title: Renin inhibitor aliskiren exerts beneficial effect on trabecular bone by regulating skeletal renin-angiotensin system and kallikrein-kinin system in ovariectomized mice.
abstract: CONCLUSIONS
  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.
  
  
  BACKGROUND
  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.
authors.affiliation: School of Pharmacy, Nantong University, Qixiu Road 19, Nantong, 226001, Jiangsu Province, China. riceandtiger@163.com.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedics, The 309th Hospital of Chinese People's Liberation Army, Beijing, 100091, China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Nantong University, Qixiu Road 19, Nantong, 226001, Jiangsu Province, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Song
authors.affiliation: School of Pharmacy, Nantong University, Qixiu Road 19, Nantong, 226001, Jiangsu Province, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong.
authors.forename: M S
authors.initials: MS
authors.lastname: Wong
authors.affiliation: School of Pharmacy, Nantong University, Qixiu Road 19, Nantong, 226001, Jiangsu Province, China.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000577:Amides / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects / Q000502:physiology; D050071:Bone Density Conservation Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000071556:Cancellous Bone / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects; D005650:Fumarates / Q000494:pharmacology* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016234:Kallikrein-Kinin System / Q000187:drug effects* / Q000502:physiology; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000187:drug effects; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects; D010024:Osteoporosis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D010052:Ovariectomy; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D055114:X-Ray Microtomography / Q000379:methods; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D015415:Biomarkers; D050071:Bone Density Conservation Agents; D005650:Fumarates; D011506:Proteins; D012333:RNA, Messenger; D012083:Renin; D000092502:Renin Inhibitors; C446481:aliskiren
keywords: Aliskiren; Kallikrein-kinin system; Ovariectomized; Renin-angiotensin system; Trabecular bone