Rapamycin-induced autophagy activity promotes bone fracture healing in rats
Authors: G E Yang
Dasheng Lin
Ten Li
Lei Wang
Deqing Luo
Xunhong Duan
Kejian Lian
Journal: Experimental and therapeutic medicine (2015)
Discipline: CLINICAL MEDICINE
Keywords: autophagy; bone fracture healing; rapamycin.

Abstract:  Autophagy is a crucial mediating process for normal bone cell function and metabolism in physiology or pathology. Rapamycin has been demonstrated to induce the autophagy pathway by inhibiting the mammalian target of rapamycin (mTOR) pathway. However, the contribution of autophagy in orthopedic diseases is rarely reported. The aim of the present study was to evaluate the capacity of pharmacologically induced autophagy to modify disease function in a rat model of bone fracture. A femur fracture model was established via surgery in adult male Sprague-Dawley rats. Rapamycin (n=63 rats) or dimethyl sulfoxide (DMSO) vehicle control (n=63 rats) was administered intraperitoneally for 2, 4 and 6 weeks, and 21 randomly selected rats were sacrificed in each group at each time point. X-ray micro-computed tomography and hematoxylin and eosin staining were used to evaluate the extent of fracture healing in each group. The effects of rapamycin on autophagy, mTOR signaling and the expression levels of vascular endothelial growth factor (VEGF) and proliferating cell nuclear antigen (PCNA) were analyzed using immunohistochemistry, immunofluorescence staining and western blot analysis. Rapamycin affected the mTOR signaling pathway in rats following fracture, as indicated by the inhibition of the phosphorylation of ribosomal protein S6, a target of mTOR, and activation of microtubule-associated protein 2 light chain 3, a key marker of autophagy. Histomorphometry and image examination indicated that the number of osteoblasts in each section was significantly (P&lt;0.01) increased in the rapamycin group compared with the control group, and this was associated with a significant (P&lt;0.05) increase in mineralized callus fraction. Furthermore, rapamycin treatment increased the expression levels of VEGF and PCNA in the rat callus tissue. These results suggest that rapamycin may serve a beneficial function in fracture healing, and that the underlying mechanism may involve the activation of autophagy. 

Retracted: No

PubPeer comments:
 This paper was found during a systematic search of papers in this journal with possible duplicated images. About 10% of the papers in this journal (n=169 examined) were found to contain inappropriately duplicated images. These papers have all been reported to the journal publisher in 2017. The editors promised to  investigate promptly but no action has been taken as of today. Figure 1B. Unexpected similarities between the  2 weeks and  6 weeks Vehicle-treated group panels. Shown with red boxes. ![file] , 
 The journal never notified me, but there is a Corrigendum, February 2021: https: www.spandidos-publications.com 10.3892 etm.2021.9749  *Following the publication of the above article, an interested reader drew to the authorsu2019 attention that, in Fig. 1B on p. 1329, there were striking similarities between the u20182 weeksu2019 and u20186 weeksu2019 Vehicle-treated group panels. The authors re-examined their original data, and realized that u20186 weeksu2019 Vehicle-treated group panel had been selected incorrectly for this Figure. The corrected version of Fig. 1, showing the correct data for the u20186 weeksu2019 Vehicle-treated group panel in Fig. 1B, is shown opposite. Note that the correction of the data panel in this figure does not affect the overall conclusions reported in the paper. The authors are grateful to the Editor of Experimental and Therapeutic Medicine for allowing them the opportunity to publish this corrigendum, and apologize to the readership for any inconvenience caused.* ,