Mechanism of triptolide in treating ankylosing spondylitis through the anti‑ossification effect of the BMP/Smad signaling pathway

Wang,Guilong; Cai,Jing; Zhang,Jinshan; Li,Cuiyun

doi:10.3892/mmr.2017.8117

Mechanism of triptolide in treating ankylosing spondylitis through the anti‑ossification effect of the BMP/Smad signaling pathway

Authors:
- Guilong Wang
- Jing Cai
- Jinshan Zhang
- Cuiyun Li
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Affiliations: Department of Orthopedics, Linyi People's Hospital, Linyi, Shandong 276000, P.R. China, Department of Neurosurgery, Linyi People's Hospital, Linyi, Shandong 276000, P.R. China, Department of Medical lmaging, Linyi People's Hospital, Linyi, Shandong 276000, P.R. China, Department of Pathology, Linyi People's Hospital, Linyi, Shandong 276000, P.R. China
Published online on: November 20, 2017 https://doi.org/10.3892/mmr.2017.8117
Pages: 2731-2737

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Abstract

The present study aimed to examine the mechanism of triptolide in the treatment of ankylosing spondylitis (AS) through the anti‑ossification effect of bone morphogenetic protein (BMP)/small mothers against decapentaplegic (Smad) pathway. Male rats were randomly divided into five groups: Normal rat group; model group; triptolide low dose group (10 mg/kg); triptolide middle dose group (20 mg/kg); triptolide high dose group (40 mg/kg). The spinal joint capsules of each group of rats were collected to perform primary cell culture to determine the levels of cell proliferation. Western blot and reverse transcription‑polymerase chain reaction analyses, and ELISA were used to detect the mRNA and protein expression levels of core‑binding factor α1 (Cbfal), BMP receptor type II (BMPRII), Smad1, Smad4, Smad5 and Smad6, the protein expression of phosphorylation indicators, including phosphorylated (p)Smad1 and pSmad5, the mRNA expression of tumor necrosis factor‑α (TNF‑α), interleukin (IL)‑1β and IL‑6 in rat plasma, and the mRNA expression of BMP/Smads in fibroblasts induced by recombinant human (rh)BMP‑2. The effects on AS in the rats were also examined. The results revealed that, following intervention with triptolide, inflammation was suppressed, and the mRNA expression levels of TNF‑α, IL‑1β and IL‑6 were reduced. The expression levels of Cbfal, BMPRII, Smad1, Smad4 and Smad5 were also reduced, whereas the expression of Smad6 was increased. Following induction by rhBMP‑2, the effects of triptolide weakened, with the most marked effects observed at the highest concentration, suggesting that triptolide functions through the BMP/Smad signaling pathway. Taken together, the results suggested that triptolide may be used to treat AS, the mechanism of which may be through the BMP/Smad pathway.

