Mechanical loading modulates heterotopic ossification in calcific tendinopathy through the mTORC1 signaling pathway

Chen,Guorong; Jiang,Huaji; Tian,Xinggui; Tang,Jiajun; Bai,Xiaochun; Zhang,Zhongmin; Wang,Liang

doi:10.3892/mmr.2017.7380

Mechanical loading modulates heterotopic ossification in calcific tendinopathy through the mTORC1 signaling pathway

Authors:
- Guorong Chen
- Huaji Jiang
- Xinggui Tian
- Jiajun Tang
- Xiaochun Bai
- Zhongmin Zhang
- Liang Wang
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Affiliations: Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510630, P.R. China
Published online on: August 29, 2017 https://doi.org/10.3892/mmr.2017.7380
Pages: 5901-5907
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Excessive mechanical loading is a major factor affecting heterotopic ossification (HO), which is a major pathological alteration in calcific tendinopathy. However, physical therapies with mechanical loading as the functional element have exhibited promising results in the treatment of calcific tendinopathy. The dual effects that mechanical loading may have on the pathogenesis and rehabilitation of calcified tendinopathy remain unclear. The present study was designed to investigate the effects of mechanical loading on HO in calcific tendinopathy. In the present study, a tendon cell in vitro stretch model and an Achilles tenotomy rat model were used to simulate different elongation mechanical loading scenarios in order to investigate the effects of mechanical loading on HO of the tendon. In addition, rapamycin, a selective mammalian target of rapamycin complex‑1 (mTORC1) signaling pathway inhibitor, was employed to determine whether mechanical loading modulates heterotopic ossification in calcific tendinopathy through the mTORC1 signaling pathway. The data indicate that mechanical loading modulated HO of the tendon through the mTORC1 signaling pathway, and that low elongation mechanical loading attenuated HO, while high elongation mechanical loading accelerated HO in vivo. This study may improve the understanding of the effect of physical therapies used to treat calcific tendinopathy, so as to guide clinical treatment more effectively. Furthermore, rapamycin may be a potential drug for the treatment of calcific tendinopathy.

