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Cecilia M Giachelli - One of the best experts on this subject based on the ideXlab platform.
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Role of av433 in Smooth Muscle Cell Migration to Osteopontin In Vitro
2016Co-Authors: Cell Surface Integrins, Lucy Liaw, Michael P. Skinner, Elaine W Raines, David A Cheresh, Stephen M Schwartz, Russell Ross, Cecilia M GiachelliAbstract:Osteopontin is an arginine-glycine-aspartate containing acidic glycoprotein postulated to mediate adhesion, migra-tion, and biomineralization in diverse tissues. The mecha-nisms explaining this multifunctionality are not well under-stood, although it is known that one Osteopontin receptor is the av.83 integrin. In this work, we studied human smooth muscle cells varying in avB83 levels to identify additional Osteopontin receptors. We report that, in addition to 0avP3, both a435 and aci31 are Osteopontin receptors. Moreover, the presence or absence of a433 on the cell surface altered the adhesive and migratory responses of smooth muscle cells to Osteopontin. Adhesion of a4v33-deficient cell populations to Osteopontin was only half that of cells containing av43, and migration toward an Osteopontin gradient in the Boyden chamber was dependent on cell surface C433. Although av.I3-deficient smooth muscle cells were unable to migrate to Osteopontin, they did migrate significantly in response to vitronectin and fibronectin. These findings represent the first description of av./5 and av4l as Osteopontin receptors and suggest that, while adhesion to Osteopontin is supported by integrins containing f3, 83, and j3, migration in response to Osteopontin appears to depend on a4v.3. Thus, interaction with distinct receptors is one mechanism by which osteopon-tin may initiate multiple functions. (J. Clin. Invest. 1995
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Osteopontin expression in human cyclosporine toxicity.
Kidney international, 2001Co-Authors: Kelly L. Hudkins, Cecilia M Giachelli, Richard J. Johnson, Stephan Segerer, Connie L. Davis, Charles E. AlpersAbstract:Osteopontin expression in human cyclosporine toxicity . Background Osteopontin is a secreted phosphoprotein that has a number of diverse biological functions, including cell signaling, mediation of cell adhesion, migration, and chemoattraction of monocytes/macrophages. Up-regulation of Osteopontin expression by proximal tubular epithelium has been demonstrated in both human and rodent models of renal injury in association with macrophage influx. Methods We studied the expression of Osteopontin protein and mRNA in renal donor biopsies ( N = 7) and renal transplant biopsies with cyclosporine A toxicity ( N = 23) by immunohistochemistry and in situ hybridization. Serial tissue sections were immunostained with a monocyte/macrophage marker, CD68, to demonstrate the pattern of macrophage infiltration. Results Strong Osteopontin expression was observed in the majority of pretransplant donor biopsies in the absence of any macrophage infiltration. In the biopsies with cyclosporine toxicity, Osteopontin expression was widespread and demonstrated moderate immunohistochemical signal intensity that did not correlate with the number of interstitial macrophages present. Conclusions Strong Osteopontin protein and mRNA expression by tubular epithelium was observed in pretransplant donor biopsies and in biopsies with cyclosporine toxicity without an inflammatory cell infiltration. Therefore, Osteopontin expression alone is insufficient to serve as the principal mediator of intrarenal monocyte/macrophage influx in the transplant setting.
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Osteopontin expression in human crescentic glomerulonephritis.
