Abstract
Osteoarthritis (OA) is the most prevalent chronic degenerative joint disease with few treatment options. The pathogenesis of OA is characterized by sustained inflammation, oxidative stress and chondrocyte apoptosis that eventually lead to cartilage degradation and joint dysfunction. In the present study, we identified a synthetic triterpenoid CDDO-Im(1-[2-cyano-3,12-dioxooleana-1,9(11)–dien-28-oyl] imidazole) as an activator of Nrf2 (nuclear factor erythroid 2-related factor 2) that displayed strong anti-OA effects. We showed that CDDO-Im (20 nM) significantly alleviated TNF-α-induced apoptosis of primary human chondrocytes and extracellular matrix degradation. In a mouse OA model incurred by DMM (destabilization of medial meniscus), administration of CDDO-Im (2.5 mg/kg, ip, every other day for 8 weeks) effectively reduced knee joint cartilage erosion and serum levels of inflammatory cytokines IL-1β and IL-6. We revealed that CDDO-Im (20 nM) significantly enhanced autophagy activities in chondrocytes, whereas the autophagy inhibition by chloroquine (CQ, 50 μM) or 3-methyladenine (3-MA, 5 mM) abrogated the anti-apoptosis and chondroprotective effects of CDDO-Im in TNF-α-treated chondrocytes. Moreover, we confirmed that CDDO-Im (1–20 nM) dose-dependently activated Nrf2 pathway in TNF-α-treated chondrocytes, and its chondroprotective and autophagy-enhancing effects were significantly diminished when Nrf2 signaling was blocked by Nrf2 inhibitor ML385 (20 μM) or siRNA-mediated Nrf2 knockdown. Together, our results demonstrate that CDDO-Im exhibits prominent chondroprotective and anti-OA activities owing to its Nrf2 activation and autophagy-enhancing properties, which might provide new insights into the strategies of OA clinical prevention and treatment.
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References
Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet. 2019;393:1745–59.
Pelletier JP, Raynauld JP, Dorais M, Bessette L, Dokoupilova E, Morin F, et al. An international, multicentre, double-blind, randomized study (DISSCO): effect of diacerein vs celecoxib on symptoms in knee osteoarthritis. Rheumatology. 2020;59:3858–68.
Jain A, Mishra SK, Vuddanda PR, Singh SK, Singh R, Singh S. Targeting of diacerein loaded lipid nanoparticles to intra-articular cartilage using chondroitin sulfate as homing carrier for treatment of osteoarthritis in rats. Nanomedicine. 2014;10:1031–40.
Aghazadeh-Habashi A, Jamali F. The glucosamine controversy; a pharmacokinetic issue. J Pharm Pharm Sci. 2011;14:264–73.
Lin Y, Wu C, Wang X, Liu S, Zhao K, Kemper T, et al. Glucosamine promotes hepatitis B virus replication through its dual effects in suppressing autophagic degradation and inhibiting MTORC1 signaling. Autophagy. 2020;16:548–61.
Zeng C, Zhang W, Doherty M, Persson MSM, Mallen C, Swain S, et al. Initial analgesic prescriptions for osteoarthritis in the United Kingdom, 2000–2016. Rheumatology. 2021;60:147–59.
Hamilton DF, Beard DJ, Barker KL, Macfarlane GJ, Tuck CE, Stoddart A, et al. Targeting rehabilitation to improve outcomes after total knee arthroplasty in patients at risk of poor outcomes: randomised controlled trial. BMJ. 2020;371:m3576.
Ansari MY, Ahmad N, Haqqi TM. Oxidative stress and inflammation in osteoarthritis pathogenesis: role of polyphenols. Biomed Pharmacother. 2020;129:110452.
Marchev AS, Dimitrova PA, Burns AJ, Kostov RV, Dinkova-Kostova AT, Georgiev MI. Oxidative stress and chronic inflammation in osteoarthritis: can NRF2 counteract these partners in crime? Ann NY Acad Sci. 2017;1401:114–35.
Cai D, Yin S, Yang J, Jiang Q, Cao W. Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis. Arthritis Res Ther. 2015;17:269.
Mizushima N, Levine B. Autophagy in human diseases. N Engl J Med. 2020;383:1564–76.
Yang H, Wen Y, Zhang M, Liu Q, Zhang H, Zhang J, et al. MTORC1 coordinates the autophagy and apoptosis signaling in articular chondrocytes in osteoarthritic temporomandibular joint. Autophagy. 2020;16:271–88.
Duan R, Xie H, Liu ZZ. The role of autophagy in osteoarthritis. Front Cell Dev Biol. 2020;8:608388.
Matsuzaki T, Alvarez-Garcia O, Mokuda S, Nagira K, Olmer M, Gamini R, et al. FoxO transcription factors modulate autophagy and proteoglycan 4 in cartilage homeostasis and osteoarthritis. Sci Transl Med. 2018;10:428.
Filomeni G, De Zio D, Cecconi F. Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ. 2015;22:377–88.
Gao Q. Oxidative stress and autophagy. Adv Exp Med Biol. 2019;1206:179–98.
