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<p>The traditional renin-angiotensin system (RAS) is involved in the pathogenesis of glucocorticoid-induced osteoporosis (GIO). Combating the classical RAS cascade has a relevant therapeutic impact on osteoporosis. This study aimed to investigate the potential osteo-protective influence of diminazene, an angiotensin converting enzyme-2 (ACE-2) activator against GIO in rats. Forty adult male rats were equally classified into: control, GIO, diminazene, and GIO + diminazene groups. Rats were scanned via dual-energy X-ray absorptiometry for evaluation of bone mineral density (BMD) and bone mineral content (BMC). Serum levels of Ca<sup>2+</sup>, inorganic phosphorus (P), osteocalcin, bone-specific alkaline phosphatase (BALP) and tartrate-resistant acid phosphatase-5b (TRACP-5b) were measured. Bone receptor activator NF-kB ligand (RANKL), Osteoprotegerin (OPG), angiotensin II (Ang II), ACE-2, Ang (1–7), malondialdehyde (MDA), superoxide dismutase (SOD) activity, tumor necrosis factor-alpha (TNF-α) were determined. Additionally, femoral TNFSF11 and TNFRSF11B gene expression were evaluated through RT-PCR, as well as histopathological examination of rats’ femur and immunohistochemistry for assessment of femoral interleukin-6 (IL-6). Rats with GIO displayed diminished BMD and BMC with elevated serum BALP and TRACP-5b. Bone RANKL/OPG ratio and Ang II levels were also increased, while serum Ca<sup>2+</sup>, osteocalcin, bone ACE-2 and angiotensin (1–7) were apparently reduced. They displayed oxidant/antioxidant imbalance, increased bone TNF-α and IL-6, disturbed TNFSF11 and TNFRSF11B gene expression and histopathological osteoporotic changes. Diminazene improved BMD, BMC and bone metabolic markers. It reversed most of histopathological abnormalities. Alongside, it markedly increased bone ACE-2, Ang (1–7) and SOD activity, while decreasing bone RANKL/OPG ratio, Ang II, MDA, TNF-α and IL-6 with modification of TNFSF11 and TNFRSF11B genes. Diminazene, alleviated GIO via mediating anti-oxidant, anti-inflammatory actions together with modulation of RANKL/OPG pathway.</p>

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Angiotensin converting enzyme-2 activation mitigates glucocorticoids-induced osteoporosis in rats by modulating oxidative stress, inflammation and the RANKL/OPG pathway

  • 期刊论文

  • 发表日期：

    2026年4月29日

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  • Heba Fathy El-Domiaty,
  • Mohamed Abdallah,
  • Nesrin Abd Allah Salman,
  • Walaa Abdellah Esa,
  • Doaa Abdelsatar Madkour,
  • Eman I. Elgizawy

摘要

The traditional renin-angiotensin system (RAS) is involved in the pathogenesis of glucocorticoid-induced osteoporosis (GIO). Combating the classical RAS cascade has a relevant therapeutic impact on osteoporosis. This study aimed to investigate the potential osteo-protective influence of diminazene, an angiotensin converting enzyme-2 (ACE-2) activator against GIO in rats. Forty adult male rats were equally classified into: control, GIO, diminazene, and GIO + diminazene groups. Rats were scanned via dual-energy X-ray absorptiometry for evaluation of bone mineral density (BMD) and bone mineral content (BMC). Serum levels of Ca2+, inorganic phosphorus (P), osteocalcin, bone-specific alkaline phosphatase (BALP) and tartrate-resistant acid phosphatase-5b (TRACP-5b) were measured. Bone receptor activator NF-kB ligand (RANKL), Osteoprotegerin (OPG), angiotensin II (Ang II), ACE-2, Ang (1–7), malondialdehyde (MDA), superoxide dismutase (SOD) activity, tumor necrosis factor-alpha (TNF-α) were determined. Additionally, femoral TNFSF11 and TNFRSF11B gene expression were evaluated through RT-PCR, as well as histopathological examination of rats’ femur and immunohistochemistry for assessment of femoral interleukin-6 (IL-6). Rats with GIO displayed diminished BMD and BMC with elevated serum BALP and TRACP-5b. Bone RANKL/OPG ratio and Ang II levels were also increased, while serum Ca2+, osteocalcin, bone ACE-2 and angiotensin (1–7) were apparently reduced. They displayed oxidant/antioxidant imbalance, increased bone TNF-α and IL-6, disturbed TNFSF11 and TNFRSF11B gene expression and histopathological osteoporotic changes. Diminazene improved BMD, BMC and bone metabolic markers. It reversed most of histopathological abnormalities. Alongside, it markedly increased bone ACE-2, Ang (1–7) and SOD activity, while decreasing bone RANKL/OPG ratio, Ang II, MDA, TNF-α and IL-6 with modification of TNFSF11 and TNFRSF11B genes. Diminazene, alleviated GIO via mediating anti-oxidant, anti-inflammatory actions together with modulation of RANKL/OPG pathway.