Angiotensin II/Angiotensin II Receptor Blockade Affects Osteoporosis via the AT1/AT2-Mediated cAMP-Dependent PKA Pathway

Abstract

Animal studies have reported on the benefits of ARB on bone mass. However, the underlying mechanism for angiotensin II (AngII)/AngII receptor blockade (ARB) in regulating bone mass remains elusive. Since high levels of plasma and urine cAMP are observed in osteoporotic and hypertensive patients, we hypothesized that cAMP may be an important molecule for the downstream events of the activation of AT receptors, members of the G-protein-coupled receptor family, in regulating bone turnover. In this study, micro-CT and X-ray analyses indicated that AngII decreased bone mass via biasing bone resorption over bone formation in osteoporotic mice. However, these adverse effects were blocked by olmesartan and PD123319. In vitro, AngII was shown to downregulate osteogenic differentiation and matrix mineralization, but to upregulate osteoclastic activity by mainly affecting osteoblasts producing osteoclastogenesis-associated key soluble factors, including M-CSF and RANKL. Similarly, ARB treatment exhibited antagonistic effects on AngII. In conclusion, osteoblasts are the directly targeted cells. ARB1 exhibits a greater capacity to increase bone mass than ARB2. The cAMP-dependent PKA pathway plays an important role in AngII/ARB on changing bone mass.

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

“…In both situations, bone tissue response was modulated by Losartan (Los, 10 −6 M, AT1R blocker), PD123319 (PD, 10 −5 M AT2R blocker), or Losartan + PD123319. Concentrations of AngII, Losartan, and PD123319 used in this study have been previously optimized in bone cell culture studies addressing RAS modulation, being routinely used in the in vitro models [ 20 ].…”

“…However, a recent meta-analysis found that the association of ACEI and ARBs with decreased risk of bone fractures remains inconsistent [ 16 ]. Additionally, RAS modulation with AngII, ACEI, and ARBs (type 1 and type 2 receptors) assessed in experimental disease models of osteoporosis, spontaneous and induced hypertension, diabetes, and knockout models [ 8 , 10 , 17 , 18 , 19 ] showed both positive results [ 20 , 21 ] or no effect [ 22 , 23 ]. Great variability is also reported in cell culture models with diverse degrees of complexity and involving a multiplicity of experimental protocols of RAS stimulation/inhibition, trying to elucidate the subjacent cellular and molecular mechanisms [ 8 , 10 , 12 , 21 , 24 ].…”

Assessment of the risk of incident heart failure in osteoporosis patients: a systematic review and meta-analysis of eligible cohort studies

“…Accumulating data have suggested that RAAS might contribute to osteoporosis development and progression. For instance, in vitro studies found that angiotensin Ⅱ could activate osteoclasts, a key mediator in osteoporosis 22,23 . Animal studies using mice or rats showed that renin and angiotensin accelerated BMD decrease and that blockage of them could improve bone quality [22][23][24][25][26][27] .…”

Effects of the Local Bone Renin-Angiotensin System on Titanium-Particle-Induced Periprosthetic Osteolysis

“… Wang et al (2018) demonstrated that the RAS components were expressed and up-regulated in synovial tissues of rheumatoid arthritis patients and collagen-induced arthritis rats, and that aberrant activation of RAS in synovial tissues participated in the pathogenesis of rheumatoid arthritis by increasing bone resorption and decreasing bone formation. Zhou et al (2017) found that bone RAS increased bone resorption and decreased bone formation by promoting osteoclast differentiation and repressing osteoblast formation, which eventually resulted in osteopenia in ovariectomized mice. Zhang et al (2014) revealed that activation of local bone RAS could be a significant reason for steroid-induced osteonecrosis in rabbits.…”