Kidney international, 2000Co-Authors: Kelly L. Hudkins, Cecilia M Giachelli, Richard J. Johnson, Frank Eitner, William G. Couser, Charles E. AlpersAbstract:Osteopontin expression in human crescentic glomerulonephritis Background Osteopontin is a molecule with diverse biological functions, including cell adhesion, migration, and signaling. The expression of Osteopontin has been demonstrated in a number of models of renal injury in association with accumulations of monocyte/macrophages, including recent reports of Osteopontin expression in glomerular crescents in a rat model of anti-glomerular basement membrane glomerulonephritis. Methods Glomerular expression of Osteopontin in biopsies of human crescentic glomerulonephritis ( N = 25), IgA nephropathy with crescents ( N = 2), and diffuse proliferative lupus glomerulonephropathy with crescents ( N = 1) was studied by immunohistochemistry, in situ hybridization, and combined immunohistochemistry/ in situ hybridization. Additionally, antibodies to cell-specific phenotypic markers were used to identify cellular components of the glomerular crescent, which express Osteopontin protein and mRNA. Results All of the crescents present in the biopsies studied contained a significant number of cells that expressed Osteopontin protein and mRNA, demonstrated by immunohistochemistry and in situ hybridization, respectively. Using replicate tissue sections and combined immunohistochemistry/ in situ hybridization, we showed that the majority of the strongly Osteopontin-positive cells are monocyte/macrophages. In addition to the very strong and cell-associated localization, a weaker and more diffuse pattern of Osteopontin protein and mRNA expression could be seen in a number of crescents. None of the Osteopontin mRNA-expressing cells could be identified as parietal epithelial cells, CD3-positive T cells, or α-smooth muscle actin-positive myofibroblasts. Interstitial monocyte/macrophages did not express Osteopontin, except when located in a periglomerular inflammatory infiltrate. Conclusions Macrophages present in the human glomerular crescent express Osteopontin protein and mRNA at a high level. This expression supports a role for Osteopontin in the formation and progression of the crescentic lesion via chemotactic and signaling properties of the molecule.
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Osteopontin: a versatile regulator of inflammation and biomineralization.
Matrix biology : journal of the International Society for Matrix Biology, 2000Co-Authors: Cecilia M Giachelli, Susan SteitzAbstract:Osteopontin is a secreted glycoprotein with a multidomain structure and functions characteristic of a matricellular protein. Osteopontin interacts with cell surface receptors via arginine-glycine-aspartate (RGD)- and non-RGD containing adhesive domains, in addition to binding to components of the structural extracellular matrix. While normally expressed in bone and kidney, Osteopontin levels are elevated during wound healing and inflammation in most tissues studied to date. Since 1986, over one thousand studies have been published on Osteopontin, including recent experiments in Osteopontin-deficient mice. These studies reveal Osteopontin as a cell adhesive, signaling, migratory, and survival stimulus for various mesenchymal, epithelial, and inflammatory cells, in addition to being a potent regulator of osseous and ectopic calcification. Based on these reports, a general picture of Osteopontin as an important regulator of inflammation and biomineralization is emerging. A common denominator in Osteopontin function in these situations is its ability to regulate the function of macrophage and macrophage-derived cells (i.e. osteoclasts). While we have learned much about Osteopontin and the processes it appears to regulate over the past decade, many questions regarding this important multifunctional protein remain unanswered and provide important directions for future studies.
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CD44 is not an adhesive receptor for Osteopontin.
Journal of cellular biochemistry, 1999Co-Authors: Laura Smith, Brad Greenfield, Alejandro Aruffo, Cecilia M GiachelliAbstract:Osteopontin is a secreted glycoprotein with adhesive and migratory functions. Cellular interactions with Osteopontin are mediated through integrin receptors which recognize the RGD domain. Recently, CD44, a non-integrin, multifunctional adhesion molecule was identified as an Osteopontin receptor. CD44 is a ubiquitous surface molecule that exists as a number of different isoforms, generated by alternative splicing. To analyze which forms of CD44 mediate binding to Osteopontin, we used the standard form of CD44 as CD44-human immunoglobulin fusion proteins and several splice variants in enzyme-linked immunosorbant assays. Multiple preparations of Osteopontin were used including native Osteopontin derived from smooth muscle cells, human urinary Osteopontin, full-length recombinant Osteopontin, and two recombinant Osteopontin fragments expected to be formed following thrombin cleavage. Our data show that although the CD44-hIg fusion proteins could interact with hyaluronic acid as expected, there was no interaction between CD44H, CD44E, CD44v3,v8-v10, or CD44v3 with Osteopontin. These studies suggest that CD44-Osteopontin interactions may not be common in vivo and may be limited to a specific CD44 isoform(s), and/or a particular modified form of Osteopontin. J. Cell. Biochem. 73:20–30, 1999. © 1999 Wiley-Liss, Inc.
