Abstract
The inflammatory cytokine IL-17A is known to have the capacity to promote osteoclastogenesis, thereby enhancing bone loss. Moreover, IL-17A can promote the expression of RANKL in osteoblasts, contributing to its pro-osteoclastogenic effect. IL-17A is an autophagy regulator, which is also responsible for its regulation on RANKL expression. However, the specific role of autophagy in IL-17A-regulated RANKL expression and the underlying mechanism of IL-17A-regulated osteoblast autophagy remain unclear. IL-17A is known to inhibit autophagy by preventing BCL2 degradation. This study aimed to explore the significance of BCL2-dependent autophagy in IL-17A-regulated RANKL expression. Our results showed that IL-17A at 50 ng/mL could inhibit autophagic activity and promote RANKL protein expression in MC3T3-E1 osteoblast line. Moreover, the corresponding concentration of IL-17A could enhance BCL2 protein expression and the protein interaction between BCL2 and Beclin1 in MC3T3-E1 cells. However, the protein expression of RANKL and BCL2 promoted by 50 ng/mL of IL-17A was blocked by autophagy activation with Beclin1 pharmacological upregulation. Furthermore, RANKL protein expression promoted by 50 ng/mL of IL-17A was also reversed by autophagy activation with BCL2 knockdown. Importantly, the supernatant from osteoblasts treated with 50 ng/mL of IL-17A made osteoclast precursors (OCPs) form larger osteoclasts, which was reversed by BCL2 knockdown in osteoblasts. In conclusion, high levels of IL-17A prevent the degradation of RANKL by inhibiting BCL2-Beclin1-autophagy activation signal transduction in osteoblasts, thereby indirectly promoting osteoclastogenesis.
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Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Atwood DJ, Pokhrel D, Brown CN, Holditch SJ, Bachu DM, Thorburn A, Hopp K, Edelstein CL (2020) Increased mTOR and suppressed autophagic flux in the heart of a hypomorphic Pkd1 mouse model of autosomal dominant polycystic kidney disease. Cell Signal 74:109730
Bhadricha H, Patel V, Singh AK, Savardekar L, Patil A, Surve S, Desai M (2021) Increased frequency of Th17 cells and IL-17 levels are associated with low bone mineral density in postmenopausal women. Sci Rep 11(1):16155
Cong LH, Li T, Wang H, Wu YN, Wang SP, Zhao YY, Zhang GQ, Duan J (2020) IL-17A-producing T cells exacerbate fine particulate matter-induced lung inflammation and fibrosis by inhibiting PI3K/Akt/mTOR-mediated autophagy. J Cell Mol Med 24(15):8532–8544
Fernández ÁF, Sebti S, Wei Y, Zou Z, Shi M, McMillan KL, He C, Ting T, Liu Y, Chiang WC, Marciano DK, Schiattarella GG, Bhagat G, Moe OW, Hu MC, Levine B (2018) Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice. Nature 558(7708):136–140
Huang H, Kim HJ, Chang EJ, Lee ZH, Hwang SJ, Kim HM, Lee Y, Kim HH (2009) IL-17 stimulates the proliferation and differentiation of human mesenchymal stem cells: implications for bone remodeling. Cell Death Differ 16(10):1332–1343
Kang C, Wei L, Song B, Chen L, Liu J, Deng B, Pan X, Shao L (2017) Involvement of autophagy in tantalum nanoparticle-induced osteoblast proliferation. Int J Nanomedicine 12:4323–4333
Ke D, Fu X, Xue Y, Wu H, Zhang Y, Chen X, Hou J (2018) IL-17A regulates the autophagic activity of osteoclast precursors through RANKL-JNK1 signaling during osteoclastogenesis in vitro. Biochem Biophys Res Commun 497(3):890–896
Kim HJ, Seo SJ, Kim JY, Kim YG, Lee Y (2020) IL-17 promotes osteoblast differentiation, bone regeneration, and remodeling in mice. Biochem Biophys Res Commun 524(4):1044–1050
Le Goff B, Bouvard B, Lequerre T, Lespessailles E, Marotte H, Pers YM, Cortet B (2019) Implication of IL-17 in bone loss and structural damage in inflammatory rheumatic diseases. Mediators Inflamm 2019:8659302
Lei L, Sun J, Han J, Jiang X, Wang Z, Chen L (2021) Interleukin-17 induces pyroptosis in osteoblasts through the NLRP3 inflammasome pathway in vitro. Int Immunopharmacol 96:107781
Li JY, D'Amelio P, Robinson J, Walker LD, Vaccaro C, Luo T, Tyagi AM, Yu M, Reott M, Sassi F, Buondonno I, Adams J, Weitzmann MN, Isaia GC, Pacifici R (2015) IL-17A is increased in humans with primary hyperparathyroidism and mediates PTH-induced bone loss in mice. Cell Metab 22(5):799–810
Li JY, Yu M, Tyagi AM, Vaccaro C, Hsu E, Adams J, Bellido T, Weitzmann MN, Pacifici R (2019a) IL-17 receptor signaling in osteoblasts/osteocytes mediates PTH-induced bone loss and enhances osteocytic RANKL production. J Bone Miner Res 34(2):349–360
Li S, Lin Z, Zheng W, Zheng L, Chen X, Yan Z, Cheng Z, Yan H, Zheng C, Guo P (2019b) IL-17A inhibits autophagic activity of HCC cells by inhibiting the degradation of Bcl2. Biochem Biophys Res Commun 509(1):194–200
