Role of αv integrin in osteoprotegerin-induced endothelial cell migration and proliferation

Kobayashi-Sakamoto, Michiyo; Isogai, Emiko; Hirose, Koichi; Chiba, Itsuo

doi:10.1016/j.mvr.2008.06.004

Cited by 40 publications

(42 citation statements)

References 27 publications

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“…14,15 These data expand the functional significance of osteoprotegerin beyond its presumed role as a receptor activator of nuclear factor-κB ligand and TRAIL decoy receptor, and suggest that it may interact with integrins or fatty acid synthase. 8,14,15 This is greatly relevant because pulmonary arterial smooth muscle cells (PASMCs) express several integrin molecules that regulate pulmonary vascular remodeling and contribute to PAH progression. 16,17 Integrins are a large family of structurally related heterodimeric transmembrane receptors that regulate cell-cell and cell-matrix contacts.…”

Section: Osteoprotegerin In Pulmonary Hypertensionmentioning

confidence: 73%

Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin α _v β ₃ /FAK/AKT Pathway Suppression

Jia

Zhu

Liu

et al. 2017

Circ Cardiovasc Genet

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Background-Pulmonary arterial remodeling characterized by increased vascular smooth muscle proliferation is commonly seen in life-threatening disease, pulmonary arterial hypertension (PAH). Clinical studies have suggested a correlation between osteoprotegerin serum levels and PAH severity. Here, we aimed to invhestigate vascular osteoprotegerin expression and its effects on pulmonary arterial smooth muscle cell proliferation in vitro and in vivo, as well as examine the signal transduction pathways mediating its activity. Methods and Results-Serum osteoprotegerin levels were significantly elevated in patients with PAH and correlated with disease severity as determined by the World Health Organization (WHO) functional classifications and 6-minute walking distance tests. Similarly, increased osteoprotegerin expression was observed in the pulmonary arteries of hypoxia plus SU5416-and monocrotaline-induced PAH animal models. Moreover, osteoprotegerin disruption attenuated hypoxia plus SU5416-induced PAH progression by reducing pulmonary vascular remodeling, whereas lentiviral osteoprotegerin reconstitution exacerbated PAH by increasing pulmonary arterial smooth muscle cell proliferation. Furthermore, pathway analysis revealed that osteoprotegerin induced pulmonary arterial smooth muscle cell proliferation by interacting with integrin α v β 3 to elicit downstream focal adhesion kinase and AKT pathway activation. Conclusions-Osteoprotegerin facilitates PAH pathogenesis by regulating pulmonary arterial smooth muscle cell proliferation, suggesting that it may be a potential biomarker and therapeutic target in this disease. Jia et al Osteoprotegerin in Pulmonary HypertensionIn addition, experimental results indicated that osteoprotegerin promotes the proliferation of various cancer cells and endothelial cells in a TRAIL-independent manner. 14,15 These data expand the functional significance of osteoprotegerin beyond its presumed role as a receptor activator of nuclear factor-κB ligand and TRAIL decoy receptor, and suggest that it may interact with integrins or fatty acid synthase. 8,14,15 This is greatly relevant because pulmonary arterial smooth muscle cells (PASMCs) express several integrin molecules that regulate pulmonary vascular remodeling and contribute to PAH progression. 16,17 Integrins are a large family of structurally related heterodimeric transmembrane receptors that regulate cell-cell and cell-matrix contacts. 18 Of the 18α and 8β subtypes identified, pulmonary vascular smooth muscles express α 1-5 , α 7 , α 8 , α v , β 1 , β 3 , and β 4 .17 On the basis of these observations, we hypothesize that osteoprotegerin may contribute to pulmonary vascular remodeling in an integrindependent manner.In this study, we demonstrated that osteoprotegerin expression was increased in both murine and human pulmonary arterial SMCs (mPASMCs and hPASMCs) in response to hypoxia and in the lung tissue and pulmonary arteries of hypoxia plus SU5416 (HySu)-induced PAH model mice. Moreover, integrin α 1 , α 8 , α v , and β 3 express...

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Section: Osteoprotegerin In Pulmonary Hypertensionmentioning

confidence: 73%

Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin α _v β ₃ /FAK/AKT Pathway Suppression

Jia

Zhu

Liu

et al. 2017

Circ Cardiovasc Genet

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“…Cell adhesion may be also modulated by OPG. Indeed, OPG stimulates the proliferation and migration of human microvascular endothelial cells (Kobayashi-Sakamoto et al 2008), and up-regulates the expression of the cell adhesion molecule angiopoietin-2 in TNF-a-activated cells (Mangan et al 2007). Furthermore, OPG treatment strongly increases the number of adherent human CD14 ?…”

Section: Discussionmentioning

confidence: 99%

Osteoprotegerin exposure at different stages of osteoclastogenesis differentially affects osteoclast formation and function

