Periostin and Discoidin Domain Receptor 1: New Biomarkers or Targets for Therapy of Renal Disease

Many patients with asthma have uncontrolled disease despite treatment with inhaled glucocorticoids. One potential cause of the variability in response to treatment is heterogeneity in the role of interleukin-13 expression in the clinical asthma phenotype. We hypothesized that anti-interleukin-13 therapy would benefit patients with asthma who had a pretreatment profile consistent with interleukin-13 activity. We conducted a randomized, double-blind, placebo-controlled study of lebrikizumab, a monoclonal antibody to interleukin-13, in 219 adults who had asthma that was inadequately controlled despite inhaled glucocorticoid therapy. The primary efficacy outcome was the relative change in prebronchodilator forced expiratory volume in 1 second (FEV(1)) from baseline to week 12. Among the secondary outcomes was the rate of asthma exacerbations through 24 weeks. Patient subgroups were prespecified according to baseline type 2 helper T-cell (Th2) status (assessed on the basis of total IgE level and blood eosinophil count) and serum periostin level. At baseline, patients had a mean FEV(1) that was 65% of the predicted value and were taking a mean dose of inhaled glucocorticoids of 580 μg per day; 80% were also taking a long-acting beta-agonist. At week 12, the mean increase in FEV(1) was 5.5 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.02). Among patients in the high-periostin subgroup, the increase from baseline FEV(1) was 8.2 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.03). Among patients in the low-periostin subgroup, the increase from baseline FEV(1) was 1.6 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.61). Musculoskeletal side effects were more common with lebrikizumab than with placebo (13.2% vs. 5.4%, P = 0.045). Lebrikizumab treatment was associated with improved lung function. Patients with high pretreatment levels of serum periostin had greater improvement in lung function with lebrikizumab than did patients with low periostin levels. (Funded by Genentech; ClinicalTrials.gov number, NCT00930163 .).

Subepithelial fibrosis is a cardinal feature of bronchial asthma. Collagen I, III, and V; fibronectin; and tenascin-C are deposited in the lamina reticularis. Extensive evidence supports the pivotal role of IL-4 and IL-13 in subepithelial fibrosis; however, the precise mechanism remains unclear. We have previously identified the POSTN gene encoding periostin as an IL-4/IL-13-inducible gene in bronchial epithelial cells. Periostin is thought to be an adhesion molecule because it possesses 4 fasciclin I domains. We explore the possibility that periostin is involved in subepithelial fibrosis in bronchial asthma. We analyzed induction of periostin in lung fibroblasts by IL-4 or IL-13. We next analyzed expression of periostin in patients with asthma and in ovalbumin-sensitized and ovalbumin-inhaled mice. Furthermore, we examined the binding ability of periostin to other extracellular matrix proteins. Both IL-4 and IL-13 induced secretion of periostin in lung fibroblasts independently of TGF-beta. Periostin colocalized with other extracellular matrix proteins involved in subepithelial fibrosis in both asthma patients and ovalbumin-sensitized and ovalbumin-inhaled wild-type mice, but not in either IL-4 or IL-13 knockout mice. Periostin had an ability to bind to fibronectin, tenascin-C, collagen V, and periostin itself. Periostin secreted by lung fibroblasts in response to IL-4 and/or IL-13 is a novel component of subepithelial fibrosis in bronchial asthma. Periostin may contribute to this process by binding to other extracellular matrix proteins. Periostin induced by IL-4/IL-13 shows promise in inhibiting subepithelial fibrosis in bronchial asthma.

The cardiac extracellular matrix is a dynamic structural support network that is both influenced by, and a regulator of, pathological remodeling and hypertrophic growth. In response to pathologic insults, the adult heart reexpresses the secreted extracellular matrix protein periostin (Pn). Here we show that Pn is critically involved in regulating the cardiac hypertrophic response, interstitial fibrosis, and ventricular remodeling following long-term pressure overload stimulation and myocardial infarction. Mice lacking the gene encoding Pn (Postn) were more prone to ventricular rupture in the first 10 days after a myocardial infarction, but surviving mice showed less fibrosis and better ventricular performance. Pn(-/-) mice also showed less fibrosis and hypertrophy following long-term pressure overload, suggesting an intimate relationship between Pn and the regulation of cardiac remodeling. In contrast, inducible overexpression of Pn in the heart protected mice from rupture following myocardial infarction and induced spontaneous hypertrophy with aging. With respect to a mechanism underlying these alterations, Pn(-/-) hearts showed an altered molecular program in fibroblast function. Indeed, fibroblasts isolated from Pn(-/-) hearts were less effective in adherence to cardiac myocytes and were characterized by a dramatic alteration in global gene expression (7% of all genes). These are the first genetic data detailing the function of Pn in the adult heart as a regulator of cardiac remodeling and hypertrophy.