Johnstone, Steven

McSharry, Charles

Polish Archives of Internal Medicine

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Periostin as a biomarker of airway inflammation

Charles McSharry

Steven Johnstone

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POLSKIE ARCHIWUM MEDYCYNY WEWNĘTRZNEJ 2016; 126 (3)118number D13664) maps to chromosome 13q13.3 and encodes a secreted 90-kDa protein with an amino-terminal cysteine-rich EMI domain (that binds type I collagen, fibronectin, and Notch1), a tandem repeat of 4 fas1 domains (that bind te-nascin C and bone morphogenetic protein 1), and a carboxyl-terminal domain giving rise to multi-ple alternative splice variants.7 Together this sug-gests an extracellular function in cell adhesion and migration, for example, as ligands for αVβ3 and αVβ5 integrins, binding to the extracellular matrix (ECM) proteins and cell surfaces and en-abling attachment and movement. The periostin literature suggests a common pat-tern of function based on its localization during tissue development and oncology, response to in-jury, epithelial-mesenchymal transition, ECM re-structuring and remodeling. Normal lung devel-opment involves coordinated periostin expres-sion,8 and experimental models using periostin gene-deleted mice show that periostin is required for normal wound repair9 and contributes to the pathogenic remodeling in a variety of chronic diseases including broncho-pulmonary dyspla-sia, bleomycin-induced fibrosis, atherosclerosis, inflammatory bowel disease, and asthma.10 The serum periostin concentration as a systemic bio-marker of local remodeling is increased in idio-pathic pulmonary fibrosis7 and predicts disease progression.11 Similarly, in severe uncontrolled asthma, the serum periostin concentration is higher in patients with persistent airflow limita-tion and has an inverse correlation with postbron-chodilator forced expiratory volume in 1 second to forced vital capacity ratio despite treatment with high-dose inhaled corticosteroids,2 and could be a diagnostic tool for targeted therapy against the remodeling component of refractory Th2/eosin-ophilic asthma inflammation.4Periostin gene expression and protein synthesis is dynamic and rapidly turned over. It is induced by IL-4, IL-13, tumor growth factor (TGF)-β1,12 TGF-β3, and by the hypoxia-responsive growth The recognition of different asthma pheno-types has helped identify distinct mechanisms of pathogenesis and thereby direct a personalized approach to therapy.1 Detailed laboratory inves-tigation of these mechanisms has in turn iden-tified distinct inflammatory pathways, or endo-types, which together with phenotype will high-light further molecular targets for therapy and im-prove patient stratification. Central to this process is biomarker discovery. Periostin is a recognized biomarker in asthma,3 and is useful for identifi-cation of patients with increased clinical bene-fit from treatment with anti-interleukin (IL)-13 and anti-immunoglobulin-E (IgE) therapy,3 and may be prognostic for increased risk of asthma exacerbations and progressive lung function de-cline.4 It is also a nascent biomarker in chronic obstructive pulmonary disease (COPD).5 There is a need for further studies in asthma phenotypes and COPD, and in this issue of Polish Archives of Internal Medicine (Pol Arch Med Wewn), Katarzy-na Górska et al6 have extended the evaluation of periostin to include steroid-naive, mild-to-mod-erate asthma as well as COPD. In a prospective study, they demonstrated that bronchial periostin deposition could be identified by immunohisto-chemistry in healthy biopsy tissue, that this was progressively greater in COPD and asthma pa-tients, and that the amount of bronchial expres-sion correlated with the periostin concentration in exhaled breath condensate (EBC). Although patient numbers were small, the study was com-prehensive and also included periostin concen-trations quantified in serum and in airway fluids derived from sputum and lung lavage, although these latter measurements seemed to be of lim-ited clinical value.Periostin is a vitamin K-dependent, γ-carbo-xylated protein and a member of the CCN family of matricellular proteins. It was first cloned from a mouse calvarial cell line, hence its original des-ignation as osteoblast-specific factor 2. The hu-man periostin gene (POSTN; GenBank accession Correspondene to:  Charles McSharry, PhD, FRCPath, Institute of Infection, Immunity and Inflammation, Room B4/30  Sir Graeme Davies Building,  University of Glasgow, 120 University Place, Glasgow G12 8TA,  United Kingdom,  phone: +44 141 330 2282, e-mail: charles.mcsharry@glasgow.ac.ukReceived: March 16, 2016.Accepted: March 16, 2016. Published online: March 23, 2016.Conflict of interest: none declared.Pol Arch Med Wewn. 2016; 126 (3): 118-120doi: 10.20452/pamw.3333Copyright by Medycyna Praktyczna, Kraków 2016EDITORIALPeriostin as a biomarker of airway inflammationCharles McSharry, Steven JohnstoneInstitute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United KingdomEDITORIAL Periostin as a biomarker of airway inflammation 119develops, and finally providing the framework for aberrant