Caveolin-1 in extracellular matrix vesicles secreted from osteoblasts

Sawada, Naoki; Taketani, Yutaka; Amizuka, Norio; Ichikawa, Masaki; Ogawa, Chiharu; Nomoto, Kaori; Nashiki, Kunitaka; Sato, Tadatoshi; Arai, Hidekazu; Isshiki, Masashi; Segawa, Hiroko; Yamamoto, Hironori; Miyamoto, Ken‐ichi; Takeda, Eiji

doi:10.1016/j.bone.2007.02.030

Cited by 26 publications

(23 citation statements)

References 27 publications

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“…The latter are secreted by VSMCs, chondrocytes, and osteoblasts, and they are instrumental in biomineralization, including that of skeletal bone, cartilage, and the artery wall (15)(16)(17). In a tightly regulated cholesterol homeostatic process, cells obtain essential cholesterol by endogenous synthesis or uptake from the extracellular milieu.…”

Section: Eralization Altogether the Results Suggest That Up-regulatmentioning

confidence: 99%

Role of Cellular Cholesterol Metabolism in Vascular Cell Calcification

Geng

Hsu

et al. 2011

Journal of Biological Chemistry

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Vascular calcification impairs vessel compliance and increases the risk of cardiovascular events. We found previously that liver X receptor agonists, which regulate intracellular cholesterol homeostasis, augment PKA agonist-or high phosphateinduced osteogenic differentiation of vascular smooth muscle cells. Because cholesterol is an integral component of the matrix vesicles that nucleate calcium mineral, we examined the role of cellular cholesterol metabolism in vascular cell mineralization. The results showed that vascular smooth muscle cells isolated from LDL receptor null (Ldlr ؊/؊ ) mice, which have impaired cholesterol uptake, had lower levels of intracellular cholesterol and less osteogenic differentiation, as indicated by alkaline phosphatase activity and matrix mineralization, compared with WT cells. PKA activation with forskolin acutely induced genes that promote cholesterol uptake (LDL receptor) and biosynthesis (HMG-CoA reductase). In WT cells, inhibition of cholesterol uptake by lipoprotein-deficient serum attenuated forskolin-induced matrix mineralization, which was partially reversed by the addition of cell-permeable cholesterol. Prolonged activation of both uptake and biosynthesis pathways by cotreatment with a liver X receptor agonist further augmented forskolin-induced matrix mineralization. Inhibition of either cholesterol uptake, using Ldlr ؊/؊ cells, or of cholesterol biosynthesis, using mevastatin-treated WT cells, failed to inhibit matrix mineralization due to up-regulation of the respective compensatory pathway. Inhibition of both pathways simultaneously using mevastatintreated Ldlr ؊/؊ cells did inhibit forskolin-induced matrix mineralization. Altogether, the results suggest that up-regulation of cholesterol metabolism is essential for matrix mineralization by vascular cells.Vascular calcification is frequently found in advanced atherosclerotic lesions and is an independent predictor of cardiovascular morbidity and mortality in patients with chronic kidney disease (1-3). Long considered to be a passive process, there now exists much evidence to suggest that vascular calcification is an active cell-mediated phenomenon that is highly regulated through complex mechanisms under active investigation (4). In vitro and in vivo studies have implicated numerous positive and negative regulatory factors in the pathogenesis of calcification (5-8).A common complication of chronic kidney disease is hyperparathyroidism. Interestingly, parathyroid hormone, an activator of the PKA pathway, has been shown to have a stimulatory role in vascular calcification both in vitro and in vivo. When parathyroid hormone levels are continuously elevated, they induce vascular calcification in rat models, irrespective of renal function (9). Additionally, parathyroid hormone-related protein, also a PKA activator, has been found in calcified atherosclerotic lesions (10). Accordingly, we and others have demonstrated previously that mineralization of vascular smooth muscle cells (VSMCs) 3 is induced by PKA agonists in vitro ...

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Section: Eralization Altogether the Results Suggest That Up-regulatmentioning

confidence: 99%

Role of Cellular Cholesterol Metabolism in Vascular Cell Calcification

Geng

Hsu

et al. 2011

Journal of Biological Chemistry

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“…Finally, Cav-1 has been reported to be present in the secretory cellular components of pancreas and salivary glands (11), in differentiating osteoblasts (12) and in cancer (13). In this regard it is important to point out that in prostate carcinoma the secreted fraction of Cav-1 is associated with cell released microvescicles (MV) which are capable to confer tumorigenicity in vitro as well as in vivo (13–15).…”