Eva Degerman - One of the best experts on this subject based on the ideXlab platform.
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regulation of the pro inflammatory cytokine Osteopontin by gip in adipocytes a role for the transcription factor nfat and phosphodiesterase 3b
Biochemical and Biophysical Research Communications, 2012Co-Authors: Bilal Omar, Elin Banke, Emilia Guirguis, Lina Akesson, Valeriya Lyssenko, Leif Groop, Vincent C. Manganiello, Maria F Gomez, Eva DegermanAbstract:The incretin - glucose-dependent insulinotropic polypeptide (GIP) - and the pro-inflammatory cytokine Osteopontin are known to have important roles in the regulation of adipose tissue functions. In this work we show that GIP stimulates lipogenesis and Osteopontin expression in primary adipocytes. The GIP-induced increase in Osteopontin expression was inhibited by the NFAT (the transcription factor nuclear factor of activated T-cells) inhibitor A285222. Also, the NFAT kinase glycogen synthase kinase (GSK) 3 was upregulated by GIP. To test whether cAMP might be involved in GIP mediated effects on Osteopontin a number of strategies were used. Thus, the β3-adrenergic receptor aganist CL316,243 stimulated Osteopontin expression, an effects which was mimicked by OPC3911, a specific inhibitor of phosphodiesterase 3. Furthermore, treatment of phosphodiesterase 3B knock-out mice with CL316,243 resulted in a dramatic upregulation of Osteopontin in adipose tissue which was not the case in wild-type mice. In summary, we delineate mechanisms by which GIP stimulate Osteopontin in adipocytes. Given the established link between Osteopontin and insulin resistance, our data suggest that GIP by stimulating Osteopontin expression, also could promote insulin resistance in adipocytes. (Less)
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Regulation of the pro-inflammatory cytokine Osteopontin by GIP in adipocytes – A role for the transcription factor NFAT and phosphodiesterase 3B
Biochemical and Biophysical Research Communications, 2012Co-Authors: Bilal Omar, Elin Banke, Emilia Guirguis, Lina Akesson, Valeriya Lyssenko, Leif Groop, Vincent C. Manganiello, Maria F Gomez, Eva DegermanAbstract:The incretin - glucose-dependent insulinotropic polypeptide (GIP) - and the pro-inflammatory cytokine Osteopontin are known to have important roles in the regulation of adipose tissue functions. In this work we show that GIP stimulates lipogenesis and Osteopontin expression in primary adipocytes. The GIP-induced increase in Osteopontin expression was inhibited by the NFAT (the transcription factor nuclear factor of activated T-cells) inhibitor A285222. Also, the NFAT kinase glycogen synthase kinase (GSK) 3 was upregulated by GIP. To test whether cAMP might be involved in GIP mediated effects on Osteopontin a number of strategies were used. Thus, the β3-adrenergic receptor aganist CL316,243 stimulated Osteopontin expression, an effects which was mimicked by OPC3911, a specific inhibitor of phosphodiesterase 3. Furthermore, treatment of phosphodiesterase 3B knock-out mice with CL316,243 resulted in a dramatic upregulation of Osteopontin in adipose tissue which was not the case in wild-type mice. In summary, we delineate mechanisms by which GIP stimulate Osteopontin in adipocytes. Given the established link between Osteopontin and insulin resistance, our data suggest that GIP by stimulating Osteopontin expression, also could promote insulin resistance in adipocytes. (Less)
Bilal Omar - One of the best experts on this subject based on the ideXlab platform.
