Salidroside inhibits steroid-induced avascular necrosis of the femoral head via the PI3K/Akt signaling pathway: In vitro and in vivo studies

Xue,Xing‑He; Feng,Zhen‑Hua; Li,Zhen‑Xing; Pan,Xiao‑Yun

doi:10.3892/mmr.2017.8349

Salidroside inhibits steroid-induced avascular necrosis of the femoral head via the PI3K/Akt signaling pathway: In vitro and in vivo studies

Authors:
- Xing‑He Xue
- Zhen‑Hua Feng
- Zhen‑Xing Li
- Xiao‑Yun Pan
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Affiliations: Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
Published online on: December 27, 2017 https://doi.org/10.3892/mmr.2017.8349
Pages: 3751-3757
Copyright: © Xue et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Dexamethasone (Dex) and other glucocorticoids are widely used to treat serious infections and immunological diseases, however they may cause steroid‑induced avascular necrosis of the femoral head (SANFH). Salidroside (Sal) has demonstrated an anti‑apoptotic effect on neurocytes by activating the phosphoinositide 3‑kinase (PI3K)/protein kinase B (Akt) signaling pathway. In the present study, primary osteoblasts were used in vitro and in rats in vivo to determine the anti-apoptotic effect of Sal on SANFH. The result of the present study demonstrated that pretreatment with Sal increased the cell survival rate while decreasing the cell apoptosis and lactate dehydrogenase release rate. Additionally, Sal also caused the reduction of TUNEL positive cells in TUNEL staining assay. Sal decreased the expression of cleaved caspase-3, cleaved caspase‑9, apoptosis regulator BAX and cytochrome C, while it increased the expression of B cell lymphoma‑2 and phosphorylated‑Akt in Dex‑induced osteoblasts. In vivo Sal protected against SANFH in rats by decreasing the percentage of empty lacunae. The present study demonstrated that Sal alleviated Dex‑induced osteoblast apoptosis by activating the PI3K/Akt signaling pathway and downregulating caspase‑3 expression in osteoblasts. Sal also protected against SANFH in a rat model of SANFH by decreasing the percentage of empty lacunae. The inhibition of the mitochondrial apoptosis pathway was also involved. Further research is required to determine the full underlying mechanisms by which Sal has an effect.