Tang Z, Hu B, Zang F, Wang J, Zhang X, Chen H. Nrf2 drives oxidative stress-induced autophagy in nucleus pulposus cells via a Keap1/Nrf2/p62 feedback loop to protect intervertebral disc from degeneration. Cell Death Dis. 2019;10:510.
Gao X, Jiang S, Du Z, Ke A, Liang Q, Li X. KLF2 protects against osteoarthritis by repressing oxidative response through activation of Nrf2/ARE signaling in vitro and in vivo. Oxid Med Cell Longev. 2019;2019:8564681.
Hou M, Zhang Y, Zhou X, Liu T, Yang H, Chen X, et al. Kartogenin prevents cartilage degradation and alleviates osteoarthritis progression in mice via the miR-146a/NRF2 axis. Cell Death Dis. 2021;12:483.
Xu D, Chen L, Chen X, Wen Y, Yu C, Yao J, et al. The triterpenoid CDDO-imidazolide ameliorates mouse liver ischemia-reperfusion injury through activating the Nrf2/HO-1 pathway enhanced autophagy. Cell Death Dis. 2017;8:e2983.
Zhu X, Chen F, Lu K, Wei A, Jiang Q, Cao W. PPARgamma preservation via promoter demethylation alleviates osteoarthritis in mice. Ann Rheum Dis. 2019;78:1420–9.
Lin J, Yu J, Zhao J, Zhang K, Zheng J, Wang J, et al. Fucoxanthin, a marine carotenoid, attenuates beta-amyloid oligomer-induced neurotoxicity possibly via regulating the PI3K/Akt and the ERK pathways in SH-SY5Y cells. Oxid Med Cell Longev. 2017;2017:6792543.
Liao Z, Luo R, Li G, Song Y, Zhan S, Zhao K, et al. Exosomes from mesenchymal stem cells modulate endoplasmic reticulum stress to protect against nucleus pulposus cell death and ameliorate intervertebral disc degeneration in vivo. Theranostics. 2019;9:4084–100.
Li G, Song Y, Liao Z, Wang K, Luo R, Lu S, et al. Bone-derived mesenchymal stem cells alleviate compression-induced apoptosis of nucleus pulposus cells by N6 methyladenosine of autophagy. Cell Death Dis. 2020;11:103.
Qin T, Du R, Huang F, Yin S, Yang J, Qin S, et al. Sinomenine activation of Nrf2 signaling prevents hyperactive inflammation and kidney injury in a mouse model of obstructive nephropathy. Free Radic Biol Med. 2016;92:90–9.
Bayliak MM, Lushchak VI. Pleiotropic effects of alpha-ketoglutarate as a potential anti-ageing agent. Ageing Res Rev. 2021;66:101237.
Deng Y, Lu J, Li W, Wu A, Zhang X, Tong W, et al. Reciprocal inhibition of YAP/TAZ and NF-kappaB regulates osteoarthritic cartilage degradation. Nat Commun. 2018;9:4564.
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.
Son YO, Park S, Kwak JS, Won Y, Choi WS, Rhee J, et al. Estrogen-related receptor gamma causes osteoarthritis by upregulating extracellular matrix-degrading enzymes. Nat Commun. 2017;8:2133.
Hui W, Litherland GJ, Elias MS, Kitson GI, Cawston TE, Rowan AD, et al. Leptin produced by joint white adipose tissue induces cartilage degradation via upregulation and activation of matrix metalloproteinases. Ann Rheum Dis. 2012;71:455–62.
Li YS, Zhang FJ, Zeng C, Luo W, Xiao WF, Gao SG, et al. Autophagy in osteoarthritis. Jt Bone Spine. 2016;83:143–8.
Duarte JH. Osteoarthritis: autophagy prevents age-related OA. Nat Rev Rheumatol. 2015;11:683.
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.
Cuadrado A, Manda G, Hassan A, Alcaraz MJ, Barbas C, Daiber A, et al. Transcription factor NRF2 as a therapeutic target for chronic diseases: a systems medicine approach. Pharmacol Rev. 2018;70:348–83.
Zhang F, Wang S, Zhang M, Weng Z, Li P, Gan Y, et al. Pharmacological induction of heme oxygenase-1 by a triterpenoid protects neurons against ischemic injury. Stroke. 2012;43:1390–7.
Liu M, Reddy NM, Higbee EM, Potteti HR, Noel S, Racusen L, et al. The Nrf2 triterpenoid activator, CDDO-imidazolide, protects kidneys from ischemia-reperfusion injury in mice. Kidney Int. 2014;85:134–41.
Chen J, Li L, Zhou Y, Zhang J, Chen L. Gambogic acid ameliorates high glucose- and palmitic acid-induced inflammatory response in ARPE-19 cells via activating Nrf2 signaling pathway: ex vivo. Cell Stress Chaperones. 2021;26:367–75.
Yamamoto M, Kensler TW, Motohashi H. The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol Rev. 2018;98:1169–203.