Section: Introductionmentioning

confidence: 99%

Caveolin‐1 tumor‐promoting role in human melanoma

Felicetti

Parolini

Bottero

et al. 2009

Intl Journal of Cancer

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Caveolin-1 (Cav-1), a member of the caveolin family, regulates caveolae-associated signaling proteins, which are involved in many biological processes, including cancer development. Cav-1 was found to exert a complex and ambiguous role as oncogene or tumor suppressor depending on the cellular microenvironment.Here we investigated Cav-1 expression and function in a panel of melanomas, finding its expression in all the cell lines. The exception was the primary vertical melanoma cell line, WM983A, characterized by the lack of Cav-1, and then utilized as a recipient for Cav-1 gene transduction to address a series of functional studies.The alleged yet controversial role of phospho (Ph)-Cav-1 on cell regulation was also tested by transducing the nonphosphorylatable Cav-1Y14A mutant. Wild-type Cav-1, but not mutated Cav-1Y14A, increased tumorigenicity as indicated by enhanced proliferation, migration, invasion and capacity of forming foci in semisolid medium. Accordingly, Cav-1 silencing inhibited melanoma cell growth reducing some of the typical traits of malignancy. Finally, we detected a secreted fraction of Cav-1 associated with cell released microvesicular particles able to stimulate in vitro anchorage independence, migration and invasion in a paracrine/ autocrine fashion and, more important, competent to convey metastatic asset from the donor melanoma to the less aggressive recipient cell line. A direct correlation between Cav-1 levels, the amount of microvesicles released in the culture medium and MMP-9 expression was also observed. ' UICCKey words: melanoma; caveolin-1; microvesicles; tumorigenicity Caveolin-1 (Cav-1) is a 22-24 kDa protein originally identified as a structural component of caveolae, specialized invaginations of the plasma membrane. These caveolae represent compartments in which key signaling transduction molecules are concentrated to provide an efficient system for cellular cross talk. Through its ''scaffold domain'' Cav-1 is able to self-interact and to regulate the activity of other caveolae-associated signaling proteins. 1 When Cav-1 was evaluated for its expression in human cancer cell lines and tumor samples of different origin, the outcome was ambiguous. The observed expression profiles indicated that the role of Cav-1 varied according to tumor types. 2,3 Although its growth inhibitory action has been clearly demonstrated in vivo in Cav-12/2 mice, 4 more recent data supported the direct correlation between Cav-1 expression level and tumor aggressiveness 5 and, in some cases, with a poorer clinical outcome. 6 Hence Cav-1 apparently possesses mutually exclusive functions, as tumor suppressor or tumor-promoting gene, depending on tumor type/stage, cell context and the deriving availability of Cav-1 interacting partners. A specific example indicating the importance of Cav-1 partnership involves the formation of a Cav-1/E-cadherin (E-cad) complex at the plasma membrane. In primary cancer cells, where E-cad is generally expressed, Cav-1 exerts its antiproliferative and proapoptotic propertie...

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“…Although this protein was originally identified as a membrane protein, Cav-1 has also been reported to be present in the secretory cellular components of the pancreas and salivary glands, in differentiating osteoblasts and in cancer cells [18-21]. This might explain the detectable serum levels of Cav-1 in healthy controls.…”

Section: Discussionmentioning

confidence: 99%

A genetic polymorphism in the CAV1 gene associates with the development of bronchiolitis obliterans syndrome after lung transplantation

Kastelijn

Moorsel

Kazemier

et al. 2011

Fibrogenesis Tissue Repair

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BackgroundCaveolin 1 (Cav-1) is the primary structural component of cell membrane invaginations called 'caveolae'. Expression of Cav-1 is implicated in the pathogenesis of pulmonary fibrosis. Genetic polymorphisms in the CAV1 gene influence the function of Cav-1 in malignancies and associate with renal allograft fibrosis. Chronic allograft rejection after lung transplantation, called 'bronchiolitis obliterans syndrome' (BOS), is also characterised by the development of fibrosis.In this study, we investigated whether CAV1 genotypes associate with BOS and whether Cav-1 serum levels are influenced by the CAV1 genotype and can be used as a biomarker to predict the development of BOS.MethodsTwenty lung transplant recipients with BOS (BOSpos), ninety without BOS (BOSneg) and four hundred twenty-two healthy individuals donated DNA samples. Four SNPs in CAV1 were genotyped. Serial Cav-1 serum levels were measured in a matched cohort of 10 BOSpos patients and 10 BOSneg patients. Furthermore, single-time point Cav-1 serum levels were measured in 33 unmatched BOSneg patients and 60 healthy controls.ResultsHomozygosity of the minor allele of rs3807989 was associated with an increased risk for BOS (odds ratio: 6.13; P = 0.0013). The median Cav-1 serum level was significantly higher in the BOSpos patients than in the matched BOSneg patients (P = 0.026). Longitudinal analysis did not show changes in Cav-1 serum levels over time in both groups. The median Cav-1 serum level in the group of 43 BOSneg patients was lower than that in the healthy control group (P = 0.046).In lung transplant recipients, homozygosity of the minor allele of rs3807989 and rs3807994 was associated with increased Cav-1 serum levels.ConclusionIn lung transplant recipients, the CAV1 SNP rs3807989 was associated with the development of BOS and Cav-1 serum levels were influenced by the CAV1 genotype.

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Caveolin-1 in extracellular matrix vesicles secreted from osteoblasts

Cited by 26 publications

References 27 publications

Role of Cellular Cholesterol Metabolism in Vascular Cell Calcification

Role of Cellular Cholesterol Metabolism in Vascular Cell Calcification

Caveolin‐1 tumor‐promoting role in human melanoma

A genetic polymorphism in the CAV1 gene associates with the development of bronchiolitis obliterans syndrome after lung transplantation

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