Osteopontin

Scatena, Marta; Liaw, Lucy; Giachelli, Cecilia M.

doi:10.1161/atvbaha.107.144824

Cited by 579 publications

(271 citation statements)

References 114 publications

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“…Indeed, the observed increased immunohistochemical and immunogold staining for OPN on Hyp mouse bone tissue sections is consistent with the accumulation of an OPN fragment(s), where the antibody used detects both full-length OPN and the $35-kDa fragment. Although fragments of OPN have been identified and show certain bioactivities related to cell adhesion, migration, and signaling, (77,(87)(88)(89)(90) this is the first report to our knowledge implicating the accumulation of an OPN fragment, in the absence of PHEX activity, in a genetic bone disease (XLH).…”

Section: Discussionmentioning

confidence: 87%

Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia

Barros

Hoac

Neves

et al. 2012

Journal of Bone and Mineral Research

125

111

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X-linked hypophosphatemia (XLH/HYP)-with renal phosphate wasting, hypophosphatemia, osteomalacia, and tooth abscesses-is caused by mutations in the zinc-metallopeptidase PHEX gene (phosphate-regulating gene with homologies to endopeptidase on the X chromosome). PHEX is highly expressed by mineralized tissue cells. Inactivating mutations in PHEX lead to distal renal effects (implying accumulation of a secreted, circulating phosphaturic factor) and accumulation in bone and teeth of mineralization-inhibiting, acidic serine-and aspartate-rich motif (ASARM)-containing peptides, which are proteolytically derived from the mineral-binding matrix proteins of the SIBLING family (small, integrin-binding ligand N-linked glycoproteins). Although the latter observation suggests a local, direct matrix effect for PHEX, its physiologically relevant substrate protein(s) have not been identified. Here, we investigated two SIBLING proteins containing the ASARM motif-osteopontin (OPN) and bone sialoprotein (BSP)-as potential substrates for PHEX. Using cleavage assays, gel electrophoresis, and mass spectrometry, we report that OPN is a full-length protein substrate for PHEX. Degradation of OPN was essentially complete, including hydrolysis of the ASARM motif, resulting in only very small residual fragments. Western blotting of Hyp (the murine homolog of human XLH) mouse bone extracts having no PHEX activity clearly showed accumulation of an $35 kDa OPN fragment that was not present in wild-type mouse bone. Immunohistochemistry and immunogold labeling (electron microscopy) for OPN in Hyp bone likewise showed an accumulation of OPN and/or its fragments compared with normal wild-type bone. Incubation of Hyp mouse bone extracts with PHEX resulted in the complete degradation of these fragments. In conclusion, these results identify full-length OPN and its fragments as novel, physiologically relevant substrates for PHEX, suggesting that accumulation of mineralization-inhibiting OPN fragments may contribute to the mineralization defect seen in the osteomalacic bone characteristic of XLH/HYP. ß

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Section: Discussionmentioning

confidence: 87%

Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia

Barros

Hoac

Neves

et al. 2012

Journal of Bone and Mineral Research

125

111

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“…2 OPN is secreted by many cell types, such as lymphocytes, macrophages, endothelial cells and vascular smooth muscle cells, 3 and exacerbates inflammation through the recruitment of monocyte macrophages and the regulation of cytokine production in macrophages, dendritic cells and T-cells. [4][5][6] Clinically, plasma OPN levels have a positive relationship with carotid atherosclerosis in patients with essential hypertension (EHT) and an absence of cardiovascular disease.…”

Section: Introductionmentioning

confidence: 99%

Plasma thrombin-cleaved osteopontin elevation after carotid artery stenting in symptomatic ischemic stroke patients

et al. 2011

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Atherothrombosis is the primary pathophysiology that underlies ischemic cerebral infarction. Osteopontin (OPN) is produced in atherosclerotic lesions and is cleaved by activated thrombin. We hypothesized that the rupture or damage of an unstable atherosclerotic plaque increases plasma levels of thrombin-cleaved OPN (trOPN). This study included 90 patients who received carotid angioplasty with stenting (CAS), 23 patients with essential hypertension (EHT) and 10 patients who were treated with carotid endarterectomy (CEA). The CAS patient group included 36 patients that had pre-and post-operative blood tests, diffusion-weighted imaging (DWI) using cerebral MRIs and estimated thrombus debris within the protection device. Immunohistochemistry of CEA specimens revealed that trOPN was detected around intra-plaque vessels. The highest tertile of plasma trOPN levels in CAS patients was higher than trOPN levels in EHT patients. Post-operative trOPN levels were significantly higher in symptomatic compared with asymptomatic patients (P¼0.003). New ipsilateral DWI-positive patients revealed higher post-operative trOPN levels (P¼0.003) and a higher grade of thrombi (Po0.001) than DWI-negative patients. TrOPN may be a novel biomarker that reflects the atherothrombotic status in ischemic stroke.

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“…24 The biological functions of OPN are heavily influenced by posttranslational modifications such as phosphorylation, glycosylation, sulfation, and proteolytic cleavage. 25,26 Currently, there is very little knowledge about the role that proteolytic cleavage of OPN has on MS and EAE. In other disease states, the cleavage of OPN by MMPs and thrombin alters the biological functions of OPN.…”

mentioning

confidence: 99%

Cleavage of Osteopontin by Matrix Metalloproteinase-12 Modulates Experimental Autoimmune Encephalomyelitis Disease in C57BL/6 Mice

DaSilva

Liaw

Yong

2010

The American Journal of Pathology

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A role for osteopontin (OPN) in promoting disease activity of multiple sclerosis or its animal model experimental autoimmune encephalomyelitis (EAE) has recently been suggested. As the biological activity of OPN is heavily influenced by posttranslational processing, we investigated the capacity of matrix metalloproteinase (MMP)-12 to cleave OPN and determined whether this influenced disease activity. We found that OPN mRNA and protein expression in the spinal cord increased with EAE disease in C57BL/6 mice concurrently with MMP-12 expression. A Western blot of EAE and control spinal cords revealed different OPNimmunoreactive bands, with a pattern that was similar to MMP-12 cleavage of recombinant OPN in vitro. In addition, OPN fragments in the spinal cord of EAEafflicted mice were reduced in MMP-12 ؊/؊ mice compared with wild-type controls. However, examination of OPN ؊/؊ mice in short-and long-term experiments revealed no difference in EAE outcomes from wildtype animals. OPN/MMP-12 double null mice were generated, and it was revealed that MMP-12 ؊/؊ mice had a worsening of disease compared with wild-type mice, which returned to wild-type levels in the OPN/ MMP-12 double null mice. These results suggest that EAE disease activity may be modulated by the cleavage of OPN by

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Osteopontin

Cited by 579 publications

References 114 publications

Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia

Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia

Plasma thrombin-cleaved osteopontin elevation after carotid artery stenting in symptomatic ischemic stroke patients

Cleavage of Osteopontin by Matrix Metalloproteinase-12 Modulates Experimental Autoimmune Encephalomyelitis Disease in C57BL/6 Mice

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