Osteopontin as a new player in mast cell biology

Abstract

The secreted glycoprotein osteopontin (OPN) sets into motion an astounding variety of activities that range from bone remodeling via immunomodulation to the inhibition of apoptosis. In the current issue of the European Journal of Immunology, OPN now also enters mast cell biology and the regulation of IgE-dependent immune responses since it is reported that connective tissue-type mast cells from fetal murine skin constitutively secrete biologically active OPN. Moreover, it is shown that, in vitro, OPN augments IgEmediated mast cell degranulation and migration via ligand binding to cognate OPN receptors on the mast cell surface (CD44, av integrin) and that the magnitude of an IgEmediated passive cutaneous anaphylaxis reaction is augmented by OPN in vivo. Here, we discuss why this newly discovered property of OPN fits well into the emerging concept that OPN may serve as a multi-purpose environmental damage-response protein.See accompanying article: http://dx.doi.org/10.1002/eji200737057Among the extracellular matrix-associated glycoproteins that increasingly cross the paths of immunologists these days, there are not many that can rival osteopontin (OPN) in terms of complexity and pleiotropy of actions. Since its discovery as a regulator of bone metabolism [1,2], in immunology, OPN has become recognized as a major component of early cellular immune responses during which it predominantly acts as a chemokine-like proinflammatory cytokine [3,4]. It is through a complex series of phosphorylation, glycosylation and proteolytic cleavage events that different functional forms of OPN are produced. OPN exists as a soluble cytokine and as an immobilized protein adsorbed to calcified matrices. While OPN is predominantly a secreted protein, an intracellular form has also been described [5]. It has been proposed that distinct cell types differ in their posttranslational modifications of OPN, which may underlie cell-type specific differences in the functions of OPN [6].In its multiple variations that result from these intricate post-translation modifications, whose controls are only very incompletely understood, this phosphorylated acidic glycoprotein then interacts with many different molecular partners: OPN serves as a substrate for thrombin and matrix metalloproteinases (MMP2, MMP3, MMP7, MMP9 and MMP12), can bind to the extracellular matrix proteins fibronectin and collagen and interacts with integrins a v (b 1 , b 2 , or b 5 ) and (a 4 , a 5 , a 8 or a 9 ) b 1 surface receptors through an Arg-Gly-Asp (RDG) sequence [1,2,6]. In addition, some variants of the hyaluronan CD44 receptor have been identified as a receptor for OPN [6][7][8].

Mast cells contribute to altered vascular reactivity and ischemia-reperfusion injury following cerium oxide nanoparticle instillation

“…A similar trend for an increase in osteopontin was observed in the hearts of CeO 2 instilled C57BL/6. Osteopontin is reported to play a role in the pathogenesis of inflammatory and immune-mediated diseases (Wang and Denhardt 2008) and more recently has been identified as a novel mast cell mediator which is produced by mast cells (Bulfone-Paus and Paus 2008; Nagasaka et al 2008). Serum osteopontin levels are proposed as a biomarker for pneumoconiosis since an increase in osteopontin has been observed in asbestosis patients compared to healthy controls (Park et al 2009).…”

The Potential of Osteopontin as a Therapeutic Target for Human Colorectal Cancer

“…3 The overexpression of OPN has been found in a variety of human cancers such as lung cancer, breast carcinoma, esophageal cancer, endometrial cancer, gastric cancer, and malignant pleural mesothelioma. [4][5][6][7][8][9] Previously, we reported that the level of OPN mRNA expression in CRC cells or tissues was significantly higher than that in normal intestinal epithelial cell line or corresponding nontumor colon tissues.…”

Suppression of Osteopontin Functions by Levocetirizine, a Histamine Receptor Antagonist, In Vitro

“…OPN engages a number of receptors such as integrins α v and β 1, and it is also a ligand for CD44 [22, 33]. These receptors directly or indirectly activate cellular signaling pathways such as p38 MAPK, NF- κ B, and AP-1, allowing OPN to mediate cell-matrix interaction and factor production [22, 33].…”

“…These receptors directly or indirectly activate cellular signaling pathways such as p38 MAPK, NF- κ B, and AP-1, allowing OPN to mediate cell-matrix interaction and factor production [22, 33]. It is also reported that OPN production from airway cells requires the activation of transcription factors, NF- κ B and AP-1, after inflammatory stimulation [13].…”