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Inflammation Research

Erschienen in:

28.02.2020 | Original Research Paper

Chondro-protective effects of celastrol on osteoarthritis through autophagy activation and NF-κB signaling pathway inhibition

verfasst von: Kai Feng, Hongfang Chen, Chen Xu

Erschienen in: Inflammation Research | Ausgabe 4/2020

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Abstract

Objective

Osteoarthritis (OA) is a degenerative articular cartilage disease accompanied by superfluous apoptosis of chondrocytes in the elderly. Celastrol is a potent bioactive medicine which can exert anti-inflammatory and anti-oxidative effects in various diseases. This study aimed to elucidate the possible role of celastrol in OA as well as the specific mechanism of celastrol in vitro and in vivo.

Methods

Autophagy-related biomarkers and apoptotic molecules were evaluated by PCR, Western blot and immunofluorescence staining. The level of autophagy was assessed by MDC staining and transmission electron microscopy. To study the downstream signaling pathway, nuclear factor kappa B (NF-κB) signaling pathway-related proteins were examined by Western blot. Moreover, an anterior cruciate ligament transection (ACLT) rat model was established to observe the protective effect of celastrol on rat cartilage.

Results

We found celastrol ameliorated IL-1β-induced chondrocyte apoptosis and increased the expression of LC3-II and Beclin-1. In addition, the suppression of celastrol-induced autophagy by 3-methyladenine (3MA) prevented the protective effect of celastrol in chondrocytes. Moreover, celastrol decreased the IL-1β-stimulated phosphorylation degree of IκBα and P65. We also found PDTC (a known NF-κB pathway inhibitor) can promote the activation of autophagy and attenuate the apoptosis of chondrocytes. Meanwhile, the results of rat ACLT model revealed the same effect as in vitro experiments.

Conclusions

In summary, celastrol protected against chondrocyte apoptosis by promoting autophagy and inhibiting NF-κB signaling pathway in vitro and in vivo.

Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum. 2012;64:1697–707.PubMedPubMedCentral

Martel-Pelletier J, Barr AJ, Cicuttini FM, Conaghan PG, Cooper C, Goldring MB, et al. Osteoarthritis. Nat Rev Dis Primers. 2016;2:16072.PubMed

Ong BN, Richardson JC, Porter T, Grime J. Exploring the relationship between multi-morbidity, resilience and social connectedness across the lifecourse. Health (London). 2014;18:302–18.

Pincus T, Gibson KA, Block JA. Premature mortality: a neglected outcome in rheumatic diseases? Arthritis Care Res (Hoboken). 2015;67:1043–6.

Reggiori F, Klionsky DJ. Autophagy in the eukaryotic cell. Eukaryotic Cell. 2002;1:11–21.PubMedPubMedCentral

Marycz K, Weiss C, Smieszek A, Kornicka K. Evaluation of oxidative stress and mitophagy during adipogenic differentiation of adipose-derived stem cells isolated from equine metabolic Syndrome (EMS) horses. Stem Cells Int. 2018;2018:5340756.PubMedPubMedCentral

Marycz K, Kornicka K, Maredziak M, Golonka P, Nicpon J. Equine metabolic syndrome impairs adipose stem cells osteogenic differentiation by predominance of autophagy over selective mitophagy. J Cell Mol Med. 2016;20:2384–404.PubMedPubMedCentral

Marycz K, Kornicka K, Grzesiak J, Smieszek A, Szlapka J. Macroautophagy and selective mitophagy ameliorate chondrogenic differentiation potential in adipose stem cells of equine metabolic syndrome: new findings in the field of progenitor cells differentiation. Oxid Med Cell Longev. 2016;2016:3718468.PubMedPubMedCentral

Kornicka K, Houston J, Marycz K. Dysfunction of mesenchymal stem cells isolated from metabolic syndrome and Type 2 diabetic patients as result of oxidative stress and autophagy may limit their potential therapeutic use. Stem Cell Rev Rep. 2018;14:337–45.PubMed

10.

Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132:27–422.PubMedPubMedCentral

11.

Mizushima N. Autophagy: process and function. Genes Dev. 2007;21:2861–73.PubMed

12.

Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008;451:1069–75.PubMedPubMedCentral

13.

Beatriz Caramés MO, Kiosses WB, Lotz M. The relationship of autophagy defects and cartilage damage during joint aging in a mouse model. Arthritis Rheumatol. 2015;67:1568–76.PubMedPubMedCentral

14.

Carames B, Hasegawa A, Taniguchi N, Miyaki S, Blanco FJ, Lotz M. Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Ann Rheum Dis. 2012;71:575–81.PubMed

15.

Carames B, Taniguchi N, Otsuki S, Blanco FJ, Lotz M. Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum. 2010;62:791–801.PubMedPubMedCentral

16.

Carames B, Taniguchi N, Seino D, Blanco FJ, D'Lima D, Lotz M. Mechanical injury suppresses autophagy regulators and pharmacologic activation of autophagy results in chondroprotection. Arthritis Rheum. 2012;64:1182–92.PubMed

17.

