Involvement of skeletal renin-angiotensin system and kallikrein-kinin system in bone deteriorations of type 1 diabetic mice with estrogen deficiency.
This study was aimed to investigate the involvement of skeletal renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) in bone deteriorations of mice in response to the combination treatment of estrogen deficiency and hyperglycemia.



The female C57BL/6J mice were sham-operated or ovariectomized with vehicle or streptozotocin (STZ) treatment. Two weeks later, the biochemistries in serum and urine were determined by standard colorimetric methods or ELISA. The H&E and TRAP staining were performed at the tibial proximal metaphysis. The polymerase chain reaction and immunoblotting were applied for molecular analysis on mRNA and protein expression.



The mice after treating with ovariectomy and STZ showed the decreased level of serum Ca and the increased level of serum PTH and urine Ca. The H&E staining showed trabecular bone abnormalities as demonstrated by the loss, disconnection and separation of trabecular bone network as well as the loss of chondrocytes and appearance of chondrocyte cluster at growth plate of tibia. The significant increase of matured osteoclast number was shown in group with double treatments. The combination treatment significantly up-regulated mRNA expression of AGT, ACE, renin receptor, MMP-9 and CAII, and protein expression of renin, and decreased the ratio of OPG/RANKL and the expression of bradykinin receptors in bone tissue.



Ovariectomy combined with STZ induction produced more detrimental actions on bone through the activation of local bone RAS and the down-regulation of bradykinin receptors, as compared to the respective single treatment.
Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China. Electronic address: medicineyan@163.com.
Yan
Y
Zhang
Department of Orthopaedics, The 309th hospital of Chinese People's Liberation Army, Beijing 100091, China.
Liang
L
Wang
School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China.
Jin-Xin
JX
Liu
Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
Xin-Luan
XL
Wang
Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
Qi
Q
Shi
Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Yong-Jun
YJ
Wang
D000818:Animals; D002118:Calcium / Q000097:blood / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D016234:Kallikrein-Kinin System; D051379:Mice; D008810:Mice, Inbred C57BL; D010024:Osteoporosis / Q000503:physiopathology*; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000097:blood; D012084:Renin-Angiotensin System
D004967:Estrogens; D010281:Parathyroid Hormone; D002118:Calcium
Bone; Bradykinin receptor; Diabetes; Kallikrein-kinin system; Ovariectomy; Renin-angiotensin system