Potential of renin-angiotensin system inhibition to improve metabolic bone disorders

Momenzadeh, Mahnaz; Khosravian, Maryam; Lakkakula, Bhaskar Vks

doi:10.34172/npj.2021.16

Cited by 6 publications

(3 citation statements)

References 31 publications

(48 reference statements)

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“…AT1R has been identified in osteoclast precursors and mature osteoclasts, indicating that the RAS may directly impact bone metabolism ( 46 ). In addition, several studies have shown that blocking AT1R with drugs can have beneficial effects on bone metabolism, potentially by reducing osteoclastogenesis and bone resorption ( 47 – 49 ).…”

Section: Discussionmentioning

confidence: 99%

Azilsartan inhibits inflammation-triggered bone resorption and osteoclastogenesis in vivo via suppression of TNF-α expression in macrophages

Fan,

Kitaura,

Ren

et al. 2023

Front. Endocrinol.

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IntroductionHypertension is a major risk factor for cardiovascular disease (CVD) and is associated with increased bone loss due to excessive activity of the local renin-angiotensin system (RAS). Angiotensinogen/Angiotensin (ANG) II/Angiotensin II type 1 receptor (AT1R) axis is considered as the core axis regulating RAS activity. Azilsartan is an FDA-approved selective AT1R antagonist that is used to treat hypertension. This study aimed to determine whether azilsartan affects formation of osteoclast, resorption of bone, and the expression of cytokines linked with osteoclastogenesis during lipopolysaccharide (LPS)-triggered inflammation in vivo.MethodsIn vivo, following a 5-day supracalvarial injection of LPS or tumor necrosis factor-alpha (TNF-α) with or without azilsartan, the proportion of bone resorption and the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells, which are identified as osteoclasts on mice calvariae were counted. The mRNA expression levels of TRAP, cathepsin K, receptor activator of NF-κB ligand (RANKL), and TNF-α were also evaluated. In vitro, the effect of azilsartan (0, 0.01, 0.1, 1, and 10 μM) on RANKL and TNF-α-triggered osteoclastogenesis were investigated. Also, whether azilsartan restrains LPS-triggered TNF-α mRNA and protein expression in macrophages and RANKL expression in osteoblasts were assessed. Furthermore, western blotting for analysis of mitogen-activated protein kinases (MAPKs) signaling was conducted.ResultsAzilsartan-treated calvariae exhibited significantly lower bone resorption and osteoclastogenesis than those treated with LPS alone. In vivo, LPS with azilsartan administration resulted in lower levels of receptor activator of RANKL and TNF-α mRNA expression than LPS administration alone. Nevertheless, azilsartan did not show inhibitory effect on RANKL- and TNF-α-triggered osteoclastogenesis in vitro. Compared to macrophages treated with LPS, TNF-α mRNA and protein levels were lower in macrophages treated by LPS with azilsartan. In contrast, RANKL mRNA and protein expression levels in osteoblasts were the same in cells co-treated with azilsartan and LPS and those exposed to LPS only. Furthermore, azilsartan suppressed LPS-triggered MAPKs signaling pathway in macrophages. After 5-day supracalvarial injection, there is no difference between TNF-α injection group and TNF-α with azilsartan injection group.ConclusionThese findings imply that azilsartan prevents LPS-triggered TNF-α production in macrophages, which in turn prevents LPS-Triggered osteoclast formation and bone resorption in vivo.

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Section: Discussionmentioning

confidence: 99%

Azilsartan inhibits inflammation-triggered bone resorption and osteoclastogenesis in vivo via suppression of TNF-α expression in macrophages

Fan,

Kitaura,

Ren

et al. 2023

Front. Endocrinol.

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“…LDLmediated cholesterol administration improves osteoclast survival, and hence their lifespan, considerably [108,109]. Therefore, Ang II modifies Cbfa1 expression, consequently reducing the number of osteoblasts and resulting in poor bone formation by stimulating the cAMP signaling pathway and regulating other downstream targets such as LDLs [110,111]. Ang II triggers prostaglandins, which stimulate cAMP signaling, leading to upregulated expression of LDL receptors [112].…”

Section: Ang II Increases Cyclic Adenosine Monophosphate (Camp)mentioning

confidence: 99%

The Relationship between Renin–Angiotensin–Aldosterone System (RAAS) Activity, Osteoporosis and Estrogen Deficiency in Type 2 Diabetes