Lian WS, Ko JY, Chen YS, Ke HC, Wu SL, Kuo CW, Wang FS (2018) Chaperonin 60 sustains osteoblast autophagy and counteracts glucocorticoid aggravation of osteoporosis by chaperoning RPTOR. Cell Death Dis 9(10):938
Liu H, Mi S, Li Z, Hua F, Hu ZW (2013) Interleukin 17A inhibits autophagy through activation of PIK3CA to interrupt the GSK3B-mediated degradation of BCL2 in lung epithelial cells. Autophagy 9(5):730–742
Liu SC, Hsieh HL, Tsai CH, Fong YC, Ko CY, Wu HC, Chang SL, Hsu CJ, Tang CH (2022) CCN2 facilitates IL-17 production and osteoclastogenesis in human osteoarthritis synovial fibroblasts by inhibiting miR-655 expression. J Bone Miner Res 37(10):1944–1955
Liu T, Han S, Dai Q, Zheng J, Liu C, Li S, Li J (2019) IL-17A-mediated excessive autophagy aggravated neuronal ischemic injuries via Src-PP2B-mTOR pathway. Front Immunol 10:2952
Roberts JL, Mella-Velazquez G, Dar HY, Liu G, Drissi H (2022) Deletion of IL-17ra in osteoclast precursors increases bone mass by decreasing osteoclast precursor abundance. Bone 157:116310
Samarpita S, Doss HM, Ganesan R, Rasool M (2018) Interleukin 17 under hypoxia mimetic condition augments osteoclast mediated bone erosion and expression of HIF-1α and MMP-9. Cell Immunol 332:39–50
Schmidt T, Schwinge D, Rolvien T, Jeschke A, Schmidt C, Neven M, Butscheidt S, Kriz M, Kunzmann L, Mussawy H, Hubert J, Hawellek T, Rüther W, Oheim R, Barvencik F, Lohse AW, Schramm C, Schinke T, Amling M (2019) Th17 cell frequency is associated with low bone mass in primary sclerosing cholangitis. J Hepatol 70(5):941–953
Shi H, Wang J, Wang J, Huang Z, Yang Z (2018) IL-17A induces autophagy and promotes microglial neuroinflammation through ATG5 and ATG7 in intracerebral hemorrhage. J Neuroimmunol 323:143–151
Shoji-Kawata S, Sumpter R, Leveno M, Campbell GR, Zou Z, Kinch L, Wilkins AD, Sun Q, Pallauf K, MacDuff D et al (2013) Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494(7436):201–206
Sun Y, Yao X, Zhang QJ, Zhu M, Liu ZP, Ci B, Xie Y, Carlson D, Rothermel BA, Sun Y et al (2018) Beclin-1-dependent autophagy protects the heart during sepsis. Circulation 138(20):2247–2262
Tateosian NL, Pellegrini JM, Amiano NO, Rolandelli A, Casco N, Palmero DJ, Colombo MI, García VE (2017) IL17A augments autophagy in Mycobacterium tuberculosis-infected monocytes from patients with active tuberculosis in association with the severity of the disease. Autophagy 13(7):1191–1204
Uluçkan Ö, Jimenez M, Karbach S, Jeschke A, Graña O, Keller J, Busse B, Croxford AL, Finzel S, Koenders M, van den Berg W, Schinke T, Amling M, Waisman A, Schett G, Wagner EF (2016) Chronic skin inflammation leads to bone loss by IL-17-mediated inhibition of Wnt signaling in osteoblasts. Sci Transl Med 8(330):330ra37
Wang Z, Wei Y, Lei L, Zhong J, Shen Y, Tan J, Xia M, Wu Y, Sun W, Chen L (2021) RANKL expression of primary osteoblasts is enhanced by an IL-17-mediated JAK2/STAT3 pathway through autophagy suppression. Connect Tissue Res 62(4):411–426
Wei Y, Pattingre S, Sinha S, Bassik M, Levine B (2008) JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell 30(6):678–688
Xue Y, Liang Z, Fu X, Wang T, Xie Q, Ke D (2019) IL-17A modulates osteoclast precursors’ apoptosis through autophagy-TRAF3 signaling during osteoclastogenesis. Biochem Biophys Res Commun 508(4):1088–1092
Zhang J, Wang AX, Wu Y, Zhang S (2022) IL-1 receptor antagonist (IL-1RA) suppresses a hyper-IL-17 response-mediated bone loss in a murine experimental periodontitis. Arch Oral Biol 144:105555
Zhong J, Wang Z, Yuan W, Shen Y, Chen L (2022) Interleukin-17 promotes osteoclastogenesis and periodontal damage via autophagy in vitro and in vivo. Int Immunopharmacol 107:108631
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This work was supported by Fujian Provincial Natural Science Foundation Projects (2019J01096).
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Yun-rong Zhu and Xia-xia Chen conceived and designed experiments; Xia-xia Chen and Hao-jie Wu performed experiments, analyzed data, and prepared figures; Dianshan Ke assisted in data analysis; Yun-rong wrote the manuscript.
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Xia-xia Chen and Hao-jie Wu are regarded as co-first authors.
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Chen, Xx., Wu, Hj., Ke, Ds. et al. IL-17A inhibits the degradation of RANKL in osteoblasts by inhibiting BCL2-Beclin1-autophagy signaling. In Vitro Cell.Dev.Biol.-Animal 59, 300–311 (2023). https://doi.org/10.1007/s11626-023-00761-7
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DOI: https://doi.org/10.1007/s11626-023-00761-7