Yan Z, Qi W, Zhan J, Lin Z, Lin J, Xue X, et al. Activating Nrf2 signalling alleviates osteoarthritis development by inhibiting inflammasome activation. J Cell Mol Med. 2020;24:13046–57.
Khan NM, Haseeb A, Ansari MY, Devarapalli P, Haynie S, Haqqi TM. Wogonin, a plant derived small molecule, exerts potent anti-inflammatory and chondroprotective effects through the activation of ROS/ERK/Nrf2 signaling pathways in human osteoarthritis chondrocytes. Free Radic Biol Med. 2017;106:288–301.
D’Adamo S, Cetrullo S, Guidotti S, Silvestri Y, Minguzzi M, Santi S, et al. Spermidine rescues the deregulated autophagic response to oxidative stress of osteoarthritic chondrocytes. Free Radic Biol Med. 2020;153:159–72.
Bao J, Chen Z, Xu L, Wu L, Xiong Y. Rapamycin protects chondrocytes against IL-18-induced apoptosis and ameliorates rat osteoarthritis. Aging. 2020;12:5152–67.
Nakatogawa H. Mechanisms governing autophagosome biogenesis. Nat Rev Mol Cell Biol. 2020;21:439–58.
Lotz MK, Carames B. Autophagy and cartilage homeostasis mechanisms in joint health, aging and OA. Nat Rev Rheumatol. 2011;7:579–87.
Sacitharan PK, Bou-Gharios G, Edwards JR. SIRT1 directly activates autophagy in human chondrocytes. Cell Death Discov. 2020;6:41.
Mathis BJ, Cui T. CDDO and its role in chronic diseases. Adv Exp Med Biol. 2016;929:291–314.
Meng X, Waddington JC, Tailor A, Lister A, Hamlett J, Berry N, et al. CDDO-imidazolide targets multiple amino acid residues on the Nrf2 Adaptor, Keap1. J Med Chem. 2020;63:9965–76.
Chintharlapalli S, Papineni S, Konopleva M, Andreef M, Samudio I, Safe S. 2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid and related compounds inhibit growth of colon cancer cells through peroxisome proliferator-activated receptor gamma-dependent and -independent pathways. Mol Pharmacol. 2005;68:119–28.
Reddy NM, Suryanaraya V, Yates MS, Kleeberger SR, Hassoun PM, Yamamoto M, et al. The triterpenoid CDDO-imidazolide confers potent protection against hyperoxic acute lung injury in mice. Am J Respir Crit Care Med. 2009;180:867–74.
Lin X, Tawch S, Wong HT, Roy S, Gaudino S, Castillo P, et al. Nrf2 through aryl hydrocarbon receptor regulates IL-22 response in CD4+ T cells. J Immunol. 2021;206:1540–8.
Rush BM, Bondi CD, Stocker SD, Barry KM, Small SA, Ong J, et al. Genetic or pharmacologic Nrf2 activation increases proteinuria in chronic kidney disease in mice. Kidney Int. 2021;99:102–16.
Hou X, Liu H, Ping Y, Zhang F, Zhi L, Jiang X, et al. CDDO-Im exerts antidepressant-like effects via the Nrf2/ARE pathway in a rat model of post-stroke depression. Brain Res Bull. 2021;173:74–81.
Shanmugam MK, Dai X, Kumar AP, Tan BK, Sethi G, Bishayee A. Oleanolic acid and its synthetic derivatives for the prevention and therapy of cancer: preclinical and clinical evidence. Cancer Lett. 2014;346:206–16.
de Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med. 2013;369:2492–503.
Acknowledgements
This work was supported by the Key Program of NSFC (81730067), Major Project of NSFC (81991514), Jiangsu Provincial Key Medical Center Foundation, Jiangsu Provincial Medical Outstanding Talent Foundation, Jiangsu Provincial Medical Youth Talent Foundation and Jiangsu Provincial Key Medical Talent Foundation. The Fundamental Research Funds for the Central Universities (14380493, 14380494). Key project in Medical Science and Technology Development of Nanjing (ZKS18020). China Postdoctoral Science Foundation (Grant No 2019M661806). Thanks to Ph.D. Xiao-bo Zhu for his sincere guidance on experimental technology.
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JD (Jian Dong) and QJ designed the experimental plan. JD (Jian Dong) and GCL performed the surgical operations and wrote the manuscript. KJZ performed some cell experiments. XRC, JWL and JJL analyzed the experimental data. ZYL and ZZD collected cartilage tissue specimens. QJ and JD (Jin Dai) performed some surgical operations. WC designed the revision plan, rearranged the results and revised the writing of the manuscript. The final manuscript was approved by all authors.
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Dong, J., Zhang, Kj., Li, Gc. et al. CDDO-Im ameliorates osteoarthritis and inhibits chondrocyte apoptosis in mice via enhancing Nrf2-dependent autophagy. Acta Pharmacol Sin 43, 1793–1802 (2022). https://doi.org/10.1038/s41401-021-00782-6
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DOI: https://doi.org/10.1038/s41401-021-00782-6
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