of phenotypes and endotypes expands, biologics are increasingly integrated into treatment strategies for severe asthma. These treatments block specific inflammatory pathways or single mediators. While single or composite biomarkers may help to identify subsets of patients who might benefit from these treatments, only a few inflammatory biomarkers have been validated for clinical application. One example is sputum eosinophilia, a particularly useful biomarker, as it may suggest corticosteroid responsiveness or reflect non-compliance to inhaled corticosteroids. As knowledge develops, a meaningful goal would be to provide individualized care to patients with asthma.

Periostin regulates lysyl oxidase through ERK1/2 MAPK-dependent serum response factor in activated cardiac fibroblasts.

Collagen crosslinking, mediated by lysyl oxidase, is an adaptive mechanism of the cardiac repair process initiated by cardiac fibroblasts postmyocardial injury. However, excessive crosslinking leads to cardiac wall stiffening, which impairs the contractile properties of the left ventricle and leads to heart failure. In this study, we investigated the role of periostin, a matricellular protein, in the regulation of lysyl oxidase in cardiac fibroblasts in response to angiotensin II and TGFß1. Our results indicated that periostin silencing abolished the angiotensin II and TGFß1-mediated upregulation of lysyl oxidase. Furthermore, the attenuation of periostin expression resulted in a notable reduction in the activity of lysyl oxidase. Downstream of periostin, ERK1/2 MAPK signaling was found to be activated, which in turn transcriptionally upregulates the serum response factor to facilitate the enhanced expression of lysyl oxidase. The periostin-lysyl oxidase association was also positively correlated in an in vivo rat model of myocardial infarction. The expression of periostin and lysyl oxidase was upregulated in the collagen-rich fibrotic scar tissue of the left ventricle. Remarkably, echocardiography data showed a reduction in the left ventricular wall movement, ejection fraction, and fractional shortening, indicative of enhanced stiffening of the cardiac wall. These findings shed light on the mechanistic role of periostin in the collagen crosslinking initiated by activated cardiac fibroblasts. Our findings signify periostin as a possible therapeutic target to reduce excessive collagen crosslinking that contributes to the structural remodeling associated with heart failure.

Serum periostin levels correlate with severity of intervertebral disc degeneration.

PURPOSE: Periostin, an extracellular matrix protein closely related to mechanical stress, inflammation, and ageing, has been implicated in intervertebral disc degeneration (IVDD) in basic research. However, it has not been examined in clinical cases. This study aimed to evaluate the association between IVDD severity and serum periostin concentration as well as to analyse potential associations between IVDD and clinical and demographic factors. METHODS: This retrospective cohort study included 198 patients who underwent lumbar disc herniation and lumbar canal stenosis between January 2020 and December 2022. The severity of IVDD was evaluated using the Pfirrmann grading, whereas serum periostin levels were measured using ELISA kits. Clinical demographics, including age, sex, body mass index, comorbidities, psoas muscle index, and spinal disease, were also recorded. RESULTS: This study demonstrated a significant correlation between high serum periostin levels and IVDD severity, as indicated by a high cumulative Pfirrmann score. Serum periostin levels were identified as an independent risk factor for IVDD in a multivariate regression model. Correlation analysis showed a correlation between periostin levels and Pfirrmann grade at each lumbar level (ρ = 0.458-0.550, p < 0.001) and a strong correlation with cumulative Pfirrmann score (ρ = 0.690, p < 0.001). CONCLUSION: The higher the serum periostin level, the higher the cumulative Pfirrmann score. Multivariate analysis showed that serum periostin was an independent risk factor for IVDD. Periostin levels may be a clinically suitable and useful biomarker for diagnosing IVDD, estimating disease progression and activity, providing prognostic information, and evaluating treatment options.

Expression of Periostin in Benign Salivary Gland Tumors.

Parotid tumors present a wide range of histological features, from benign to malignant. Periostin, an extracellular matrix protein specifically expressed in the periosteum and periodontal ligament, is isolated from osteoblast cell lines. It regulates fibrosis and collagen deposition and plays an important role in myocardial repair after myocardial infarction. It is also known to be involved in otorhinolaryngological-diseases. This study included 36 patients [38 specimens; 16 men and 20 women, mean age 59.2 (range 26-82) years] who underwent parotid tumor resection at the Division of Otorhinolaryngology, Tohoku Medical and Pharmaceutical University, between April 2017 and March 2022 and were clinically and pathologically diagnosed as having benign parotid tumors. Formalin-fixed, paraffin-embedded sections from the surgical specimens were autoclaved and immunostained with anti-periostin antibodies to evaluate the expression and distribution of periostin. Histologically, the tumors were diagnosed as pleomorphic adenomas in 15 cases (15 specimens), Warthin's tumors in 13 cases (15 specimens), basal cell adenomas in 2 cases (2 specimens), oncocytomas in 4 cases (4 specimens), and myoepitheliomas in 2 cases (2 specimens). An increased expression of periostin was found in 32 of 38 samples (84.2%) in the stroma of benign parotid tumors. Four distinct patterns of periostin expression were observed in benign parotid gland tumors: negative, superficial, infiltrative, and diffuse. Statistically significant differences were found between periostin expression patterns and histological classification of the tumors. Our results suggest that periostin may be involved in the pathogenesis of benign parotid tumors and could serve as a new biomarker for these tumors.