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regulation of the pro inflammatory cytokine Osteopontin by gip in adipocytes a role for the transcription factor nfat and phosphodiesterase 3b
Biochemical and Biophysical Research Communications, 2012Co-Authors: Bilal Omar, Elin Banke, Emilia Guirguis, Lina Akesson, Valeriya Lyssenko, Leif Groop, Vincent C. Manganiello, Maria F Gomez, Eva DegermanAbstract:The incretin - glucose-dependent insulinotropic polypeptide (GIP) - and the pro-inflammatory cytokine Osteopontin are known to have important roles in the regulation of adipose tissue functions. In this work we show that GIP stimulates lipogenesis and Osteopontin expression in primary adipocytes. The GIP-induced increase in Osteopontin expression was inhibited by the NFAT (the transcription factor nuclear factor of activated T-cells) inhibitor A285222. Also, the NFAT kinase glycogen synthase kinase (GSK) 3 was upregulated by GIP. To test whether cAMP might be involved in GIP mediated effects on Osteopontin a number of strategies were used. Thus, the β3-adrenergic receptor aganist CL316,243 stimulated Osteopontin expression, an effects which was mimicked by OPC3911, a specific inhibitor of phosphodiesterase 3. Furthermore, treatment of phosphodiesterase 3B knock-out mice with CL316,243 resulted in a dramatic upregulation of Osteopontin in adipose tissue which was not the case in wild-type mice. In summary, we delineate mechanisms by which GIP stimulate Osteopontin in adipocytes. Given the established link between Osteopontin and insulin resistance, our data suggest that GIP by stimulating Osteopontin expression, also could promote insulin resistance in adipocytes. (Less)
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Regulation of the pro-inflammatory cytokine Osteopontin by GIP in adipocytes – A role for the transcription factor NFAT and phosphodiesterase 3B
Biochemical and Biophysical Research Communications, 2012Co-Authors: Bilal Omar, Elin Banke, Emilia Guirguis, Lina Akesson, Valeriya Lyssenko, Leif Groop, Vincent C. Manganiello, Maria F Gomez, Eva DegermanAbstract:The incretin - glucose-dependent insulinotropic polypeptide (GIP) - and the pro-inflammatory cytokine Osteopontin are known to have important roles in the regulation of adipose tissue functions. In this work we show that GIP stimulates lipogenesis and Osteopontin expression in primary adipocytes. The GIP-induced increase in Osteopontin expression was inhibited by the NFAT (the transcription factor nuclear factor of activated T-cells) inhibitor A285222. Also, the NFAT kinase glycogen synthase kinase (GSK) 3 was upregulated by GIP. To test whether cAMP might be involved in GIP mediated effects on Osteopontin a number of strategies were used. Thus, the β3-adrenergic receptor aganist CL316,243 stimulated Osteopontin expression, an effects which was mimicked by OPC3911, a specific inhibitor of phosphodiesterase 3. Furthermore, treatment of phosphodiesterase 3B knock-out mice with CL316,243 resulted in a dramatic upregulation of Osteopontin in adipose tissue which was not the case in wild-type mice. In summary, we delineate mechanisms by which GIP stimulate Osteopontin in adipocytes. Given the established link between Osteopontin and insulin resistance, our data suggest that GIP by stimulating Osteopontin expression, also could promote insulin resistance in adipocytes. (Less)
Jeffrey S. Berman - One of the best experts on this subject based on the ideXlab platform.
