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

Abstract

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.

Analysis of factors influencing vascular calcification in peritoneal dialysis patients and their impact on long-term prognosis

“…Sclerostin (SOST) is a protein produced by bone cells and plays an important regulatory role in bone metabolism [ 16 ]. Under normal conditions, Sclerostin regulates bone metabolism by inhibiting the process of bone formation.…”

“…In this study, logistic regression analysis was used to analyze the factors influencing the occurrence of AAC in PD patients, and the results also suggested a significant role of SOST (OR = 1.006, 95% CI: 1.000-1.011, P = 0.038) in the development of AAC in PD patients. Sclerostin (SOST) is a protein produced by bone cells and plays an important regulatory role in bone metabolism [16]. Under normal conditions, Sclerostin regulates bone metabolism by inhibiting the process of bone formation.…”

Animal models of disuse-induced bone loss: study protocol for a systematic review

“…Since several risk factors have been associated with osteoporosis like age [ 22 ], menopausal status [ 23 ], hormonal dysregulation [ 24 ], malabsorption [ 25 ], side effects to medication like prednisolone [ 26 ], smoking [ 27 ], low BMI [ 28 ], immobilization [ 29 ], and disuse [ 30 ], it is crucial to select the appropriate animal model. Previous studies have revealed that the magnitude of bone loss varies between the different models used [ 7 , 11 , 31 ]. In addition, it has also been established that the bone loss observed by a particular disuse model is strain-specific underlining the importance of the genetic background of the animals used [ 32 , 33 ].…”