remodeling and chronicity. These func-tions might not be easily demonstrated in cross-sectional studies in patients or in a gene-delet-ed mouse model, and might explain conflicting findings. It is possible that these different func-tions are associated with different periostin splice variant isoforms. POSTN can undergo alterna-tive splicing in its C-terminal region, generating isoforms that mediate extended β-zipper bind-ing interactions with other proteins during re-modeling.7,16 The function of these unique vari-ants has only begun to be examined and isoform-specific expression has been found in a variety of cell and tissue types, such as in psoriatic arthritis where periostin isoforms are putative biomark-ers. Also in idiopathic pulmonary fibrosis (IPF), there is increased gene-level expression differen-tial splicing of periostin that has been associat-ed with clinical progression.7 A more comprehen-sive understanding of periostin variant function in asthma and COPD will undoubtedly yield new insight into their pathological processes and re-veal potential therapeutic strategies.One practical point with the study of perios-tin is that different isoforms may be produced by cells in different tissues and that some anti-periostin antibodies may not necessarily detect all the isoforms. These reasons may help explain the lack of correlation between periostin con-centrations found in the different airway sam-ples in the study of Górska et al.6 There is clear-ly more work to be done to develop isoform-spe-cific assays, for example, by using liquid chroma-tography–tandem mass spectrometry, which has shown 3 phosphorylation modification sites of periostin that might further contribute to sub-tle functional differences.17 Furthermore, perios-tin is a γ-carboxylated protein and this has pro-found effects on protein structure and function, which is still to be explored in periostin. Perios-tin measurement for evaluating airway disease is more conveniently done using serum3 rather than using sputum or bronchoalveolar lavage. For ex-ample, periostin is a disulphide-linked protein and its immunoreactive detection may6 or may not2 be compromised by the use of the reducing agent 0.1% dithiothreitol (DTT) to liquefy spu-tum plugs. This effect may be mitigated by using a lower DTT concentration or by using less tox-ic dithioerythritol. The measurement of serum periostin levels in asthma may be compromised by additional periostin synthesis contributed by comorbidities, such as atopic dermatitis. There-fore, the observation of Górska et al6 that peri-ostin can be quantified in EBC and that its con-centration correlated with airway expression lev-els suggests that this may become the preferred noninvasive technique.What are the therapeutic options for target-ing periostin? The in vitro decellularized aber-rant ECM derived from cultured lung fibroblasts from IPF patients, compared with that from non-fibrotic lung tissue, had a greater impact on gene factors angiotensin 11 and fibroblast growth fac-tor 1. In the lungs, periostin expression colocal-izes with α-smooth muscle actin suggesting syn-thesis by myofibroblasts8 and periostin expres-sion in airway epithelial cells in asthmatic sub-jects correlated with the extent of subepithelial fibrosis.13 Periostin can in turn modulate TGF-β function by enhancing airway fibroblast type-1 collagen production and cross-linking and stiff-ening of the ECM.13 In addition to this matricellu-lar role, periostin has broader functions relevant to asthma and airway disease. It is a chemotactic factor and provides the appropriate matrix sub-strate for recruitment of blood eosinophils into the airways.12 Similarly, periostin is a chemotac-tic factor for monocyte recruitment from periph-eral blood into the tissue environment of tumors via αVβ3 integrin signaling, where they differen-tiate into M2-type immunosuppressive macro-phages.14 The significance of these macrophages is that they are proremodeling by providing TGF-β, which is a chemotactic and activating factor for fibroblasts, and divert arginine metabolism to hydroxyproline production, which supports col-lagen synthesis. Periostin binding to αVβ3 inte-grins can activate Akt/PKB signaling to increase cell survival and can activate nuclear factor κB signaling, which is essential for many immune cell functions, particularly dendritic cells (DCs). Experimental allergic airway inflammation using house dust mite allergen was reduced in a postn-/- mouse model and this was partly rescued by pas-sive transfer of wild-type postn-sufficient DCs,10 suggesting that periostin may have an immuno-regulatory function by providing a matricellular platform for lymphocyte interactions.The literature above typically supports a strong association between periostin and airway disease; yet there is an emerging literature that periostin might have a protective role in asthma. Postn-/- mice sensitized with Aspergillus fumigatus anti-gen had increased serum IgE, airway responsive-ness, inflammation, and remodeling compared with wild-type mice.15 The authors suggest that periostin may form a negative-feedback loop reg-ulating allergen-induced