Int J Med Sci 2015; 12(3):270-279. doi:10.7150/ijms.11078

Research Paper

Paradoxical Response to Mechanical Unloading in Bone Loss, Microarchitecture, and Bone Turnover Markers

Xiaodi Sun1,3, Kaiyun Yang2, Chune Wang2, Sensen Cao2, Mackenzie Merritt4, Yingwei Hu2,✉, Xin Xu1,3,✉

1. School of Stomatology, Shandong University, Wenhuaxi Road 44-1, Jinan 250012, China.
2. Institute of Dental Medicine, Qilu Hospital, Shandong University, Wenhuaxi Road 107, Jinan 250012, China.
3. Shandong Provincial Key Laboratory of Oral Biomedicine, Jinan, China.
4. Department of Biology, Faculty of Science, University of Waterloo, 200 University Ave W, Waterloo, Ontario, Canada, N2L 3G1.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) License. See for full terms and conditions.
Sun X, Yang K, Wang C, Cao S, Merritt M, Hu Y, Xu X. Paradoxical Response to Mechanical Unloading in Bone Loss, Microarchitecture, and Bone Turnover Markers. Int J Med Sci 2015; 12(3):270-279. doi:10.7150/ijms.11078. Available from

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Background: Sclerostin, encoded by the SOST gene, has been implicated in the response to mechanical loading in bone. Some studies demonstrated that unloading leads to up-regulated SOST expression, which may induce bone loss.

Purpose: Most reported studies regarding the changes caused by mechanical unloading were only based on a single site. Considering that the longitudinal bone growth leads to cells of different age with different sensitivity to unloading, we hypothesized that bone turnover in response to unloading is site specific.

Methods: We established a disuse rat model by sciatic neurectomy in tibia. In various regions at two time-points, we evaluated the bone mass and microarchitecture in surgically-operated rats and control rats by micro-Computed Tomography (micro-CT) and histology, sclerostin/SOST by immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and quantitative reverse transcription polymerase chain reaction (qPCR), tartrate resistant acid phosphatase 5b (TRAP 5b) by ELISA and TRAP staining, and other bone markers by ELISA. Results: Micro-CT and histological analysis confirmed bone volume in the disuse rats was significantly decreased compared with those in the time-matched control rats, and microarchitecture also changed 2 and 8 weeks after surgery. Compared with the control groups, SOST mRNA expression in the diaphysis was down-regulated at both week 2 and 8. On the contrary, the percentage of sclerostin-positive osteocytes showed an up-regulated response in the 5 - 6 mm region away from the growth plate, while in the 2.5 - 3.5 mm region, the percentage was no significant difference. Nevertheless, in 0.5 - 1.5 mm region, the percentage of sclerostin-positive osteocytes decreased after 8 weeks, consistent with serum SOST level. Besides, the results of TRAP also suggested that the expression in response to unloading may be opposite in different sites or system.

Conclusion: Our data indicated that unloading-induced changes in bone turnover are probably site specific. This implies a more complex response pattern to unloading and unpredictable therapeutics which target SOST or TRAP 5b.

Keywords: micro-CT, bone loss, bone microarchitecture, sclerostin, TRAP