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1	Simon JP, Berger P and Bellemans J: Total hip arthroplasty in patients less than 40 years old with avascular necrosis of the femoral head. A 5 to 19-year follow-up study. Acta Orthop Belg. 77:53–60. 2011.PubMed/NCBI
2	Motomura G, Yamamoto T, Yamaguchi R, Ikemura S, Nakashima Y, Mawatari T and Iwamoto Y: Morphological analysis of collapsed regions in osteonecrosis of the femoral head. J Bone Joint Surg Br. 93:184–187. 2011. View Article : Google Scholar : PubMed/NCBI
3	Tanaka Y, Yoshikawa N, Hattori S, Sasaki S, Ando T, Ikeda M and Honda M; Japanese Study Group for Renal Disease in Children, : Combination therapy with steroids and mizoribine in juvenile SLE: A randomized controlled trial. Pediatr Nephrol. 25:877–882. 2010. View Article : Google Scholar : PubMed/NCBI
4	Hodson EM and Alexander SI: Evaluation and management of steroid-sensitive nephrotic syndrome. Curr Opin Pediatr. 20:145–150. 2008. View Article : Google Scholar : PubMed/NCBI
5	Tönshoff B, Höcker B and Weber LT: Steroid withdrawal in pediatric and adult renal transplant recipients. Pediatr Nephrol. 20:409–417. 2005. View Article : Google Scholar : PubMed/NCBI
6	Schäcke H, Döcke WD and Asadullah K: Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther. 96:23–43. 2002. View Article : Google Scholar : PubMed/NCBI
7	Nagasawa K, Tada Y, Koarada S, Tsukamoto H, Horiuchi T, Yoshizawa S, Murai K, Ueda A, Haruta Y and Ohta A: Prevention of steroid-induced osteonecrosis of femoral head in systemic lupus erythematosus by anti-coagulant. Lupus. 15:354–357. 2006. View Article : Google Scholar : PubMed/NCBI
8	Weinstein RS, Jilka RL, Parfitt AM and Manolagas SC: Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest. 102:274–282. 1998. View Article : Google Scholar : PubMed/NCBI
9	Kim HJ: New understanding of glucocorticoid action in bone cells. BMB Rep. 43:524–529. 2010. View Article : Google Scholar : PubMed/NCBI
10	Souttou B, Raulais D and Vigny M: Pleiotrophin induces angiogenesis: Involvement of the phosphoinositide-3 kinase but not the nitric oxide synthase pathways. J Cell Physiol. 187:59–64. 2001. View Article : Google Scholar : PubMed/NCBI
11	Himburg HA, Muramoto GG, Daher P, Meadows SK, Russell JL, Doan P, Chi JT, Salter AB, Lento WE, Reya T, et al: Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells. Nat Med. 16:475–482. 2010. View Article : Google Scholar : PubMed/NCBI
12	Feng Z, Zheng W, Tang Q, Cheng L, Li H, Ni W and Pan X: Fludarabine inhibits STAT1-mediated up-regulation of caspase-3 expression in dexamethasone-induced osteoblasts apoptosis and slows the progression of steroid-induced avascular necrosis of the femoral head in rats. Apoptosis. 22:1001–1012. 2017. View Article : Google Scholar : PubMed/NCBI
13	Chen X, Zhang Q, Cheng Q and Ding F: Protective effect of salidroside against H₂O₂-induced cell apoptosis in primary culture of rat hippocampal neurons. Mol Cell Biochem. 332:85–93. 2009. View Article : Google Scholar : PubMed/NCBI
14	Huang SC, Lee FT, Kuo TY, Yang JH and Chien CT: Attenuation of long-term Rhodiola rosea supplementation on exhaustive swimming-evoked oxidative stress in the rat. Chin J Physiol. 52:316–324. 2009. View Article : Google Scholar : PubMed/NCBI
15	Ma L, Cai D, Li H, Tong B, Song L and Wang Y: Anti-fatigue effects of salidroside in mice. J Med Coll PLA. 23:88–93. 2008. View Article : Google Scholar
16	Van Diermen D, Marston A, Bravo J, Reist M, Carrupt PA and Hostettmann K: Monoamine oxidase inhibition by Rhodiola rosea L. roots. J Ethnopharmacol. 122:397–401. 2009. View Article : Google Scholar : PubMed/NCBI
17	Zhang L, Yu H, Sun Y, Lin X, Chen B, Tan C, Cao G and Wang Z: Protective effects of salidroside on hydrogen peroxide-induced apoptosis in SH-SY5Y human neuroblastoma cells. Eur J Pharmacol. 564:18–25. 2007. View Article : Google Scholar : PubMed/NCBI
18	Chen X, Liu J, Gu X and Ding F: Salidroside attenuates glutamate-induced apoptotic cell death in primary cultured hippocampal neurons of rats. Brain Res. 1238:189–198. 2008. View Article : Google Scholar : PubMed/NCBI
19	Lu Z, Jiang G, Chen Y, Wang J, Muhammad I, Zhang L, Wang R, Liu F, Li R, Qian F and Li J: Salidroside attenuates colistin-induced neurotoxicity in RSC96 Schwann cells through PI3K/Akt pathway. Chem Biol Interact. 271:67–78. 2017. View Article : Google Scholar : PubMed/NCBI
20	Aziz SA, Davies M, Pick E, Zito C, Jilaveanu L, Camp RL, Rimm DL, Kluger Y and Kluger HM: Phosphatidylinositol-3-kinase as a therapeutic target in melanoma. Clin Cancer Res. 15:3029–3036. 2009. View Article : Google Scholar : PubMed/NCBI
21	Cantrell DA: Phosphoinositide 3-kinase signaling pathways. J Cell Sci. 114:1439–1445. 2001.PubMed/NCBI