Periostin's role in uterine leiomyoma development: a mini-review on the potential periostin poses as a pharmacological intervention for uterine leiomyoma.

Uterine leiomyomas, also known as fibroids or myomas, occur in an estimated 70-80% of reproductive aged women. Many experience debilitating symptoms including pelvic pain, abnormal uterine bleeding (AUB), dyspareunia, dysmenorrhea, and infertility. Current treatment options are limited in preserving fertility, with many opting for sterilizing hysterectomy as a form of treatment. Currently, surgical interventions include hysterectomy, myomectomy, and uterine artery embolization in addition to endometrial ablation to control AUB. Non-surgical hormonal interventions, including GnRH agonists, are connotated with negative side effects and are unacceptable for women desiring fertility. Periostin, a regulatory extra cellular matrix (ECM) protein, has been found to be expressed in various gynecological diseases including leiomyomas. We previously determined that periostin over-expression in immortalized myometrial cells led to the development of a leiomyoma-like cellular phenotype. Periostin is induced by TGF-ß, signals through the PI3K/AKT pathway, induces collagen production, and mediates wound repair and fibrosis, all of which are implicated in leiomyoma pathology. Periostin has been linked to other gynecological diseases including ovarian cancer and endometriosis and is being investigated as pharmacological target for treating ovarian cancer, post-surgical scarring, and numerous other fibrotic conditions. In this review, we provide discussion linking pathological inflammation and wound repair, with a TGF-ß-periostin-collagen signaling in the pathogenesis of leiomyomas, and ultimately the potential of periostin as a druggable target to treat leiomyomas.

Residual nasal polyp tissue following dupilumab therapy is associated with periostin-associated fibrosis.

PURPOSE: Dupilumab, an anti-interleukin-4 receptor alpha monoclonal antibody, is a new treatment for severe uncontrolled chronic rhinosinusitis with nasal polyps. However, data on the effect of dupilumab on histological changes in nasal polyp tissue are lacking. We aimed to investigate the effect of dupilumab on real-life clinical conditions and nasal polyp tissues from patients with eosinophilic chronic rhinosinusitis (ECRS), which is a refractory subtype. METHODS: We conducted an open-label, prospective, observational, single-centre study on 63 patients with refractory ECRS on the basis of the criteria of the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis Study. These patients had a history of surgery and received dupilumab for 24 weeks. Patient-reported sinonasal symptoms, T&T olfactometry and nasal polyp scores were prospectively evaluated. In 23 patients with residual nasal polyps following dupilumab treatment, changes in systemic and local periostin expression, and total collagen deposition in nasal polyp tissues were investigated before and after dupilumab administration. RESULTS: Dupilumab rapidly improved sinonasal symptoms and reduced the nasal polyp score 24 weeks after initiation. 40 (63.5%) patients had resolution of nasal polyps, but the reduction was limited in the remaining 23 (36.5%) patients. Periostin expression in serum and nasal lavage fluid was decreased, whereas periostin and the total collagen deposition area in subepithelial tissues in residual nasal polyps were enhanced after dupilumab administration. CONCLUSION: Dupilumab improves sinonasal symptoms and reduces the nasal polyp score in refractory ECRS. Periostin-associated tissue fibrosis may be involved in the differential effect of dupilumab on nasal polyp reduction.

IL-31-generating network in atopic dermatitis comprising macrophages, basophils, thymic stromal lymphopoietin, and periostin.

BACKGROUND: IL-31 is a type 2 cytokine involved in the itch sensation in atopic dermatitis (AD). The cellular origins of IL-31 are generally considered to be TH2 cells. Macrophages have also been implicated as cellular sources of IL-31. OBJECTIVE: We sought to determine the expression of IL-31 by macrophages and to elucidate the productive mechanisms and contributions to itch in AD skin lesions. METHODS: Expression of IL-31 by macrophages, expressions of thymic stromal lymphopoietin (TSLP) and periostin, and presence of infiltrating basophils in human AD lesions were examined through immunofluorescent staining, and correlations were assessed. Furthermore, mechanisms of inducing IL-31-expressing macrophages were analyzed in an MC903-induced murine model for AD in vivo and in mouse peritoneal macrophages ex vivo. RESULTS: A significant population of IL-31+ cells in human AD lesions was that of CD68+ cells expressing CD163, an M2 macrophage marker. The number of IL-31+/CD68+ cells correlated with epidermal TSLP, dermal periostin, and the number of dermal-infiltrating basophils. In the MC903-induced murine AD model, significant scratching behaviors with enhanced expressions of TSLP and periostin were observed, accompanied by massive infiltration of basophils and IL-31+/MOMA-2+/Arg-1+ cells. Blockade of IL-31 signaling with anti-IL-31RA antibody or direct depletion of macrophages by clodronate resulted in attenuation of scratching behaviors. To effectively reduce lesional IL-31+ macrophages and itch, basophil depletion was essential in combination with TSLP- and periostin-signal blocking. Murine peritoneal macrophages produced IL-31 when stimulated with TSLP, periostin, and basophils. CONCLUSIONS: A network comprising IL-31-expressing macrophages, TSLP, periostin, and basophils plays a significant role in AD itch.