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Interleukin‐1β induces Osteopontin expression in pulmonary fibroblasts
Journal of cellular biochemistry, 2006Co-Authors: David M. Serlin, Jeffrey S. Berman, Ping Ping Kuang, Mangalalaxmy Subramanian, Anthony O'regan, Ronald H. GoldsteinAbstract:Osteopontin is a multifunctional matricellular protein identified as one of the most upregulated genes in pulmonary fibrosis. Experimental animal models have identified early pro-fibrotic cytokines as essential to the pathogenesis of inflammation-induced pulmonary fibrosis. However, the principal sources of Osteopontin in the fibroproliferative lung, and the factors responsible for its induction, have not been fully defined. We isolated primary rat lung fibroblasts in culture to examine the expression and regulation of lung fibroblast-derived Osteopontin. Our results demonstrate a potent and dramatic increase in Osteopontin expression induced by interleukin-1beta (IL-1beta), whereas tumor necrosis factor-alpha, transforming growth factor-beta, and angiotensin II had minimal effect. Stimulation with IL-1beta resulted in the secretion of soluble Osteopontin protein. We found that Osteopontin expression by IL-1beta was regulated via signaling primarily through the mitogen-activated protein kinase member ERK1/2, partially by p38 MAPK, but not at all by JNK. Finally, the mechanism of IL-1beta increase in Osteopontin mRNA requires de novo transcription and translation. In conclusion, we find that Osteopontin is expressed by primary lung fibroblasts and is potently upregulated by the early inflammatory and pro-fibrotic cytokine IL-1beta. Activated fibroblasts may be a significant source of Osteopontin production during lung fibrogenesis.
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Asbestos exposure and serum Osteopontin.
The New England journal of medicine, 2006Co-Authors: Anthony W. O'regan, David M. Serlin, Jeffrey S. BermanAbstract:To the Editor: Pass et al. (Oct. 13 issue)1 report that elevated Osteopontin levels in workers with pleural disease who have been exposed to asbestos support a diagnosis of mesothelioma. The authors acknowledge that other cancers express Osteopontin, and they mention the need for further studies. The expression of Osteopontin in numerous benign inflammatory and fibrotic lung diseases,2 which considerably limits the potential use of Osteopontin as a tumor marker, was not discussed. In addition to the Osteopontin levels associated with lung carcinoma, similar levels are seen in tuberculosis, interstitial lung diseases, and cardiac disease.2,3 These clinical entities pose diagnostic difficulties in patients with asbestosrelated pleural disease. Therefore, measurement of Osteopontin levels is unlikely to help diagnostically in this clinical scenario. The functional diversity of Osteopontin in part reflects allelic variation and extensive post-translational modification.2 Certain isoforms of Osteopontin have differing biologic functions.4 Tumorderived Osteopontin functions in a manner distinct from non–tumor-derived Osteopontin.5 Much as specific isoforms may account for the role of Osteopontin in cancer, future studies may define variants with higher diagnostic potential. Until then, the specificity of Osteopontin measurement is too low for it to be used as a screening tool for mesothelioma. Anthony W. O’Regan, M.D. National University of Ireland, Galway Galway, Ireland anthony.oregan@whb.ie
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Abnormal Pulmonary Granuloma Formation in Osteopontin-deficient Mice
American journal of respiratory and critical care medicine, 2001Co-Authors: Anthony W. O'regan, Lucy Liaw, Jason M. Hayden, Steven Body, Niall Mulligan, Margo Goetschkes, Jeffrey S. BermanAbstract:Osteopontin is a novel cytokine that is expressed in pulmonary granulomatous disease such as sarcoidosis and tuberculosis. It can regulate macrophage and T cell migration, activation, and cytokine expression, yet its role in granuloma formation and evolution is unknown. We induced hypersensitivity pulmonary granulomas by embolizing Schistosoma mansoni eggs to the lungs of Osteopontin-deficient (null mutant) mice and Osteopontin-sufficient (wild-type control) mice. Granulomas from Osteopontin-null animals were smaller at early time points and contained remarkably few macrophages and macrophage-derived epithelioid cells and giant cells. T cell accumulation was unaffected by Osteopontin deficiency. These results demonstrate that Osteopontin regulates macrophage accumulation during pulmonary granuloma formation, and may explain the impaired ability of Osteopontin-deficient hosts to control mycobacterial disease.
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Osteopontin is associated with t cells in sarcoid granulomas and has t cell adhesive and cytokine like properties in vitro
Journal of Immunology, 1999Co-Authors: Anthony W Oregan, Niall Mulligan, Margo Goetschkes, Geoffrey L Chupp, John A Lowry, Jeffrey S. BermanAbstract: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.
