Browsing by Subject "Periostin"

Now showing 1 - 5 of 5
  • Thumbnail Image
    Item
    Cross-Talk between Transforming Growth Factor-β and Periostin Can Be Targeted for Pulmonary Fibrosis
    (American Thoracic Society, 2020-02) Nanri, Yasuhiro; Nunomura, Satoshi; Terasaki, Yasuhiro; Yoshihara, Tomohito; Hirano, Yusuke; Yokosaki, Yasuyuki; Yamaguchi, Yukie; Feghali-Bostwick, Carol; Ajito, Keiichi; Murakami, Shoichi; Conway, Simon J.; Izuhara, Kenji; Pediatrics, School of Medicine
    Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized as progressive and irreversible fibrosis in the interstitium of lung tissues. There is still an unmet need to develop a novel therapeutic drug for IPF. We have previously demonstrated that periostin, a matricellular protein, plays an important role in the pathogenesis of pulmonary fibrosis. However, the underlying mechanism of how periostin causes pulmonary fibrosis remains unclear. In this study, we sought to learn whether the cross-talk between TGF-β (transforming growth factor-β), a central mediator in pulmonary fibrosis, and periostin in lung fibroblasts leads to generation of pulmonary fibrosis and whether inhibitors for integrin αVβ3, a periostin receptor, can block pulmonary fibrosis in model mice and the TGF-β signals in fibroblasts from patients with IPF. We found that cross-talk exists between TGF-β and periostin signals via αVβ3/β5 converging into Smad3. This cross-talk is necessary for the expression of TGF-β downstream effector molecules important for pulmonary fibrosis. Moreover, we identified several potent integrin low-molecular-weight inhibitors capable of blocking cross-talk with TGF-β signaling. One of the compounds, CP4715, attenuated bleomycin-induced pulmonary fibrosis in vivo in mice and the TGF-β signals in vitro in fibroblasts from patients with IPF. These results suggest that the cross-talk between TGF-β and periostin can be targeted for pulmonary fibrosis and that CP4715 can be a potential therapeutic agent to block this cross-talk.
  • Thumbnail Image
    Item
    Periostin activates distinct modules of inflammation and itching downstream of the type 2 inflammation pathway
    (Elsevier, 2023) Nunomura, Satoshi; Uta, Daisuke; Kitajima, Isao; Nanri, Yasuhiro; Matsuda, Kosuke; Ejiri, Naoko; Kitajima, Midori; Ikemitsu, Hitoshi; Koga, Misaki; Yamamoto, Sayaka; Honda, Yuko; Takedomi, Hironobu; Andoh, Tsugunobu; Conway, Simon J.; Izuhara, Kenji; Pediatrics, School of Medicine
    Atopic dermatitis (AD) is a chronic relapsing skin disease accompanied by recurrent itching. Although type 2 inflammation is dominant in allergic skin inflammation, it is not fully understood how non-type 2 inflammation co-exists with type 2 inflammation or how type 2 inflammation causes itching. We have recently established the FADS mouse, a mouse model of AD. In FADS mice, either genetic disruption or pharmacological inhibition of periostin, a downstream molecule of type 2 inflammation, inhibits NF-κB activation in keratinocytes, leading to downregulating eczema, epidermal hyperplasia, and infiltration of neutrophils, without regulating the enhanced type 2 inflammation. Moreover, inhibition of periostin blocks spontaneous firing of superficial dorsal horn neurons followed by a decrease in scratching behaviors due to itching. Taken together, periostin links NF-κB-mediated inflammation with type 2 inflammation and promotes itching in allergic skin inflammation, suggesting that periostin is a promising therapeutic target for AD.
  • Thumbnail Image
    Item
    Periostin and matrix stiffness combine to regulate myofibroblast differentiation and fibronectin synthesis during palatal healing
    (Elsevier, 2020) Nikoloudaki, Georgia; Snider, Paige; Simmons, Olga; Conway, Simon J.; Hamilton, Douglas W.; Pediatrics, School of Medicine
    Although the matricellular protein periostin is prominently upregulated in skin and gingival healing, it plays contrasting roles in myofibroblast differentiation and matrix synthesis respectively. Palatal healing is associated with scarring that can alter or restrict maxilla growth, but the expression pattern and contribution of periostin in palatal healing is unknown. Using periostin-knockout (Postn-/-) and wild-type (WT) mice, the contribution of periostin to palatal healing was investigated through 1.5 mm full-thickness excisional wounds in the hard palate. In WT mice, periostin was upregulated 6 days post-wounding, with mRNA levels peaking at day 12. Genetic deletion of periostin significantly reduced wound closure rates compared to WT mice. Absence of periostin reduced mRNA levels of pivotal genes in wound repair, including α-SMA/acta2, fibronectin and βigh3. Recruitment of fibroblasts and inflammatory cells, as visualized by immunofluorescent staining for fibroblast specific factor-1, vimentin, and macrophages markers Arginase-1 and iNOS was also impaired in Postn-/-, but not WT mice. Palatal fibroblasts isolated from the hard palate of mice were cultured on collagen gels and prefabricated silicon substrates with varying stiffness. Postn-/- fibroblasts showed a significantly reduced ability to contract a collagen gel, which was rescued by the exogenous addition of recombinant periostin. As the stiffness increased, Postn-/- fibroblasts increasingly differentiated into myofibroblasts, but not to the same degree as the WT. Pharmacological inhibition of Rac rescued the deficient myofibroblastic phenotype of Postn-/- cells. Low stiffness substrates (0.2 kPa) resulted in upregulation of fibronectin in WT cells, an effect which was significantly reduced in Postn-/- cells. Quantification of immunostaining for vinculin and integrinβ1 adhesions revealed that Periostin is required for the formation of focal and fibrillar adhesions in mPFBs. Our results suggest that periostin modulates myofibroblast differentiation and contraction via integrinβ1/RhoA pathway, and fibronectin synthesis in an ECM stiffness dependent manner in palatal healing.