Koji Takayama YK, Kobayashi M, Greco N, Cummins JH, Matsushita T, Kuroda R, Kurosaka M, Fu FH, Huard J. Local intra-articular injection of rapamycin delays articular cartilage degeneration in a murine model of osteoarthritis. Arthritis Res Therapy. 2014;16:482.

18.

Ansari MY, Ahmad N, Haqqi TM (2018) Butein activates autophagy through AMPK/TSC2/ULK1/mTOR pathway to inhibit IL-6 expression in IL-1beta stimulated human chondrocytes. Cell Physiol Biochem 49:IPubMed

19.

Hu J, Cui W, Ding W, Gu Y, Wang Z, Fan W. Globular adiponectin attenuated H%3csub%3e2%3c/sub%3eO%3csub%3e2%3c/sub%3e-induced apoptosis in rat chondrocytes by inducing autophagy through the AMPK/ mTOR pathway. Cell Physiol Biochem. 2017;43:367–82.PubMed

20.

Calixto JB, Campos MM, Otuki MF, Santos AR. Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. Planta Med. 2004;70:93–103.PubMed

21.

Yang H, Chen D, Cui QC, Yuan X, Dou QP. Celastrol, a triterpene extracted from the chinese “Thunder of God Vine”, is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice. Cancer Res. 2006;66:4758–65.PubMed

22.

Hu M, Luo Q, Alitongbieke G, Chong S, Xu C, Xie L, et al. Celastrol-induced Nur77 interaction with TRAF2 alleviates inflammation by promoting mitochondrial ubiquitination and autophagy. Molecular Cell. 2017;66(141–153):e6.

23.

Lee J-H, Koo TH, Yoon H, Jung HS, Jin HZ, Lee K, et al. Inhibition of NF-κB activation through targeting IκB kinase by celastrol, a quinone methide triterpenoid. Biochem Pharmacol. 2006;72:1311–21.PubMed

24.

Kannaiyan R, Shanmugam MK, Sethi G. Molecular targets of celastrol derived from Thunder of God Vine: Potential role in the treatment of inflammatory disorders and cancer. Cancer Lett. 2011;303:9–20.PubMed

25.

Setty AR, Sigal LH. Herbal medications commonly used in the practice of rheumatology: mechanisms of action, efficacy, and side effects. Semin Arthritis Rheum. 2005;34:773–84.PubMed

26.

Klaic L, Morimoto RI, Silverman RB. Celastrol analogues as inducers of the heat shock response Design and synthesis of affinity probes for the identification of protein targets. ACS Chem Biol. 2012;7:928–37.PubMedPubMedCentral

27.

Zhang T, Li Y, Yu Y, Zou P, Jiang Y, Sun D. Characterization of Celastrol to inhibit Hsp90 and Cdc37 interaction. J Biol Chem. 2009;284:35381–9.PubMedPubMedCentral

28.

Venkatesha SH, Astry B, Nanjundaiah SM, Yu H, Moudgil KD. Suppression of autoimmune arthritis by Celastrus-derived Celastrol through modulation of pro-inflammatory chemokines. Bioorg Med Chem. 2012;20:5229–344.PubMedPubMedCentral

29.

Yu X, Tao W, Jiang F, Li C, Lin J, Liu C. Celastrol attenuates hypertension-induced inflammation and oxidative stress in vascular smooth muscle cells via induction of heme oxygenase-1. Am J Hypertens. 2010;23:895–903.PubMed

30.

Cleren C, Calingasan NY, Chen J, Beal MF. Celastrol protects against MPTP- and 3-nitropropionic acid-induced neurotoxicity. J Neurochem. 2005;94:995–1004.PubMed

31.

Faust K, Gehrke S, Yang Y, Yang L, Beal MF, Lu B. Neuroprotective effects of compounds with antioxidant and anti-inflammatory properties in a Drosophila model of Parkinson's disease. BMC Neurosci. 2009;10:109.PubMedPubMedCentral

32.

Deng Y-N, Shi J, Liu J, Qu Q-M. Celastrol protects human neuroblastoma SH-SY5Y cells from rotenone-induced injury through induction of autophagy. Neurochem Int. 2013;63:1–9.PubMed

33.

Divya T, Sureshkumar A, Sudhandiran G. Autophagy induction by celastrol augments protection against bleomycin-induced experimental pulmonary fibrosis in rats: Role of adaptor protein p62/ SQSTM1. Pulm Pharmacol Ther. 2017;45:47–61.PubMed

34.

Zhao J, Sun Y, Shi P, Dong JN, Zuo LG, Wang HG, et al. Celastrol ameliorates experimental colitis in IL-10 deficient mice via the up-regulation of autophagy. Int Immunopharmacol. 2015;26:221–8.PubMed

35.

Ding QH, Cheng Y, Chen WP, Zhong HM, Wang XH. Celastrol, an inhibitor of heat shock protein 90β potently suppresses the expression of matrix metalloproteinases, inducible nitric oxide synthase and cyclooxygenase-2 in primary human osteoarthritic chondrocytes. Eur J Pharmacol. 2013;708:1–7.PubMed

36.

