Abstract
Cadmium (Cd) contamination in the environment is a major public health concern since it has been linked to osteoporosis and other bone deformities. Linarin is a flavonoid glycoside, and it can promote osteoblastogenesis. This research aimed to investigate the potential role of linarin against Cd-exposed bone deformations in mice model. In our research, male mice were randomly allocated into four groups: control, Cd-exposed, and Cd + linarin (20 and 40mg/kg/bw, respectively). Linarin prevented body weight loss, increased serum calcium (Ca) and phosphorus (P), and bone alkaline phosphatase (BAP) levels in Cd-exposed groups. Furthermore, linarin treatment at 20 and 40mg/kg/bw significantly decreased RANK and OPG, resulting in an increase in RANKL mRNA levels and protein distribution in the bone of Cd-exposed mice. In addition, the bone of Cd-exposed mice administered with linarin showed higher TRAP, NFATc1, MMP9, and RUNX2 mRNA levels and protein distribution. Linarin significantly decreased oxidative stress in Cd-exposed mice bone by decreasing MDA, a lipid peroxidation product. Moreover, linarin protects Cd-exposed mice antioxidant enzymes by increasing bone SOD, CAT, and GPx levels. Besides, linarin suppresses alterations in the inflammatory system, i.e., NF-κB p65/IKKβ, by reducing NF-κB p65, IKKβ, IL-6, and TNF-α in the bone of Cd-exposed animals. This study concluded that linarin has potential to cure osteoporosis in Cd-exposed mice by reducing oxidative stress and inflammation and modulating the RANK/RANKL/OPG pathway.
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14 January 2022
A Correction to this paper has been published: https://doi.org/10.1007/s12011-022-03108-7
References
Suhani I, Sahab S, Srivastava V, Singh RP (2021) Impact of cadmium pollution on food safety and human health. Curr Opinion Toxicol 27:1–7. https://doi.org/10.1016/j.cotox.2021.04.004
Zhang H, Reynolds M (2019) Cadmium exposure in living organisms: a short review. Sci Total Environ 678:761–767. https://doi.org/10.1016/j.scitotenv.2019.04.395
Fatima G, Raza AM, Hadi N, Nigam N, Mahdi AA (2019) Cadmium in human diseases: it’s more than just a mere metal. Indian J Clin Biochem 34:371–378. https://doi.org/10.1007/s12291-019-00839-8
Hayat MT, Nauman M, Nazir N, Ali S, Bangash N (2019) Environmental hazards of cadmium: past, present, and future. In: Cadmium Toxicity and Tolerance in Plants. Elsevier, pp 163-183
Ma Y, Ran D, Shi X, Zhao H, Liu Z (2021) Cadmium toxicity: a role in bone cell function and teeth development. Sci Total Environ 769:144646. https://doi.org/10.1016/j.scitotenv.2020.144646
Blanuša M, Rabar I, Kostial K The health effect of cadmium in relation to changes in physiological levels of dietary calcium and iron in rats. In: Volume 2 Proceedings of the Second International Workshop Neuherberg, Federal Republic of Germany, April 1982, 2021. De Gruyter, pp 401-412
Currey JD (2006) Bones: structure and mechanics. Princeton university press.
Gregory CA, Prockop DJ, Spees JL (2005) Non-hematopoietic bone marrow stem cells: molecular control of expansion and differentiation. Exp Cell Res 306:330–335. https://doi.org/10.1016/j.yexcr.2005.03.018
Pino AM, Rosen CJ, Rodríguez JP (2012) In osteoporosis, differentiation of mesenchymal stem cells (MSCs) improves bone marrow adipogenesis. Biol Res 45:279–287. https://doi.org/10.4067/S0716-97602012000300009
Nordberg GF (2009) Historical perspectives on cadmium toxicology. Toxicol Appl Pharmacol 238:192–200. https://doi.org/10.1016/j.taap.2009.03.015
Nguyen D-H (2020) Itai-Itai disease: the role of mining in the degradation of Japanese society and public health. The Ohio State University.