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1	Kannus P and Józsa L: Histopathological changes preceding spontaneous rupture of a tendon. A controlled study of 891 patients. J Bone Joint Surg Am. 73:1507–1525. 1991. View Article : Google Scholar : PubMed/NCBI
2	Greis AC, Derrington SM and McAuliffe M: Evaluation and nonsurgical management of rotator cuff calcific tendinopathy. Orthop Clin North Am. 46:293–302. 2015. View Article : Google Scholar : PubMed/NCBI
3	Saithna A, Gogna R, Baraza N, Modi C and Spencer S: Eccentric exercise protocols for patella tendinopathy: Should we really be withdrawing athletes from sport? A systematic review. Open Orthop J. 6:553–557. 2012. View Article : Google Scholar : PubMed/NCBI
4	Larsson ME, Käll I and Nilsson-Helander K: Treatment of patellar tendinopathy-a systematic review of randomized controlled trials. Knee Surg Sports Traumatol Arthrosc. 20:1632–1646. 2012. View Article : Google Scholar : PubMed/NCBI
5	Gaida JE, Cook JL, Bass SL, Austen S and Kiss ZS: Are unilateral and bilateral patellar tendinopathy distinguished by differences in anthropometry, body composition, or muscle strength in elite female basketball players? Br J Sports Med. 38:581–585. 2004. View Article : Google Scholar : PubMed/NCBI
6	Laplante M and Sabatini DM: mTOR signaling in growth control and disease. Cell. 149:274–293. 2012. View Article : Google Scholar : PubMed/NCBI
7	Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P and Sabatini DM: mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 110:163–175. 2002. View Article : Google Scholar : PubMed/NCBI
8	Burry M, Hawkins D and Spangenburg EE: Lengthening contractions differentially affect p70s6k phosphorylation compared to isometric contractions in rat skeletal muscle. Eur J Appl Physiol. 100:409–415. 2007. View Article : Google Scholar : PubMed/NCBI
9	Haddad F and Adams GR: Aging-sensitive cellular and molecular mechanisms associated with skeletal muscle hypertrophy. J Appl Physiol (1985). 100:1188–1203. 2006. View Article : Google Scholar : PubMed/NCBI
10	Hornberger TA, Stuppard R, Conley KE, Fedele MJ, Fiorotto ML, Chin ER and Esser KA: Mechanical stimuli regulate rapamycin-sensitive signalling by a phosphoinositide 3-kinase-, protein kinase B- and growth factor-independent mechanism. Biochem J. 380:795–804. 2004. View Article : Google Scholar : PubMed/NCBI
11	Tong Y, Feng W, Wu Y, Lv H, Jia Y and Jiang D: Mechano-growth factor accelerates the proliferation and osteogenic differentiation of rabbit mesenchymal stem cells through the PI3K/AKT pathway. BMC Biochem. 16:12015. View Article : Google Scholar : PubMed/NCBI
12	Chen C, Akiyama K, Wang D, Xu X, Li B, Moshaverinia A, Brombacher F, Sun L and Shi S: mTOR inhibition rescues osteopenia in mice with systemic sclerosis. J Exp Med. 212:73–91. 2015. View Article : Google Scholar : PubMed/NCBI
13	Rolfing JH, Baatrup A, Stiehler M, Jensen J, Lysdahl H and Bunger C: The osteogenic effect of erythropoietin on human mesenchymal stromal cells is dose-dependent and involves non-hematopoietic receptors and multiple intracellular signaling pathways. Stem Cell Rev. 10:69–78. 2014. View Article : Google Scholar : PubMed/NCBI
14	Gharibi B, Farzadi S, Ghuman M and Hughes FJ: Inhibition of Akt/mTOR attenuates age-related changes in mesenchymal stem cells. Stem Cells. 32:2256–2266. 2014. View Article : Google Scholar : PubMed/NCBI
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
16	Bring DK, Kreicbergs A, Renstrom PA and Ackermann PW: Physical activity modulates nerve plasticity and stimulates repair after Achilles tendon rupture. J Orthop Res. 25:164–172. 2007. View Article : Google Scholar : PubMed/NCBI
17	Gu L, Cong J, Zhang J, Tian YY and Zhai XY: A microwave antigen retrieval method using two heating steps for enhanced immunostaining on aldehyde-fixed paraffin-embedded tissue sections. Histochem Cell Biol. 145:675–680. 2016. View Article : Google Scholar : PubMed/NCBI
18	Liu X, Chen W, Zhou Y, Tang K and Zhang J: Mechanical tension promotes the osteogenic differentiation of rat tendon-derived stem cells through the Wnt5a/Wnt5b/JNK signaling pathway. Cell Physiol Biochem. 36:517–530. 2015. View Article : Google Scholar : PubMed/NCBI
19	Li R, Liang L, Dou Y, Huan Z, Mo H, Wang Y and Yu B: Mechanical strain regulates osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells. Biomed Res Int. 2015:8732512015.PubMed/NCBI
20	Shi Y, Fu Y, Tong W, Geng Y, Lui PP, Tang T, Zhang X and Dai K: Uniaxial mechanical tension promoted osteogenic differentiation of rat tendon-derived stem cells (rTDSCs) via the Wnt5a-RhoA pathway. J Cell Biochem. 113:3133–3142. 2012. View Article : Google Scholar : PubMed/NCBI
21	Shi Y, Li H, Zhang X, Fu Y, Huang Y, Lui PP, Tang T and Dai K: Continuous cyclic mechanical tension inhibited Runx2 expression in mesenchymal stem cells through RhoA-ERK1/2 pathway. J Cell Physiol. 226:2159–2169. 2011. View Article : Google Scholar : PubMed/NCBI
22	Lee HW, Suh JH, Kim HN, Kim AY, Park SY, Shin CS, Choi JY and Kim JB: Berberine promotes osteoblast differentiation by Runx2 activation with p38 MAPK. J Bone Miner Res. 32:1227–1237. 2008. View Article : Google Scholar
23	Zhang K, Wang L, Zhang S, Yu B, Liu F, Cui Z, Jin D and Bai X: Celecoxib inhibits the heterotopic ossification in the rat model with Achilles tenotomy. Eur J Orthop Surg Traumatol. 23:145–148. 2013. View Article : Google Scholar : PubMed/NCBI
24	Lin L, Shen Q, Xue T and Yu C: Heterotopic ossification induced by Achilles tenotomy via endochondral bone formation: Expression of bone and cartilage related genes. Bone. 46:425–431. 2010. View Article : Google Scholar : PubMed/NCBI
25	McClure J: The effect of diphosphonates on heterotopic ossification in regenerating Achilles tendon of the mouse. J Pathol. 139:419–430. 1983. View Article : Google Scholar : PubMed/NCBI
26	Rompe JD, Furia J and Maffulli N: Eccentric loading compared with shock wave treatment for chronic insertional achilles tendinopathy. A randomized, controlled trial. J Bone Joint Surg Am. 90:52–61. 2008. View Article : Google Scholar : PubMed/NCBI
27	Fahlström M, Jonsson P, Lorentzon R and Alfredson H: Chronic Achilles tendon pain treated with eccentric calf-muscle training. Knee Surg Sports Traumatol Arthrosc. 11:327–333. 2003. View Article : Google Scholar : PubMed/NCBI
28	Zeng Z, Jing D, Zhang X, Duan Y and Xue F: Cyclic mechanical stretch promotes energy metabolism in osteoblast-like cells through an mTOR signaling-associated mechanism. Int J Mol Med. 36:947–956. 2015. View Article : Google Scholar : PubMed/NCBI