Nanjundaiah SM, Venkatesha SH, Yu H, Tong L, Stains JP, Moudgil KD. Celastrus and its bioactive celastrol protect against bone damage in autoimmune arthritis by modulating osteoimmune cross-talk. J Biol Chem. 2012;287:22216–26.PubMedPubMedCentral

37.

Wang W, Ha C, Lin T, Wang D, Wang Y, Gong M. Celastrol attenuates pain and cartilage damage via SDF-1/CXCR4 signalling pathway in osteoarthritis rats. J Pharm Pharmacol. 2018;70:81–8.PubMed

38.

Gerwin N, Bendele AM, Glasson S, Carlson CS. The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the rat. Osteoarthr Cartil. 2010;18(Suppl 3):S24–34.PubMed

39.

Choi MC, MaruYama T, Chun CH, Park Y. Alleviation of murine osteoarthritis by cartilage-specific deletion of IkappaBzeta. Arthritis Rheumatol. 2018;70:1440–9.PubMed

40.

Kobayashi H, Chang SH, Mori D, Itoh S, Hirata M, Hosaka Y, et al. Biphasic regulation of chondrocytes by Rela through induction of anti-apoptotic and catabolic target genes. Nat Commun. 2016;7:13336.PubMedPubMedCentral

41.

Kamekura S, Hoshi K, Shimoaka T, Chung U, Chikuda H, Yamada T, et al. Osteoarthritis development in novel experimental mouse models induced by knee joint instability. Osteoarthr Cartil. 2005;13:632–41.PubMed

42.

Carmine Settembre EAS, Ballabio A, Karsenty G. Self-eating in skeletal development: Implications for lysosomal storage disorders. Autophagy. 2009;5:228–9.PubMedPubMedCentral

43.

Chen Z, Jin T, Lu Y. AntimiR-30b inhibits TNF-alpha mediated apoptosis and attenuated cartilage degradation through enhancing autophagy. Cell Physiol Biochem. 2016;40:883–94.PubMed

44.

Shen C, Cai GQ, Peng JP, Chen XD. Autophagy protects chondrocytes from glucocorticoids-induced apoptosis via ROS/Akt/FOXO3 signaling. Osteoarthr Cartil. 2015;23:2279–87.PubMed

45.

Appleton CT. Osteoarthritis year in review 2017: biology. Osteoarthr Cartil. 2018;26:296–303.PubMed

46.

Hosseinzadeh A, Kamrava SK, Joghataei MT, Darabi R, Shakeri-Zadeh A, Shahriari M, et al. Apoptosis signaling pathways in osteoarthritis and possible protective role of melatonin. J Pineal Res. 2016;61:411–25.PubMed

47.

Johannes Stöve KH, Günther K-P, Scharf H-P. Interleukin-1ß induces different gene expression of stromelysin, aggrecan and tumor-necrosis-factor-stimulated gene 6 in human osteoarthritic chondrocytes in vitro. Pathobiology. 2000;68:144–9.

48.

Xue H, Tu Y, Ma T, Liu X, Wen T, Cai M, et al. Lactoferrin inhibits IL-1beta-induced chondrocyte apoptosis through AKT1-induced CREB1 activation. Cell Physiol Biochem. 2015;36:2456–65.PubMed

49.

Lotz MK, Carames B. Autophagy and cartilage homeostasis mechanisms in joint health, aging and OA. Nat Rev Rheumatol. 2011;7:579–87.PubMedPubMedCentral

50.

Jin M, Klionsky DJ. Regulation of autophagy: Modulation of the size and number of autophagosomes. FEBS Lett. 2014;588:2457–63.PubMedPubMedCentral

51.

Cascão R, Vidal B, Jalmari Finnilä MA, Lopes IP, Teixeira RL, Saarakkala S, et al. Effect of celastrol on bone structure and mechanics in arthritic rats. RMD Open. 2017;3:e000438.PubMedPubMedCentral

52.

Olivotto E, Otero M, Marcu KB, Goldring MB. Pathophysiology of osteoarthritis: canonical NF-kappaB/IKKbeta-dependent and kinase-independent effects of IKKalpha in cartilage degradation and chondrocyte differentiation. RMD Open. 2015;1:e000061.PubMedPubMedCentral

53.

Marcu KB, Otero M, Olivotto E, Borzi RM, Goldring MB. NF-κB Signaling: Multiple angles to target OA. Curr Drug Targets. 2010;11:599–613.PubMedPubMedCentral

Titel: Chondro-protective effects of celastrol on osteoarthritis through autophagy activation and NF-κB signaling pathway inhibition
verfasst von: Kai Feng
Hongfang Chen
Chen Xu
Publikationsdatum: 28.02.2020
Verlag: Springer International Publishing
Erschienen in: Inflammation Research / Ausgabe 4/2020
Print ISSN: 1023-3830
Elektronische ISSN: 1420-908X
DOI: https://doi.org/10.1007/s00011-020-01327-z

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Abstract

Objective

Methods

Results

Conclusions

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