22	Gu YX, Du J, Si MS, Mo JJ, Qiao SC and Lai HC: The roles of PI3K/Akt signaling pathway in regulating MC3T3-E1 preosteoblast proliferation and differentiation on SLA and SLActive titanium surfaces. J Biomed Mater Res A. 101:748–754. 2013. View Article : Google Scholar : PubMed/NCBI
23	Guntur AR and Rosen CJ: The skeleton: A multi-functional complex organ: New insights into osteoblasts and their role in bone formation: The central role of PI3Kinase. J Endocrinol. 211:123–130. 2011. View Article : Google Scholar : PubMed/NCBI
24	Li L, Xia Y, Wang Z, Cao X, Da Z, Guo G, Qian J, Liu X, Fan Y, Sun L, et al: Suppression of the PI3K-Akt pathway is involved in the decreased adhesion and migration of bone marrow-derived mesenchymal stem cells from nonobese diabetic mice. Cell Biol Int. 35:961–966. 2011. View Article : Google Scholar : PubMed/NCBI
25	Wang J, Ma XY, Feng YF, Ma ZS, Ma TC, Zhang Y, Li X, Wang L and Lei W: Magnesium ions promote the biological behaviour of rat calvarial osteoblasts by activating the PI3K/Akt signaling pathway. Biol Trace Elem Res. 179:284–293. 2017. View Article : Google Scholar : PubMed/NCBI
26	Abdi A, Sadraie H, Dargahi L, Khalaj L and Ahmadiani A: Apoptosis inhibition can be threatening in Aβ-induced neuroinflammation, through promoting cell proliferation. Neurochem Res. 36:39–48. 2011. View Article : Google Scholar : PubMed/NCBI
27	Yamamoto T, Irisa T, Sugioka Y and Sueishi K: Effects of pulse methylprednisolone on bone and marrow tissues: Corticosteroid-induced osteonecrosis in rabbits. Arthritis Rheum. 40:2055–2064. 1997. View Article : Google Scholar : PubMed/NCBI
28	Xu X, Wen H, Hu Y, Yu H, Zhang Y, Chen C and Pan X: STAT1-caspase 3 pathway in the apoptotic process associated with steroid-induced necrosis of the femoral head. J Mol Histol. 45:473–485. 2014. View Article : Google Scholar : PubMed/NCBI
29	Zhang W, He H, Song H, Zhao J, Li T, Wu L, Zhang X and Chen J: Neuroprotective effects of salidroside in the MPTP mouse model of Parkinson's disease: Involvement of the PI3K/Akt/GSK3β pathway. Parkinsons Dis. 2016:94501372016.PubMed/NCBI
30	Dai WW, Wang LB, Jin GQ, Wu HJ, Zhang J, Wang CL, Wei YJ, Lee JH, Lay YE and Yao W: Beta-ecdysone protects mouse osteoblasts from glucocorticoid-induced apoptosis in vitro. Planta Med. 83:888–894. 2017. View Article : Google Scholar : PubMed/NCBI
31	Chua CC, Chua BH, Chen Z, Landy C and Hamdy RC: Dexamethasone induces caspase activation in murine osteoblastic MC3T3-E1 cells. Biochim Biophys Acta. 1642:79–85. 2003. View Article : Google Scholar : PubMed/NCBI
32	Ryu JS, Ko JH, Kim MK, Wee WR and Oh JY: Prednisolone induces apoptosis in corneal epithelial cells through the intrinsic pathway. Sci Rep. 7:41352017. View Article : Google Scholar : PubMed/NCBI
33	Calder JD, Buttery L, Revell PA, Pearse M and Polak JM: Apoptosis-a significant cause of bone cell death in osteonecrosis of the femoral head. J Bone Joint Surg Br. 86:1209–1213. 2004. View Article : Google Scholar : PubMed/NCBI
34	Manning BD and Cantley LC: AKT/PKB signaling: Navigating downstream. Cell. 129:1261–1274. 2007. View Article : Google Scholar : PubMed/NCBI
35	Pap M and Cooper GM: Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-kinase/Akt cell survival pathway. J Biol Chem. 273:19929–19932. 1998. View Article : Google Scholar : PubMed/NCBI
36	Kang JQ, Chong ZZ and Maiese K: Critical role for Akt1 in the modulation of apoptotic phosphatidylserine exposure and microglial activation. Mol Pharmacol. 64:557–569. 2003. View Article : Google Scholar : PubMed/NCBI
37	Zhu Y, Shi YP, Wu D, Ji YJ, Wang X, Chen HL, Wu SS, Huang DJ and Jiang W: Salidroside protects against hydrogen peroxide-induced injury in cardiac H9c2 cells via PI3K-Akt dependent pathway. DNA Cell Biol. 30:809–819. 2011. View Article : Google Scholar : PubMed/NCBI
38	Zhang L, Ding W, Sun H, Zhou Q, Huang J, Li X, Xie Y and Chen J: Salidroside protects PC12 cell from MPP⁺-induced apoptosis via activation of the PI3K/Akt pathway. Food Chem Toxicol. 50:2591–2597. 2012. View Article : Google Scholar : PubMed/NCBI
39	Li DW, Liu ZQ, Chen W, Yao M and Li GR: Association of glycogen synthase kinase-3β with Parkinson's disease (review). Mol Med Rep. 9:2043–2050. 2014. View Article : Google Scholar : PubMed/NCBI
40	Chao DT and Korsmeyer SJ: BCL-2 family: Regulators of cell death. Annu Rev Immunol. 16:395–419. 1998. View Article : Google Scholar : PubMed/NCBI
41	Hu WP, Yu HS, Sung PJ, Tsai FY, Shen YK, Chang LS and Wang JJ: DC-81-Indole conjugate agent induces mitochondria mediated apoptosis in human melanoma A375 cells. Chem Res Toxicol. 20:905–912. 2007. View Article : Google Scholar : PubMed/NCBI
42	Steffen RT, Athanasou NA, Gill HS and Murray DW: Avascular necrosis associated with fracture of the femoral neck after hip resurfacing: Histological assessment of femoral bone from retrieval specimens. J Bone Joint Surg Br. 92:787–793. 2010. View Article : Google Scholar : PubMed/NCBI