Anthony O’Regan

Osteopontin (OPN) is a phosphorylated acidic glycoprotein that has been implicated in a number of physiological and pathological events, including maintenance or reconfiguration of tissue integrity during inflammatory processes. As such, it is required for stress-induced bone remodeling and certain types of cell-mediated immunity. It also acts in dystrophic calcification, coronary restenosis, and tumor cell metastasis. An RGD-containing protein, OPN exists both as an immobilized ECM molecule in mineralized tissues and as a cytokine in body fluids; it is not a significant part of typical nonmineralized ECM.

Osteopontin (Opn) is a secreted adhesive, glycosylated phosphoprotein that contains the arginine-glycine-aspartic acid (RGD) cell-binding sequence that is found in many extracellular matrix (ECM) proteins (for a review of Opn see References Denhardt & Guo 1993; Patarca et al. 1993; Rittling & Denhardt 1999). Since its initial description in 1979 as a secreted protein associated with malignant transformation, Opn has been independently discovered by investigators from diverse scientific disciplines, and has been associated with a remarkable range of pathologic responses. Opn is an important bone matrix protein, where it is thought to mediate adhesion of osteoclasts to resorbing bone. However, studies from the past decade have identified an alternative role for Opn as a key cytokine regulating tissue repair and inflammation. Recent work by our laboratory and that of others has underlined the importance of Opn as a pivotal cytokine in the cellular immune response. Despite this Opn is not well known to the immunologist. In this review we will focus on studies that pertain to the role of Opn in cell-mediated and granulomatous inflammation.

Sarcoidosis is a systemic disease characterized by the accumulation of activated T cells and widespread granuloma formation. In addition, individual genetic predisposition appears to be important in this disease. Osteopontin, a noncollagenous matrix protein produced by macrophages and T lymphocytes, is expressed in the granulomas of tuberculosis, and is associated with genetic susceptibility to intracellular infection. The function of osteopontin in these T cell-mediated responses is unknown. We sought to elucidate the role of osteopontin in granulomatous inflammation by characterizing its expression in different stages of sarcoidosis and its effector function on T cells in vitro. Lymphocyte-associated expression of osteopontin in sarcoidosis was demonstrated by immunohistochemistry, and its expression correlated with granuloma maturity. In addition, osteopontin induced T cell chemotaxis, supported T cell adhesion (an effect enhanced by thrombin cleavage of osteopontin), and costimulated T cell proliferation. These results suggest a novel mechanism by which osteopontin and thrombin modulate T cell recruitment and activation in granulomatous inflammation.

Tracheobronchial amyloidosis (TBA), an idiopathic disorder characterized by deposition of fibrillar proteins in the tracheobronchial tree, occurred in 10 patients referred to the Amyloid Program at Boston University over the past 15 years. Fewer than 100 cases of TBA have been described; only 1 series encompassed more than 3 patients. We analyzed our experience with biopsy-proven TBA to define better its natural history. Follow-up averaged approximately 8 years and was obtained in all cases, making this outcome reporting the largest and most complete to date. Three of these patients were prospectively studied for up to 24 months to examine the utility of bronchoscopy, computerized tomography (CT) imaging, and pulmonary function tests (PFTs) in monitoring disease progression. No patient with TBA developed signs or symptoms of systemic amyloidosis during the period reviewed. Conversely, tracheobronchial disease was not diagnosed in 685 patients with primary systemic (AL) amyloidosis during the 15-year study period at Boston University. Bronchoscopy proved most useful in establishing the diagnosis by biopsy. Narrowing of major airways limited its inspection of the tracheobronchial tree, however. In contrast, CT imaging provided quantitative assessment of airway narrowing and mural thickening--2 major consequences of amyloid infiltration. These CT features, in the presence of mural calcifications sparing the posterior tracheal membrane, have been reported in few disorders other than TBA. The ability of CT to map airway involvement and identify extraluminal manifestations of TBA made it the study of choice for establishing disease extent. Three patterns of disease were evident by CT imaging and bronchoscopic examination: proximal, mid, and distal airways involvement. Those with severe proximal disease had significantly decreased air flows, air trapping, and fixed upper airway obstruction on PFTs. Patients with distal disease had normal airflows. PFTs could not clearly distinguish proximal from severe mid airways disease. Thirty percent of patients died within 7-12 years after diagnosis, all having proximal or severe mid airways disease. Repeated rigid bronchoscopic debridement and laser treatments did not prevent progressive airways narrowing in patients dying from TBA. Most patients with mid airways involvement, and all distal airway cases, had either stagnant disease or slowly increasing amyloid deposits when followed for up to 14 years. In a small subset of patients followed prospectively, serial PFTs were most sensitive to disease progression. CT-derived measures of airway lumen diameter and wall thickness did not change significantly despite marked improvements in airflow after rigid bronchoscopy. Our experience suggests that serial PFTs and CT imaging together offer the best assessment of airway involvement and disease progression in patients with TBA. In the future, radiation therapy may provide more definitive treatment of TBA than debulking procedure have to date.