Endothelin-1 regulates rat bone sialoprotein gene transcription

Li, Xinyue; Wang, Zhitao; Yang, Li; Li, Zhengyang; Ogata, Yorimasa

doi:10.2334/josnusd.52.221

Cited by 6 publications

(4 citation statements)

References 51 publications

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“…This result suggested that the endothelin system was not directly implicated in tumor cell proliferation. This assertion was supported by previous works on osteoblasts which showed that endothelins (more specifically ET1) stimulated bone formation [ 16 , 34 , 35 , 36 , 37 ] through control of osteoblast differentiation, and activation by regulating expression of various proteins implicated in bone mineralization: osteocalcin [ 30 , 38 , 39 ], osteopontin [ 38 ], bone sialoprotein [ 40 ], and alkaline phosphatase [ 28 ]. The bone phenotype associated with the conditional invalidation of ETA, driven by the osteocalcin promoter in mature osteoblasts (Cre-Lox system), was highly demonstrative regarding the implication of the endothelin system in the late stage of osteoblast differentiation, with a significant reduction in bone formation [ 39 ].…”

Section: Discussionsupporting

confidence: 56%

Inhibiting Endothelin Receptors with Macitentan Strengthens the Bone Protective Action of RANKL Inhibition and Reduces Metastatic Dissemination in Osteosarcoma

Muñoz-García

Vargas-Franco

Royer

et al. 2022

Cancers

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Current treatments for osteosarcoma, combining conventional polychemotherapy and surgery, make it possible to attain a five-year survival rate of 70% in affected individuals. The presence of chemoresistance and metastases significantly shorten the patient’s lifespan, making identification of new therapeutic tools essential. Inhibiting bone resorption has been shown to be an efficient adjuvant strategy impacting the metastatic dissemination of osteosarcoma, tumor growth, and associated bone destruction. Unfortunately, over-apposition of mineralized matrix by normal and tumoral osteoblasts was associated with this inhibition. Endothelin signaling is implicated in the functional differentiation of osteoblasts, raising the question of the potential value of inhibiting it alone, or in combination with bone resorption repression. Using mouse models of osteosarcoma, the impact of macitentan, an endothelin receptor inhibitor, was evaluated regarding tumor growth, metastatic dissemination, matrix over-apposition secondary to RANKL blockade, and safety when combined with chemotherapy. The results showed that macitentan has no impact on tumor growth or sensitivity to ifosfamide, but significantly reduces tumoral osteoid tissue formation and the metastatic capacity of the osteosarcoma. To conclude, macitentan appears to be a promising therapeutic adjuvant for osteosarcoma alone or associated with bone resorption inhibitors.

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Section: Discussionsupporting

confidence: 56%

Inhibiting Endothelin Receptors with Macitentan Strengthens the Bone Protective Action of RANKL Inhibition and Reduces Metastatic Dissemination in Osteosarcoma

Muñoz-García

Vargas-Franco

Royer

et al. 2022

Cancers

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“…Several growth factors, hormones, and vasoactive agonists, including ET-1, have been shown to increase OPN expression in the vasculature (10,11). While OPN deficiency results in reduced atherosclerotic lesions, OPN overexpression leads to enhanced lesion size (12,13).…”

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confidence: 99%

Glucose-Dependent Insulinotropic Polypeptide Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB

et al. 2015

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Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with extrapancreatic effects beyond glycemic control. Here we demonstrate unexpected effects of GIP signaling in the vasculature. GIP induces the expression of the proatherogenic cytokine osteopontin (OPN) in mouse arteries via local release of endothelin-1 and activation of CREB. Infusion of GIP increases plasma OPN concentrations in healthy individuals. Plasma endothelin-1 and OPN concentrations are positively correlated in patients with critical limb ischemia. Fasting GIP concentrations are higher in individuals with a history of cardiovascular disease (myocardial infarction, stroke) when compared with control subjects. GIP receptor (GIPR) and OPN mRNA levels are higher in carotid endarterectomies from patients with symptoms (stroke, transient ischemic attacks, amaurosis fugax) than in asymptomatic patients, and expression associates with parameters that are characteristic of unstable and inflammatory plaques (increased lipid accumulation, macrophage infiltration, and reduced smooth muscle cell content). While GIPR expression is predominantly endothelial in healthy arteries from humans, mice, rats, and pigs, remarkable upregulation is observed in endothelial and smooth muscle cells upon culture conditions, yielding a “vascular disease–like” phenotype. Moreover, the common variant rs10423928 in the GIPR gene is associated with increased risk of stroke in patients with type 2 diabetes.

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“…To test our hypothesis that OPN was mediating the calcification within the 3D hydrogel system, we sought to induce OPN gene expression in VICs via exogenous stimulation with ET‐1. ET‐1 has been shown to induce OPN expression in cell types such as cardiomyocytes 46 and osteoblasts. 47 Female or male VICs were encapsulated within the PEG + Col hydrogel system and cultured for 12 days in the presence of calcifying stimuli (CM) with either 0, 10 nM, or 100 nM ET‐1 (Figure 6a ).…”

Section: Resultsmentioning

confidence: 99%

Osteopontin activity modulates sex‐specific calcification in engineered valve tissue mimics

Schroeder

Batan

Rodriguez

et al. 2022

Bioengineering & Transla Med

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Patients with aortic valve stenosis (AVS) have sexually dimorphic phenotypes in their valve tissue, where male valvular tissue adopts a calcified phenotype and female tissue becomes more fibrotic. The molecular mechanisms that regulate sex‐specific calcification in valvular tissue remain poorly understood. Here, we explored the role of osteopontin (OPN), a pro‐fibrotic but anti‐calcific bone sialoprotein, in regulating the calcification of female aortic valve tissue. Recognizing that OPN mediates calcification processes, we hypothesized that aortic valvular interstitial cells (VICs) in female tissue have reduced expression of osteogenic markers in the presence of elevated OPN relative to male VICs. Human female valve leaflets displayed reduced and smaller microcalcifications, but increased OPN expression relative to male leaflets. To understand how OPN expression contributes to observed sex dimorphisms in valve tissue, we employed enzymatically degradable hydrogels as a 3D cell culture platform to recapitulate male or female VIC interactions with the extracellular matrix. Using this system, we recapitulated sex differences observed in human tissue, specifically demonstrating that female VICs exposed to calcifying medium have smaller mineral deposits within the hydrogel relative to male VICs. We identified a change in OPN dynamics in female VICs in the presence of calcification stimuli, where OPN deposition localized from the extracellular matrix to perinuclear regions. Additionally, exogenously delivered endothelin‐1 to encapsulated VICs increased OPN gene expression in male cells, which resulted in reduced calcification. Collectively, our results suggest that increased OPN in female valve tissue may play a sex‐specific role in mitigating mineralization during AVS progression.

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Endothelin-1 regulates rat bone sialoprotein gene transcription

Cited by 6 publications

References 51 publications

Inhibiting Endothelin Receptors with Macitentan Strengthens the Bone Protective Action of RANKL Inhibition and Reduces Metastatic Dissemination in Osteosarcoma

Inhibiting Endothelin Receptors with Macitentan Strengthens the Bone Protective Action of RANKL Inhibition and Reduces Metastatic Dissemination in Osteosarcoma

Glucose-Dependent Insulinotropic Polypeptide Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB

Osteopontin activity modulates sex‐specific calcification in engineered valve tissue mimics

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