Mkhize

Mosili

Ngubane

et al. 2023

IJMS

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Type 2 diabetes (T2D) is associated with a plethora of comorbidities, including osteoporosis, which occurs due to an imbalance between bone resorption and formation. Numerous mechanisms have been explored to understand this association, including the renin–angiotensin–aldosterone system (RAAS). An upregulated RAAS has been positively correlated with T2D and estrogen deficiency in comorbidities such as osteoporosis in humans and experimental studies. Therefore, research has focused on these associations in order to find ways to improve glucose handling, osteoporosis and the downstream effects of estrogen deficiency. Upregulation of RAAS may alter the bone microenvironment by altering the bone marrow inflammatory status by shifting the osteoprotegerin (OPG)/nuclear factor kappa-Β ligand (RANKL) ratio. The angiotensin-converting-enzyme/angiotensin II/Angiotensin II type 1 receptor (ACE/Ang II/AT1R) has been evidenced to promote osteoclastogenesis and decrease osteoblast formation and differentiation. ACE/Ang II/AT1R inhibits the wingless-related integration site (Wnt)/β-catenin pathway, which is integral in bone formation. While a lot of literature exists on the effects of RAAS and osteoporosis on T2D, the work is yet to be consolidated. Therefore, this review looks at RAAS activity in relation to osteoporosis and T2D. This review also highlights the relationship between RAAS activity, osteoporosis and estrogen deficiency in T2D.

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“…(4) It has been suggested that the risk of hip fractures is reduced with the use of ACE inhibitors and ARBs. (5) A study demonstrated a positive effect on the healing of fractures of enalapril, as an ACE inhibitor, in contrast to losartan, as an ARB, which did not show a positive effect. (6) The use of enalapril leads to increased blood flow and improved microcirculation in the fracture zone, which provides an appropriate microenvironment for osteoblast activity to produce bone matrix.…”

Section: Introductionmentioning

confidence: 99%

The Enalapril Use in Arterial Hypertension Stimulates The Reparative Processes in Fractures of The Proximal Femur

et al. 2022

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BACKGROUND: In patients with a fracture of the proximal femur and concomitant arterial hypertension, there is a disturbance of the reparative processes of bone tissue. This research aimed to study the regulation of the reparative processes of fractures of the proximal femur with intramedullary osteosynthesis during the correction of concomitant hypertension, which was examined based on some markers using the rat model.METHODS: The study involved healthy Wistar rats and spontaneously hypertensive rats (SHR). The subjects were then grouped into healthy rats without exposure (1.1) SHR without exposure (2.1), healthy rats with modeled fractures of the proximal femur (1.2), SHR with modeled fractures of the proximal femur (2.2), SHR underwent hypertension correction with enalapril in subgroups without fracture (2.3) and SHR underwent hypertension correction with enalapril in subgroups with fracture (2.4). The levels of interleukin (IL)-6, tumor necrosis factor alpha (TNF-a), IL-10, amino-terminal propeptide procollagen type III (PIIINP), glucose, uric acid, creatinine, urea, cholesterol, and albumin were determined in the blood serum of the animals. Femur preparations were examined after the removal of intramedullary fixation. RESULTS: Serum IL-6 level of animal in group 2.4 (2.297±0.361 pg/mL) were reduced compared to the corresponding indicators of rats in group 2.3 (4.054±0.491 pg/mL, p<0.05). Serum glucose and urea levels of animal in group 2.4 (3.951±0.156 mmol/L, 6.552±0.426 mmol/L, respectively) were significantly reduced in comparison with the group 2.3 (6.384±0.890 mmol/L, 10.369±0.888 mmol/L, respectively). The histological results indicated a positive effect of the drug enalapril on the healing of fractures of the proximal femur in animals with hypertension.CONCLUSION: Correction of arterial hypertension with enalapril in fractures of the proximal femur improves the reparative processes of bone tissue.KEYWORDS: injury healing, remodeling, concomitant diseases, angiotensin-converting enzyme inhibitors, cytokines, growth factor, collagen, biochemical parameters

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Potential of renin-angiotensin system inhibition to improve metabolic bone disorders

Cited by 6 publications

References 31 publications

Azilsartan inhibits inflammation-triggered bone resorption and osteoclastogenesis in vivo via suppression of TNF-α expression in macrophages

Azilsartan inhibits inflammation-triggered bone resorption and osteoclastogenesis in vivo via suppression of TNF-α expression in macrophages

The Relationship between Renin–Angiotensin–Aldosterone System (RAAS) Activity, Osteoporosis and Estrogen Deficiency in Type 2 Diabetes

The Enalapril Use in Arterial Hypertension Stimulates The Reparative Processes in Fractures of The Proximal Femur

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