The Renin–Angiotensin System and Bone

Tamargo, Juan; Caballero, Ricardo; Delpón, Eva

doi:10.1007/s12018-015-9189-6

Cited by 14 publications

(18 citation statements)

References 169 publications

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“…Runx2, Osterix, and β-catenin are the vital transcription factors for osteoblast differentiation ( 6 ). Runx2 is a main transcription factor required for the differentiation of osteoblasts from mesenchymal precursors and subsequent bone matrix mineralization ( 31 ). Moreover, recent research has proven that Runx2 can directly stimulate the osteoblast marker gene expression, such as Ocn ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-221 promotes cell proliferation, migration, and differentiation by regulation of ZFPM2 in osteoblasts

Zheng

Dai

Zhang

et al. 2018

Braz J Med Biol Res

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Bone fracture is a common medical condition, which may occur due to traumatic injury or disease-related conditions. Evidence suggests that microRNAs (miRNAs) can regulate osteoblast differentiation and function. In this study, we explored the effects and mechanism of miR-221 on the growth and migration of osteoblasts using MC3T3-E1 cells. The expression levels of miR-221 in the different groups were measured by qRT-PCR. Then, miR-221 mimic and inhibitor were transfected into MC3T3-E1 cells, and cell viability and migration were measured using the CCK-8 assay and the Transwell migration assay. Additionally, the expression levels of differentiation-related factors (Runx2 and Ocn) and ZFPM2 were measured by qRT-PCR. Western blot was used to measure the expression of cell cycle-related proteins, epithelial-mesenchymal transition (EMT)-related proteins, ZFPM2, and Wnt/Notch, and Smad signaling pathway proteins. miR-221 was significantly up-regulated in the patients with lumbar compression fracture (LCM) and trochanteric fracture (TF). miR-221 promoted ALP, Runx2, and OPN expressions in MC3T3-E1 cells. miR-221 overexpression significantly increased cell proliferation, migration, differentiation, and matrix mineralization, whereas suppression of miR-221 reversed these effects. Additionally, the results displayed that ZFPM2 was a direct target gene of miR-221, and overexpression of ZFPM2 reversed the promoting effects of miR-221 overexpression on osteoblasts. Mechanistic study revealed that overexpression of miR-221 inactivated the Wnt/Notch and Smad signaling pathways by regulating ZFPM2 expression. We drew the conclusions that miR-221 overexpression promoted osteoblast proliferation, migration, and differentiation by regulation of ZFPM2 expression and deactivating the Wnt/Notch and Smad signaling pathways.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-221 promotes cell proliferation, migration, and differentiation by regulation of ZFPM2 in osteoblasts

Zheng

Dai

Zhang

et al. 2018

Braz J Med Biol Res

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“…This receptor subtype is essentially associated with bone protective effects [ 6 , 21 , 40 , 41 ], which might explain the negligible effect in bone volume fraction, although the increased bone surface fraction is suggestive of alterations in the structural features of the formed bone. On the other hand, upon AT2R blockade, AngII-AT1R-mediated effects are prone to predominate, possibly explaining the decreased bone volume fraction, which is in line with the deleterious effects associated to AT1R [ 6 , 24 ], although maintaining the bone surface fraction. Alternatively, the simultaneous blockade of AT1 and AT2 receptors, by preventing AngII effects, opens the possibility of activation or increased relevance of other/alternative RAS axis triggered by feedback regulatory mechanisms [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

“…As referred above, the disturbance of bone metabolic activities occurring in a variety of chronic diseases is associated with decreased bone mass and a higher incidence of bone fracture [ 6 , 7 , 8 , 9 ]. Within the complexity of the subjacent mechanisms, RAS activation occurring in such conditions, due to increased AngII levels, appears to play a role in bone deterioration [ 9 , 10 , 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…The biological relevance of systemic and local RAS seems significant in conditions of its activation. Regarding the bone tissue, available clinical, in vivo, and cellular data strongly suggest that RAS activation plays a role in bone deterioration associated with metabolic disorders such as osteoporosis, arthritis, bone, risk fracture, and fracture healing, due to the increased activity of AngII acting via AT1R [ 6 , 7 , 8 , 9 ]. In line with this, therapeutic approaches involving RAS inhibition, such as the use of Angiotensin I converting enzyme inhibitors (ACEI) and Angiotensin II type 1 receptor blockers, appears to have positive bone effects by adjusting the balance of AngII [ 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…Otherwise, the RAS branch mediated by Ang1-7, formed by the cleavage of AngII by ACE2, appears to have modulatory effects on the AngII-mediated RAS by acting on the G protein-coupled receptor Mas (MasR) attenuating AT1R-mediated Pharmaceuticals 2021, 14, 469 2 of 14 negative effects [1][2][3][4]. In addition to the endocrine RAS, local/tissue RAS exerting autocrine and paracrine effects modulate the activity of multiple tissues and organs, including the bone tissue [5,6], playing an important role in physiological and pathological conditions. Thus, this system has a role in the cellular fate, namely cell migration, proliferation, differentiation, and apoptosis [2].…”