responses by augment-ing TGF-β-induced T-regulatory cell differenti-ation. Thus the suggestion that periostin itself could be a potential therapeutic in the treatment of atopic disease should be a caution to its use as a therapeutic target as discussed in the final para-graph. In this context of the uncertainty of the role of periostin in airway disease, there is added value in the depth of the study of Górska et al.6 They unexpectedly found that there was no cor-relation between airway tissue periostin expres-sion levels and protein concentrations, and this potentially anomalous observation might be in-formative of a more dynamic role for periostin that has hitherto been unrecognized. It is pos-sible that periostin has a variety of roles oper-ating during different phases of disease, for ex-ample, tethering DCs for initial allergen sensi-tization, then recruiting eosinophils as disease POLSKIE ARCHIWUM MEDYCYNY WEWNĘTRZNEJ 2016; 126 (3)120expression than did cell origin18; therefore, tar-geting matricellular proteins may hold promise for treating the pathogenic remodeling in asth-ma and COPD. The excess extracellular activity of periostin in the lung may be mitigated by an in-tervention administered during the remodeling phase of disease. This could be administered by inhalation to avoid affecting its normal function in other tissues. Possible interventions could in-clude humanized periostin-neutralizing antibody, equivalent to OC-20 monoclonal antibodies, rep-licating postn-/- mice that have reduced pathogen-ic remodeling in experimental asthma.10 Other therapeutics could include the vitamin D analog 22-oxacalcitriol, which might be effective by inhi-bition of Th2 cytokine- and TGFβ-induced POSTN expression or aptamers that bind to periostin and antagonize its interaction with integrins and in-hibit adhesion and migration.19REfEREncEs1 Kraft M. Asthma phenotypes and interleukin-13 — moving closer to per-sonalized medicine. New Eng J Med. 2011; 365: 1141-1144.2 Bobolea I, Barranco P, Del Pozo V, et al. Sputum periostin in patients with different severe asthma phenotypes. Allergy. 2015; 70: 540-546.3 Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011; 365: 1088-1098.4 Izuhara K, Conway SJ, Moore BB, et al. Roles of Periostin in Respiratory Disorders. Am J Respir Crit Care Med. 2016 Jan 12. [Epub ahead of print].5 Park HY, Lee H, Koh WJ, et al. Association of blood eosinophils and plas-ma periostin with FEV1 response after 3-month inhaled corticosteroid and long-acting beta2-agonist treatment in stable COPD patients. Int J Chron Obstruct Pulmon Dis. 2015; 11: 23-30.6 Górska K, Maskey-Warzęchowska M, Nejman-Gryz P, et al. Comparative study of periostin expression in different respiratory samples in patients with asthma and chronic obstructive pulmonary disease. Pol Arch Med Wewn. 2016; 126: 124-137.7 Nance T, Smith KS, Anaya V, et al. Transcriptome analysis reveals differ-ential splicing events in IPF lung tissue. PLoS One. 2014 Mar 19; 9: e92111.8 Ahlfeld SK, Gao Y, Wang J, et al. Periostin downregulation is an early marker of inhibited neonatal murine lung alveolar septation. Birth Defects Res A Clin Mol Teratol. 2013; 97: 373-385.9 Elliott CG, Kim SS, Hamilton DW. Functional significance of periostin in excisional skin repair: is the devil in the detail? Cell Adh Migr. 2012; 6: 319-326.10 Bentley JK, Chen Q, Hong JY, et al. Periostin is required for maxi-mal airways inflammation and hyperresponsiveness in mice. J Allergy Clin Immunol. 2014; 134: 1433-1442.11 Naik PK, Bozyk PD, Bentley JK, et al. Periostin promotes fibrosis and predicts progression in patients with idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2012; 303: L1046-1056.12 Blanchard C, Mingler MK, McBride M, et al. Periostin facilitates eosin-ophil tissue infiltration in allergic lung and esophageal responses. Mucosal Immunol. 2008; 1: 289-296.13 Sidhu SS, Yuan S, Innes AL, et al. Roles of epithelial cell-derived perios-tin in TGF-beta activation, collagen production, and collagen gel elasticity in asthma. Proc Natl Acad Sci U S A. 2010; 107: 14170-14175.14 Zhou W, Ke SQ, Huang Z, et al. Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth. Nat Cell Biol. 2015; 17: 170-182.15 Gordon ED, Sidhu SS, Wang ZE, et al. A protective role for periostin and TGF-β in IgE-mediated allergy and airway hyperresponsiveness. Clin Exp Allergy. 2012; 42: 144-155.16 Morita H, Komuro I. Periostin Isoforms and Cardiac Remodeling Af-ter Myocardial Infarction: Is the Dispute Settled? Hypertension. 2016; 67: 504-505.17 Zhao Y, Song L, Li L, et al. Mass Spectrometric Analysis Revealing Phosphorylation Modifications of Periostin. Chem Res Chin. Univ. 2015; 31: 21-24.18 Parker MW, Rossi D, Peterson M, et al. Fibrotic extracellular matrix activates a profibrotic positive feedback loop. J Clin Invest. 2014; 124: 1622-1635.19 Liu GX, Xi HQ, Sun XY, et al. Role of periostin and its antago-nist PNDA-3 in gastric cancer metastasis. World J Gastroenterol. 2015; 21: 2605-2613.

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Periostin as a biomarker of airway inflammation

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