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Glucocorticoids activate the local renin–angiotensin system in bone: possible mechanism for glucocorticoid-induced osteoporosis

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Abstract

Bone metabolism disorder has been identified to play a vital role in the pathogenesis of glucocorticoid-induced osteoporosis (GIOP). The local renin–angiotensin system (RAS) in bone is newly defined to be closely related to the bone metabolism. However, it is unknown whether the local RAS is involved in GIOP. Adult male New Zealand white rabbits were treated with saline, dexamethasone (DXM) alone, or DXM combined with perindopril. The expression of main RAS components in trabecular bone was examined at mRNA and/or protein levels. Bone metabolism was analyzed using dual-energy X-ray absorptiometry, histomorphometry, biomechanics, biochemical techniques, and quantitative RT-PCR. The expressions of local bone angiotensin II, angiotensin types 1 and 2 receptors, and angiotensin-converting enzyme at mRNA and/or protein levels increased when DXM-induced osteoporosis was present. Whereas, perindopril significantly blocked the activation of the local RAS and partially reversed GIOP. Mineralizing surface, mineral apposition rate, and bone formation rate were decreased by DXM, along with serum osteocalcin being downregulated. These changes were then reversed by the use of perindopril. Osteoclast number, osteoclast surface, and eroded surface increased after the administration of DXM, and urinary deoxypyridinoline was upregulated. These were also inhibited when perindopril was given. Quantitative RT-PCR using RNA isolated from the lumbar vertebrae revealed an increase in the SOST expression and a decrease in the Runx2 expression, whereas the receptor activator of nuclear factor-κB ligand/osteoprotegerin ratio and the expression of tartrate resistant acid phosphatase were increased, which were all inhibited by perindopril. The results of this study provide evidence for the role of local RAS is involved in GIOP, and GIOP may be ameliorated by blocking the activation of local RAS in the bone.

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Acknowledgments

The authors thank Xiaoge Zhao for his excellent technical assistance and Qi Chen for providing language help. This work was supported by the National Natural Science foundation No. 81101337.

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Authors and Affiliations

  1. Department of Orthopaedics, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, Shaanxi, China

    Zhang Yongtao, Wang Kunzheng, Liu Ruiyu & Wang Chunsheng

  2. Medical College of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, China

    Zheng Jingjing & Shan Hu

  3. Department of Orthopedics, The Affiliated Hospital of Medical School Qingdao University, Qingdao, 26000, Shandong, China

    Kou Jianqiang

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  1. Zhang Yongtao
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Correspondence to Wang Chunsheng.

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Fig. S1

Bone mineral density (BMD) of the lumbar spine. BMD of the lumbar spine in the four groups was measured using a dual-energy X-ray absorptiometer at baseline and at week 6 and 12 after intervention (n = 3 per group). Data are mean ± SD. ☆ P < 0.05 versus CONT group; ▲ P < 0.05 versus DXM group. Supplementary material 1 (TIFF 1,722 kb)

Fig. S2

Body weight and mean arterial blood pressure (MAP). a Body weight was measured every 2 weeks throughout the study (n = 12 per group). b MAP was measured prior to sacrifice, at t = 12 weeks (n = 10 per group). Data are mean ± SD. ☆ P < 0.05 versus CONT group; ▲ P < 0.05 versus DXM group. Supplementary material 2 (TIFF 3,713 kb)

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Yongtao, Z., Kunzheng, W., Jingjing, Z. et al. Glucocorticoids activate the local renin–angiotensin system in bone: possible mechanism for glucocorticoid-induced osteoporosis. Endocrine 47, 598–608 (2014). https://doi.org/10.1007/s12020-014-0196-z

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