Section: Introductionmentioning

confidence: 99%

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The Embryonic Chick Femur Organotypic Model as a Tool to Analyze the Angiotensin II Axis on Bone Tissue

et al. 2021

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Activation of renin–angiotensin system (RAS) plays a role in bone deterioration associated with bone metabolic disorders, via increased Angiotensin II (AngII) targeting Angiotensin II type 1 receptor/Angiotensin II type 2 receptor (AT1R/AT2R). Despite the wide data availability, the RAS role remains controversial. This study analyzes the feasibility of using the embryonic chick femur organotypic model to address AngII/AT1R/AT2R axis in bone, which is an application not yet considered. Embryonic day-11 femurs were cultured ex vivo for 11 days in three settings: basal conditions, exposure to AngII, and modulation of AngII effects by prior receptor blockade, i.e., AT1R, AT2R, and AT1R + AT2R. Tissue response was evaluated by combining µCT and histological analysis. Basal-cultured femurs expressed components of RAS, namely ACE, AT1R, AT2R, and MasR (qPCR analysis). Bone formation occurred in the diaphyseal region in all conditions. In basal-cultured femurs, AT1R blocking increased Bone Surface/Bone Volume (BS/BV), whereas Bone Volume/Tissue Volume (BV/TV) decreased with AT2R or AT1R + AT2R blockade. Exposure to AngII greatly decreased BV/TV compared to basal conditions. Receptor blockade prior to AngII addition prevented this effect, i.e., AT1R blockade induced BV/TV, whereas blocking AT2R caused lower BV/TV increase but greater BS/BV; AT1R + AT2R blockade also improved BV/TV. Concluding, the embryonic chick femur model was sensitive to three relevant RAS research setups, proving its usefulness to address AngII/AT1R/AT2R axis in bone both in basal and activated conditions.

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Fracture Risk and Use of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II Receptor Blockers

et al. 2022

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Medications used to treat hypertension may affect fracture risk. This study investigated fracture risk for users of angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB). Participants (899 men, median age 70.3 yr (59.9–79.1), range 50.0–96.6 yr; 574 women, median age 65.5 yr (58.1–75.4), range 50.1–94.6 yr) were from the Geelong Osteoporosis Study. Medication use was self-reported and incident fractures were ascertained using radiological reports. Bone mineral density (BMD) was measured at the femoral neck. Participants were divided into four groups: (1) non-users without hypertension, (2) non-users with hypertension, (3) ACEI users and (4) ARB users. Dosage was calculated using the defined daily dose (DDD) criteria. Participants were followed from date of visit to first fracture, death or 31 December 2016, whichever occurred first. Cox proportional hazards models were used for analyses. At least one incident fracture was sustained by 156 men and 135 women over a median(IQR) of 11.5(6.2–13.2) and 10.9(6.3–11.6) years of follow-up, respectively. In unadjusted analyses, compared to non-users without hypertension, men in all three other groups had a higher risk of fracture (Hazard Ratio (HR, 95%CI) 1.54, 1.00–2.37; 1.90, 1.18–3.05; 2.15, 1.26–3.66), for non-users with hypertension, ACEI and ARB users, respectively). Following adjustment for age, prior fracture and BMD, these associations became non-significant. A dose effect for ARB use was observed; men using lower doses had a higher risk of fracture than non-users without hypertension, in both unadjusted (2.66, 1.34–5.29) and adjusted (2.03, 1.01–4.08) analyses, but this association was not observed at higher doses. For women, unadjusted analyses showed a higher risk for ACEI users compared to non-users without hypertension (1.74, 1.07–2.83). This was explained after adjustment for age, alcohol consumption, prior fracture and BMD (1.28, 0.74–2.22). No other differences were observed. In men, lower dose (0 < DDD ≤ 1) ARB use was associated with an increased risk of fracture. ACEI or ARB use was not associated with increased risk of incident fracture in women. These findings may be important for antihypertensive treatment decisions in individuals with a high risk of fracture.

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The Renin–Angiotensin System and Bone

Cited by 14 publications

References 169 publications

MicroRNA-221 promotes cell proliferation, migration, and differentiation by regulation of ZFPM2 in osteoblasts

MicroRNA-221 promotes cell proliferation, migration, and differentiation by regulation of ZFPM2 in osteoblasts

The Embryonic Chick Femur Organotypic Model as a Tool to Analyze the Angiotensin II Axis on Bone Tissue

Fracture Risk and Use of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II Receptor Blockers

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