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1	Meyer K, Niedermann K, Tschopp A and Klipstein A: Is the work ability index useful to evaluate absence days in ankylosing spondylitis patients? A cross-sectional study. BMJ Open. 3:pii: e0022312013. View Article : Google Scholar
2	Gerdan V, Akar S, Solmaz D, Pehlivan Y, Onat AM, Kisacik B, Sayarlioglu M, Erhan C, Tezcan ME, Ozturk MA, et al: Initial diagnosis of lumbar disc herniation is associated with a delay in diagnosis of ankylosing spondylitis. J Rheumatol. 39:1996–1999. 2012. View Article : Google Scholar : PubMed/NCBI
3	van den Berg R and van der Heijde DM: How should we diagnose spondyloarthritis according to the ASAS classification criteria: A guide for practicing physicians. Pol Arch Med Wewn. 120:452–457. 2010.PubMed/NCBI
4	Arends S, Brouwer E, van der Veer E, Groen H, Leijsma MK, Houtman PM, Th A, Jansen TL, Kallenberg CG and Spoorenberg A: Baseline predictors of response and discontinuation of tumor necrosis factor-alpha blocking therapy in ankylosing spondylitis: A prospective longitudinal observational cohort study. Arthritis Res Tlier. 13:R942011. View Article : Google Scholar
5	Bao J and Dai SM: A Chinese herb Tripterygium wilfordii Hook F in the treatment of rheumatoid arthritis: Mechanism, efficacy, and safety. Rheumatol Int. 31:1123–1129. 2011. View Article : Google Scholar : PubMed/NCBI
6	Qin W, Yang F, Deng R, Li D, Song Z, Tian Y, Wang R, Ling J and Lin Z: Smad 1/5 is involved in bone morphogenetic protein-2-induced odontoblastic differentiation in human dental pulp cells. J Endod. 38:66–71. 2012. View Article : Google Scholar : PubMed/NCBI
7	Ecalco-Cruz AC, Sosa-Garrocho M, Vázquez-Victorio G, Ortiz-García L, Domínguez-Hüttinger E and Macías-Silva M: Transforming growth factor-β/SMAD Target gene SKIL is negatively regulated by the transcriptional cofactor complex SNON-SMAD4. J Biol Chem. 287:26764–26776. 2012. View Article : Google Scholar : PubMed/NCBI
8	Kokabu S, Ohte S, Sasanuma H, Shin M, Yoneyama K, Murata E, Kanomata K, Nojima J, Ono Y, Yoda T, et al: Suppression of BMP-Smad signaling axis-induced osteoblastic differentiation by small C-terminal domain phosphatase 1, a Smad phosphatase. Mol Endocrinol. 25:474–481. 2011. View Article : Google Scholar : PubMed/NCBI
9	Poddubnyy D, Rudwaleit M, Haibel H, Listing J, Märker-Hermann E, Zeidler H, Braun J and Sieper J: Effect of non-steroidal anti-inflammatory drags on radiographic spinal progression in patients with axial spondyloarthritis: Results from the German Spondyloarthritis Inception Cohort. Ann Rheum Dis. 71:1616–1622. 2012. View Article : Google Scholar : PubMed/NCBI
10	Yi JF and Tang XL: The effect of paeoniflorin, collagen, hypothalamus pituitary kidney in rats with collagen induced arthritis. China Adrenal Axis J Pharmacol Toxicol. 27:668–672. 2013.
11	Wang J: Experimental study of recombinant expression and anti-tumor effect of ING4 gene (unpublished PhD thesis). Soochow University; 2005
12	Kroon F, Landewé R, Dougados M and van der Heijde D: Continuous NSAID use reverts the effects of inflammation on radiographic progression in patients with ankylosing spondylitis. Ann Rheum Dis. 71:1623–1629. 2012. View Article : Google Scholar : PubMed/NCBI
13	Ikushima H and Miyazono K: TGF-β signal transduction spreading to a wider field: A broad variety of mechanisms for context-dependent effects of TGF-β. Cell Tissue Res. 347:37–49. 2012. View Article : Google Scholar : PubMed/NCBI
14	Thatcher JD: The TGF-beta signal transduction pathway. Sci Signal. 3:tr42010. View Article : Google Scholar : PubMed/NCBI
15	Song B, Estrada KD and Lyons KM: Smad signaling in skeletal development and regeneration. Cytokine Growth Factor Rev. 20:379–388. 2009. View Article : Google Scholar : PubMed/NCBI
16	Ekman M, Mu Y, Lee SY, Edlund S, Kozakai T, Thakur N, Tran H, Qian J, Groeden J, Heldin CH and Landström M: APC and Smad7 link TGFβ type I receptors to the microtubule system to promote cell migration. Mol Biol Cell. 23:2109–2121. 2012. View Article : Google Scholar : PubMed/NCBI
17	Vardouli L, Vasilaki E, Papadimitriou E, Kardassis D and Stournaras C: A novel mechanism of TGFbeta-induced actin reorganization mediated by Smad proteins and Rho GTPases. FEBS J. 275:4074–4087. 2008. View Article : Google Scholar : PubMed/NCBI
18	Edlund S, Landström M, Heldin CH and Aspenström P: Smad7 is required for TGF-beta-induced activation of the small GTPase Cdc42. J Cell Sci. 117:1835–1847. 2004. View Article : Google Scholar : PubMed/NCBI
19	Konstantinidis G, Moustakas A and Stournaras C: Regulation of myosin light chain function by BMP signaling controls actin cytoskeleton remodeling. Cell Physiol Biochem. 28:1031–1044. 2011. View Article : Google Scholar : PubMed/NCBI
20	Chen G, Deng C and Li YP: TGF-β and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci. 8:272–288. 2012. View Article : Google Scholar : PubMed/NCBI
21	Jun JH, Yoon WJ, Seo SB, Woo KM, Kim GS, Ryoo HM and Baek JH: BMP2-activated Erk/MAP kinase stabilizes Runx2 by increasing p300 levels and histone acetyltransferase activity. J Biol Chem. 285:36410–36419. 2010. View Article : Google Scholar : PubMed/NCBI
22	Huang Q, Zhang H, Pei FX, Chen ZY, Wang GL, Shen B, Yang J, Zhou ZK and Kong QQ: Use of small interfering ribonucleic acids to inhibit the adipogenic effect of alcohol on human bone marrow-derived mesenchymal cells. Int Orthop. 34:1059–1068. 2010. View Article : Google Scholar : PubMed/NCBI
23	Shi XM, Blair HC, Yang X, McDonald JM and Cao X: Tandem repeat of C/EBP binding sites mediates PPAR gamma2 gene transcription in glucocorticoid-induced adipocyte differentiation. J Cell Biochem. 76:518–527. 2000. View Article : Google Scholar : PubMed/NCBI