Zhao

Dai

et al. 2015

Cytotechnology

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This study aimed to investigate the effects of osteoprotegerin (OPG), a decoy receptor for receptor activator for nuclear factor jB ligand (RANKL), during the various stages of osteoclast differentiation, and additionally investigate its effects on osteoclast adhesion and activity. RAW264.7 murine monocytic cells were incubated with macrophage colony-stimulating factor and RANKL for 1, 3, 5, or 7 days, followed by an additional 24-h incubation in the presence or absence of OPG (80 ng/mL). We examined osteoclast differentiation and adhesion capacity using the tartrate-resistant acid phosphatase (TRAP) assay and immunofluorescence microscopy, and additionally examined cell growth in real time using the xCELLigence system. Furthermore, the expression levels of TRAP, RANK, integrin b3, matrix metalloproteinase 9, cathepsin K, carbonic anhydrase II, and vesicular-type H ? -ATPase A1 were examined using western blotting. OPG exposure on day 1 enhanced the osteoclast growth curve as well as adhesion, and increased RANK and integrin b3 expression. In contrast, exposure to OPG at later time points (days 3-7) inhibited osteoclast differentiation, adhesion structure formation, and protease expression. In conclusion, the biological effects of OPG exposure at the various stages of osteoclast differentiation were varied, and included the enhanced adhesion and survival of preosteoclasts, the block of differentiation from the early to the terminal stages of osteoclastogenesis, and suppression of mature osteoclast activation following OPG exposure during the terminal differentiation stage, suggesting that the effects of OPG exposure differ based on the stage of differentiation.

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“…We do not believe, however, that osteoprotegerin contained in ascites directly binds to TRAIL to inhibit its effect because the prosurvival effect of ascites is almost completely abolished by the Akt inhibition (Lane et al, 2007). Interestingly, osteoprotegerin may bind to avb5 integrin to stimulate cell migration and proliferation of endothelial cells (Kobayashi-Sakamoto et al, 2008). Periostin is secreted by epithelial ovarian carcinoma and accumulates in ascites (Gillan et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Ovarian cancer ascites protects from TRAIL-induced cell death through αvβ5 integrin-mediated focal adhesion kinase and Akt activation

et al. 2010

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Interactions between ovarian cancer cells and the surrounding tumor microenvironment are not well characterized. We have earlier shown that ovarian cancer ascites induces Akt activation and protect tumor cells from TRAIL-induced apoptosis. Here, we investigated the mechanism by which ascites activates Akt. The ability of ovarian cancer ascites to activate Akt and inhibit TRAILinduced cell death and caspase activity was decreased by heat inactivation, but was retained in ascites fractions 45 kDa. The survival promoting activity of ascites was not affected by inhibitors of growth factor receptor including epidermal growth factor receptor (EGFR), VEGFR, FGFR, Her2/neu, and IGF-R1. However, this activity was inhibited by an avb5 integrin-blocking antibody, but not by blocking antibodies against avb3, b1, or b3 integrins. avb5 integrin-blocking antibodies also inhibited ascites-induced Akt phosphorylation and c-FLIPs up-regulation. Ovarian cancer ascites induced a rapid phosphorylation of focal adhesion kinase (FAK), which closely correlated with the phosphorylation of Akt overtime. FAK phosphorylation was strongly inhibited by avb5 integrin-blocking antibodies. Depletion of FAK content by RNA interference was also associated with inhibition of ascites-mediated Akt activation and survival. These results suggest that ovarian cancer ascites induces FAK and Akt activation in an avb5 integrin-dependent pathway, which confers protection from TRAIL-induced cell death and caspase activation.

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Role of αv integrin in osteoprotegerin-induced endothelial cell migration and proliferation

Cited by 40 publications

References 27 publications

Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin α _v β ₃ /FAK/AKT Pathway Suppression

Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin α _v β ₃ /FAK/AKT Pathway Suppression

Osteoprotegerin exposure at different stages of osteoclastogenesis differentially affects osteoclast formation and function

Ovarian cancer ascites protects from TRAIL-induced cell death through αvβ5 integrin-mediated focal adhesion kinase and Akt activation

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Role of αv integrin in osteoprotegerin-induced endothelial cell migration and proliferation

Cited by 40 publications

References 27 publications

Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin α v β 3 /FAK/AKT Pathway Suppression

Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin α v β 3 /FAK/AKT Pathway Suppression

Osteoprotegerin exposure at different stages of osteoclastogenesis differentially affects osteoclast formation and function

Ovarian cancer ascites protects from TRAIL-induced cell death through αvβ5 integrin-mediated focal adhesion kinase and Akt activation

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Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin α _v β ₃ /FAK/AKT Pathway Suppression

Osteoprotegerin Disruption Attenuates HySu-Induced Pulmonary Hypertension Through Integrin α _v β ₃ /FAK/AKT Pathway Suppression