The effect of light compressive and tensile mechanical forces on SOST and POSTN expressions in human periodontal ligament cells: an in vitro study.

Periodontal ligament (PDL) cells play an important role in mechanosensing and secretion of signaling molecules during bone remodeling. However, the regulatory mechanism is unknown. The aim of the present study is to investigate the expression pattern of periostin and sclerostin in response to orthodontic forces in periodontal ligament cells in vitro. PDL cells were isolated from extracted teeth and treated with compressive forces of 25 gr/cm2 or equiaxial tension forces at frequency 1 Hz for 0, 24, 48, and 72 h. qRT-PCR was applied to evaluate the gene expressions. The secretion of sclerostin and periostin was assessed using ELISA. DAPI staining was used to evaluate apoptosis. The expression of sclerostin elevated significantly at protein and gene levels under compression forces after 24 h, while the application of tensile forces induced the expression of periostin and its upstream regulator RUNX2 (p < 0.05). Gene expression up-regulation was significant for POSTN and RUNX2 after 48 and 72 h tensile forces. Also, the gene expression of sclerostin reduced in a time-dependent manner after application of tensile force. The compression forces enhanced apoptosis to 7.5 ± 3.5% and induced gene expression of apoptotic markers of CASP9, and BCL2 within 72 h of exposure. Periostin and sclerostin play an important role in orthodontic loads and their expressions are affected oppositely by compressive and tensile forces that might be suggested as a biomarker for assessment of bone remodeling during orthodontic treatment.

Targeted Antisense Oligonucleotide-Mediated Skipping of Murine Postn Exon 17 Partially Addresses Fibrosis in D2.mdx Mice.

Periostin, a multifunctional 90 kDa protein, plays a pivotal role in the pathogenesis of fibrosis across various tissues, including skeletal muscle. It operates within the transforming growth factor beta 1 (Tgf-ß1) signalling pathway and is upregulated in fibrotic tissue. Alternative splicing of Periostin's C-terminal region leads to six protein-coding isoforms. This study aimed to elucidate the contribution of the isoforms containing the amino acids encoded by exon 17 (e17+ Periostin) to skeletal muscle fibrosis and investigate the therapeutic potential of manipulating exon 17 splicing. We identified distinct structural differences between e17+ Periostin isoforms, affecting their interaction with key fibrotic proteins, including Tgf-ß1 and integrin alpha V. In vitro mouse fibroblast experimentation confirmed the TGF-ß1-induced upregulation of e17+ Periostin mRNA, mitigated by an antisense approach that induces the skipping of exon 17 of the Postn gene. Subsequent in vivo studies in the D2.mdx mouse model of Duchenne muscular dystrophy (DMD) demonstrated that our antisense treatment effectively reduced e17+ Periostin mRNA expression, which coincided with reduced full-length Periostin protein expression and collagen accumulation. The grip strength of the treated mice was rescued to the wild-type level. These results suggest a pivotal role of e17+ Periostin isoforms in the fibrotic pathology of skeletal muscle and highlight the potential of targeted exon skipping strategies as a promising therapeutic approach for mitigating fibrosis-associated complications.

Simultaneous Expression of CD70 and POSTN in Cancer-Associated Fibroblasts Predicts Worse Survival of Colorectal Cancer Patients.

Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide, with high morbidity and mortality rates. The evidence for the tumor-supporting capacities of cancer-associated fibroblasts (CAFs) that modulate cancer cell proliferation, invasion, metastasis, and tumor immunity, including in CRC, has been attracting attention. The present study examined the expression status of CD70 and POSTN in CRC and analyzed their association with clinicopathological features and clinical outcomes. In the present study, in total 15% (40/269) and 44% (119/269) of cases exhibited CD70 and POSTN expression on CAFs, respectively. Co-expression of CD70 and POSTN was detected in 8% (21/269) of patients. Fluorescent immunohistochemistry identified the co-expression of CD70 and POSTN with FAP and PDPN, respectively. ACTA2 was not co-expressed with CD70 or POSTN in CRC CAFs. CRC with CD70+/POSTN+ status in CAFs was significantly associated with distant organ metastasis (p = 0.0020) or incomplete resection status (p = 0.0011). CD70+/POSTN+ status tended to associate with advanced pT stage (p = 0.032) or peritoneal metastasis (p = 0.0059). Multivariate Cox hazards regression analysis identified CD70+/POSTN+ status in CAFs [hazard ratio (HR) = 3.78] as a potential independent risk factor. In vitro experiments revealed the activated phenotypes of colonic fibroblasts induced by CD70 and POSTN, while migration and invasion assays identified enhanced migration and invasion of CRC cells co-cultured with CD70- and POSTN-expressing colonic fibroblasts. On the basis of our observations, CD70 and POSTN immunohistochemistry can be used in the prognostication of CRC patients. CRC CAFs may be a promising target in the treatment of CRC patients.