angiotensin-i and Osteoporosis

Osteoporosis, diabetes, and hypertension are common concurrent chronic disorders. This study aimed to explore the respective effects of angiotensin II (ANG II) and angiotensin(1-7) [ANG(1-7)], active peptides in the renin-angiotensin system, on osteoblasts and osteoclasts under high-glucose level, as well as to investigate the osteo-preservative effects of ANG II type 1 receptor (AT1R) blocker and ANG(1-7) in diabetic spontaneously hypertensive rats (SHR). ANG II and ANG(1-7), respectively, decreased and increased the formation of calcified nodules and alkaline phosphatase activity in MC3T3-E1 cells under high-glucose level, and respectively stimulated and inhibited the number of matured osteoclasts and pit resorptive area in RANKL-induced bone marrow macrophages. Olmesartan and Mas receptor antagonist A779 could abolish those effects. ANG II and ANG(1-7), respectively, downregulated and upregulated the expressions of osteogenesis factors in MC3T3-E1 cells. ANG II promoted the expressions of cathepsin K and MMP9 in RAW 264.7 cells, whereas ANG(1-7) repressed these osteoclastogenesis factors. ANG II rapidly increased the phosphorylation of Akt and p38 in RAW 264.7 cells, whereas ANG(1-7) markedly reduced the phosphorylation of p38 and ERK under high-glucose condition. After treatments of diabetic SHR with valsartan and ANG(1-7), a significant increase in trabecular bone area, bone mineral density, and mechanical strength was only found in the ANG(1-7)-treated group. Treatment with ANG(1-7) significantly suppressed the increase in renin expression and ANG II content in the bone of SHR. Taken together, ANG II/AT1R and ANG(1-7)/Mas distinctly regulated the differentiation and functions of osteoblasts and osteoclasts upon exposure to high-glucose condition. ANG(1-7) could protect SHR from diabetes-induced osteoporosis.

Topics: 3T3 Cells; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Bone and Bones; Bone Density; Bone Density Conservation Agents; Bone Development; Glucose; Male; Mice; Osteoblasts; Osteoclasts; Osteoporosis; Peptide Fragments; Phosphorylation; Rats; Rats, Inbred SHR; RAW 264.7 Cells

The local and systemic renin angiotensin system (RAS) influences the skeletal system micro-structure and metabolism. Studies suggested angiotensin 1-7 (Ang(1-7)) as the beneficial RAS molecule via Mas receptor activation. This study examines the function of Ang(1-7) in bone micro-architecture and metabolism in an ovariectomized (OVX) rodent model of osteoporosis. OVX rats showed structural and bone metabolic degeneration in parallel with suppressed expressions of the angiotensin converting enzyme-2 (ACE-2)/Ang(1-7)/Mas components. The infusion of Ang(1-7) markedly alleviated the altered bone metabolism and significantly enhanced both trabecular (metaphyseal) and cortical (metaphyseal-diaphyseal) morphometry. Urinary and bones minerals were also improved in OVX rats by Ang(1-7). The infusion of the heptapeptide enhanced ACE-2/Mas receptor expressions, while down-regulated AngII, ACE, and AngII type-1 receptor (AT1R) in OVX animals. Moreover, Ang(1-7) markedly improved osteoprotegerin (OPG) and lowered receptor activator NF-κB ligand (RANKL) expressions. The defensive properties of Ang(1-7) on bone metabolism, structure and minerals were considerably eradicated after blockage of Mas receptor with A-779. Ang(1-7)-induced up-regulated ACE-2/Ang(1-7)/Mas cascade and OPG expressions were abolished and the expressions of ACE/AngII/AT1R and RANKL were provoked by A-779. These findings shows for the first time the novel valuable therapeutic role of Ang(1-7) on bone health and metabolism through the ACE-2/Mas cascade.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Blotting, Western; Female; Humans; Organ Size; Osteoporosis; Osteoprotegerin; Ovariectomy; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; RANK Ligand; Rats, Wistar; Receptors, G-Protein-Coupled; Signal Transduction; Uterus