Akira Ooshima - One of the best experts on this subject based on the ideXlab platform.
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Osteopontin a component of matrix in capsular opacification and subcapsular cataract
Investigative Ophthalmology & Visual Science, 2003Co-Authors: Shizuya Saika, Iku Ishida, Takeshi Miyamoto, Yoshitaka Ohnishi, Akira OoshimaAbstract:PURPOSE. To examine whether tissues of human capsular opacification and subcapsular cataract contain Osteopontin, an adhesive matrix protein, and whether mouse lens epithelium expresses Osteopontin after injury. METHODS. An immunohistochemical examination was conducted to determine whether matrices in human postoperative capsular specimens and anterior subcapsular cataract contain Osteopontin. The spatial and temporal protein expression patterns of Osteopontin were then determined in epithelium of a healing mouse lens after a capsular incision. RESULTS. Human lens epithelial cells in the specimens extracted at the time of vitrectomy 10 days after cataract surgery and also after longer healing intervals were labeled with an anti-Osteopontin antibody, whereas uninjured lens epithelium was not. In the later healing phase, matrix of capsular opacification was positive for Osteopontin. Lens cells amid anterior subcapsular cataract tissue were also positive. Osteopontin was detected in the cell surface and membrane and the cytoplasm of lens cells, as well as in the matrix. Unlike normal uninjured specimens, anterior lens capsule of some of the healing postoperative specimens and anterior subcapsular cataract specimens also faintly or weakly stained for Osteopontin. Mouse lens epithelium started to express Osteopontin protein at 8 hours after injury, before the cells changed their shape from epithelial cell type to fibroblast type. Expression of Osteopontin lasted during the healing interval, even after the cells transformed into fibroblast-like cells. CONCLUSIONS. Extracellular matrix in human postoperative capsular opacification and anterior subcapsular cataract contains Osteopontin. Epithelial cells of a mouse lens also ectopically express Osteopontin in response to capsular injury.
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Osteopontin a component of matrix in capsular opacification and subcapsular cataract
Investigative Ophthalmology & Visual Science, 2003Co-Authors: Shizuya Saika, Iku Ishida, Takeshi Miyamoto, Yoshitaka Ohnishi, Akira OoshimaAbstract:PURPOSE. To examine whether tissues of human capsular opacification and subcapsular cataract contain Osteopontin, an adhesive matrix protein, and whether mouse lens epithelium expresses Osteopontin after injury. METHODS. An immunohistochemical examination was conducted to determine whether matrices in human postoperative capsular specimens and anterior subcapsular cataract contain Osteopontin. The spatial and temporal protein expression patterns of Osteopontin were then determined in epithelium of a healing mouse lens after a capsular incision. RESULTS. Human lens epithelial cells in the specimens extracted at the time of vitrectomy 10 days after cataract surgery and also after longer healing intervals were labeled with an anti-Osteopontin antibody, whereas uninjured lens epithelium was not. In the later healing phase, matrix of capsular opacification was positive for Osteopontin. Lens cells amid anterior subcapsular cataract tissue were also positive. Osteopontin was detected in the cell surface and membrane and the cytoplasm of lens cells, as well as in the matrix. Unlike normal uninjured specimens, anterior lens capsule of some of the healing postoperative specimens and anterior subcapsular cataract specimens also faintly or weakly stained for Osteopontin. Mouse lens epithelium started to express Osteopontin protein at 8 hours after injury, before the cells changed their shape from epithelial cell type to fibroblast type. Expression of Osteopontin lasted during the healing interval, even after the cells transformed into fibroblast-like cells. CONCLUSIONS. Extracellular matrix in human postoperative capsular opacification and anterior subcapsular cataract contains Osteopontin. Epithelial cells of a mouse lens also ectopically express Osteopontin in response to capsular injury.
