Renin inhibitor aliskiren exerts beneficial effect on trabecular bone by regulating skeletal renin-angiotensin system and kallikrein-kinin system in ovariectomized mice

• Published in: Osteoporosis international 2016-03, Vol.27 (3), p.1083-1092
• Main Authors: Zhang, Y., Wang, L., Song, Y., Zhao, X., Wong, M. S., Zhang, W.
• Format: Article
• Language: English
• Subjects: Amides - pharmacology; Amides - therapeutic use; Animals; Biomarkers - metabolism; Blood Pressure - drug effects; Bone Density - drug effects; Bone Density - physiology; Bone Density Conservation Agents - pharmacology; Bone Density Conservation Agents - therapeutic use; Cancellous Bone - diagnostic imaging; Cancellous Bone - drug effects; Cancellous Bone - metabolism; Drug Evaluation, Preclinical - methods; Endocrinology; Female; Femur - diagnostic imaging; Femur - drug effects; Fumarates - pharmacology; Fumarates - therapeutic use; Gene Expression Regulation - drug effects; Hormones; Humans; Kallikrein-Kinin System - drug effects; Kallikrein-Kinin System - physiology; Lumbar Vertebrae - diagnostic imaging; Lumbar Vertebrae - drug effects; Medicine; Medicine & Public Health; Mice, Inbred C57BL; Original Article; Orthopedics; Osteoclasts - drug effects; Osteoporosis; Osteoporosis - diagnostic imaging; Osteoporosis - drug therapy; Osteoporosis - physiopathology; Ovariectomy; Proteins - metabolism; Renin - antagonists & inhibitors; Renin - blood; Renin-Angiotensin System - drug effects; Renin-Angiotensin System - genetics; Renin-Angiotensin System - physiology; Rheumatology; RNA, Messenger - genetics; Skeletal system; X-Ray Microtomography - methods
• ISSN: 0937-941X; 1433-2965
• DOI: 10.1007/s00198-015-3348-y

Summary The skeletal renin-angiotensin system contributes to the development of osteoporosis. The renin inhibitor aliskiren exhibited beneficial effects on trabecular bone of osteoporotic mice, and this action might be mediated through angiotensin and bradykinin receptor pathways. This study implies the potential application of renin inhibitor in the management for postmenopausal osteoporosis. Introduction The skeletal renin-angiotensin system plays key role in the pathological process of osteoporosis. The present study is designed to elucidate the effect of renin inhibitor aliskiren on trabecular bone and its potential action mechanism in ovariectomized (OVX) mice. Methods The OVX mice were treated with low dose (5 mg/kg) or high dose (25 mg/kg) of aliskiren or its vehicle for 8 weeks. The bone turnover markers were measured by ELISA. The structural parameters of trabecular bone at lumbar vertebra (LV) and distal femoral metaphysis were measured by micro-CT. The expression of messenger RNA (mRNA) and protein was studied by RT-PCR and immunoblotting, respectively. Results Aliskiren treatment reduced urinary excretion of calcium and serum level of tartrate-resistant acid phosphatase in OVX mice. The treatment with aliskiren significantly increased bone volume (BV/TV) and connectivity density (Conn.D) of trabecular bone at LV-2 and LV-5 as well as dramatically enhanced BV/TV, Conn.D, bone mineral density (BMD/BV) and decreased bone surface (BS/BV) at the distal femoral end. Aliskiren significantly down-regulated the expression of angiotensinogen, angiotensin II (Ang II), Ang II type 1 receptor, bradykinin receptor (BR)-1, and osteocytic-specific gene sclerostin as well as the osteoclast-specific genes, including carbonic anhydrase II, matrix metalloproteinase-9, and cathepsin K. Conclusions This study revealed that renin inhibitor aliskiren exhibited the beneficial effects on trabecular bone of ovariectomy-induced osteoporotic mice, and the underlying mechanism for this action might be mediated through Ang II and BR signaling pathways in bone.