  • Thumbnail Image
    Item
    Periostin-related progression of different types of experimental pulmonary hypertension: A role for M2 macrophage and FGF-2 signalling
    (Wiley, 2022) Yoshida, Takashi; Nagaoka, Tetsutaro; Nagata, Yuichi; Suzuki, Yoshifumi; Tsutsumi, Takeo; Kuriyama, Sachiko; Watanabe, Junko; Togo, Shinsaku; Takahashi, Fumiyuki; Matsushita, Masakazu; Joki, Yusuke; Konishi, Hakuoh; Nunomura, Satoshi; Izuhara, Kenji; Conway, Simon J.; Takahashi, Kazuhisa; Pediatrics, School of Medicine
    Background and objective: Remodelling of pulmonary arteries (PA) contributes to the progression of pulmonary hypertension (PH). Periostin, a matricellular protein, has been reported to be involved in the development of PH. We examined the role of periostin in the pathogenesis of PH using different types of experimental PH. Methods: PH was induced by vascular endothelial growth factor receptor antagonist (Sugen5416) plus hypoxic exposure (SuHx) and venous injection of monocrotaline-pyrrole (MCT-P) in wild-type (WT) and periostin-/- mice. Pulmonary haemodynamics, PA remodelling, expression of chemokines and fibroblast growth factor (FGF)-2, accumulation of macrophages to small PA and the right ventricle (RV) were examined in PH-induced WT and periostin-/- mice. Additionally, the role of periostin in the migration of macrophages, human PA smooth muscle (HPASMCs) and endothelial cells (HPMVECs) was investigated. Results: In PH induced by SuHx and MCT-P, PH and accumulation of M2 macrophage to small PA were attenuated in periostin-/- mice. PA remodelling post-SuHx treatment was also mild in periostin-/- mice compared to WT mice. Expression of macrophage-associated chemokines and FGF-2 in lung tissue, and accumulation of CD68-positive cells in the RV were less in SuHx periostin-/- than in SuHx WT mice. Periostin secretion in HPASMCs and HPMVECs was enhanced by transforming growth factor-β. Periostin also augmented macrophage, HPASMCs and HPMVECs migration. Separately, serum periostin levels were significantly elevated in patients with PH compared to healthy controls. Conclusion: Periostin is involved in the development of different types of experimental PH, and may also contribute to the pathogenesis of human PH.
  • Thumbnail Image
    Item
    Roles of Periostin in Respiratory Disorders
    (American Thoracic Society, 2016-05) Izuhara, Kenji; Conway, Simon J.; Moore, Bethany B.; Matsumoto, Hisako; Holweg, Cecile T. J.; Matthews, John G.; Arron, Joseph R.; Medicine, School of Medicine
    Periostin is a matricellular protein that has been implicated in many disease states. It interacts with multiple signaling cascades to modulate the expression of downstream genes that regulate cellular interactions within the extracellular matrix. This review focuses on the role of periostin in respiratory diseases, including asthma and idiopathic pulmonary fibrosis, and its potential to help guide treatment or assess prognosis. Epithelial injury is a common feature of many respiratory diseases, resulting in the secretion, among others, of periostin, which is subsequently involved in airway remodeling and other aspects of pulmonary pathophysiology. In asthma, periostin is recognized as a biomarker of type 2 inflammation; POSTN gene expression is up-regulated in bronchial epithelial cells by IL-13 and IL-4. Serum periostin has been evaluated for the identification of patients with increased clinical benefit from treatment with anti-IL-13 (lebrikizumab, tralokinumab) and anti-IgE (omalizumab) therapy and may be prognostic for increased risk of asthma exacerbations and progressive lung function decline. Furthermore, in asthma, periostin may regulate subepithelial fibrosis and mucus production and may serve as a systemic biomarker of eosinophilic airway inflammation. Periostin is also highly expressed in the lungs of patients with idiopathic pulmonary fibrosis, and its serum levels may predict clinical progression. Overall, periostin contributes to multiple pathogenic processes across respiratory diseases, and peripheral blood levels of periostin may have utility as a biomarker of treatment response and disease progression.