Martineau C, Abed E, Médina G, Jomphe L-A, Mantha M, Jumarie C, Moreau R (2010) Involvement of transient receptor potential melastatin-related 7 (TRPM7) channels in cadmium uptake and cytotoxicity in MC3T3-E1 osteoblasts. Toxicol Lett 199:357–363. https://doi.org/10.1016/j.toxlet.2010.09.019
Ou L, Wang H, Wu Z, Wang P, Yang L, Li X, Sun K, Zhu X, Zhang R (2021) Effects of cadmium on osteoblast cell line: exportin 1 accumulation, p-JNK activation, DNA damage and cell apoptosis. Ecotoxicol Environ Saf 208:111668. https://doi.org/10.1016/j.ecoenv.2020.111668
Lau RY-C, Guo X (2011) A review on current osteoporosis research: with special focus on disuse bone loss. J Osteoporos 2011. https://doi.org/10.4061/2011/293808
Rauner M, Hofbauer LC (2016) Basics of bone biology. Principles of Osteoimmunology. Springer, In, pp 1–30
Udagawa N, Koide M, Nakamura M, Nakamichi Y, Yamashita T, Uehara S, Kobayashi Y, Furuya Y, Yasuda H, Fukuda C (2021) Osteoclast differentiation by RANKL and OPG signaling pathways. J Bone Miner Metab 39:19–26. https://doi.org/10.1007/s00774-020-01162-6
Karim K, Giribabu N, Salleh N (2021) Marantodes pumilum var. alata (Kacip Fatimah) ameliorates derangement in RANK/RANKL/OPG pathway and reduces inflammation and oxidative stress in the bone of estrogen-deficient female rats with type-2 diabetes. Phytomedicine 91:153677. https://doi.org/10.1016/j.phymed.2021.153677
Brzóska MM, Rogalska J (2013) Protective effect of zinc supplementation against cadmium-induced oxidative stress and the RANK/RANKL/OPG system imbalance in the bone tissue of rats. Toxicol Appl Pharmacol 272:208–220. https://doi.org/10.1016/j.taap.2013.05.016
Zhao Y, Wang H-L, Li T-T, Yang F, Tzeng C-M (2020) Baicalin ameliorates dexamethasone-induced osteoporosis by regulation of the RANK/RANKL/OPG signaling pathway. Drug Design, Development and Therapy 14:195. https://doi.org/10.2147/DDDT.S225516
Buha A, Jugdaohsingh R, Matovic V, Bulat Z, Antonijevic B, Kerns JG, Goodship A, Hart A, Powell JJ (2019) Bone mineral health is sensitively related to environmental cadmium exposure-experimental and human data. Environ Res 176:108539. https://doi.org/10.1016/j.envres.2019.108539
Xu J, Wu HF, Ang ES, Yip K, Woloszyn M, Zheng MH, Tan RX (2009) NF-κB modulators in osteolytic bone diseases. Cytokine Growth Factor Rev 20:7–17. https://doi.org/10.1016/j.cytogfr.2008.11.007
Brzóska MM, Rogalska J, Kupraszewicz E (2011) The involvement of oxidative stress in the mechanisms of damaging cadmium action in bone tissue: a study in a rat model of moderate and relatively high human exposure. Toxicol Appl Pharmacol 250:327–335. https://doi.org/10.1016/j.taap.2010.11.012
Kim SJ, Cho HI, Kim SJ, Park JH, Kim JS, Kim YH, Lee SK, Kwak J-H, Lee S-M (2014) Protective effect of linarin against D-galactosamine and lipopolysaccharide-induced fulminant hepatic failure. Eur J Pharmacol 738:66–73. https://doi.org/10.1016/j.ejphar.2014.05.024
Han X, Wu YC, Meng M, Sun QS, Gao SM, Sun H (2018) Linarin prevents LPS-induced acute lung injury by suppressing oxidative stress and inflammation via inhibition of TXNIP/NLRP3 and NF-κB pathways. Int J Mol Med 42:1460–1472. https://doi.org/10.3892/ijmm.2018.3710
Zhuang Z-J, Shan C-W, Li B, Pang M-X, Wang H, Luo Y, Liu Y-L, Song Y, Wang N-N, Chen S-H (2017, 2017) Linarin enriched extract attenuates liver injury and inflammation induced by high-fat high-cholesterol diet in rats. Evid Based Complement Alternat Med. https://doi.org/10.1155/2017/4701570
Kim SI, Kim YH, Kang BG, Kang MK, Lee EJ, Kim DY, Oh H, Oh SY, Na W, Lim SS (2020) Linarin and its aglycone acacetin abrogate actin ring formation and focal contact to bone matrix of bone-resorbing osteoclasts through inhibition of αvβ3 integrin and core-linked CD44. Phytomedicine 79:153351. https://doi.org/10.1016/j.phymed.2020.153351
Li J, Hao L, Wu J, Zhang J, Su J (2016) Linarin promotes osteogenic differentiation by activating the BMP-2/RUNX2 pathway via protein kinase a signaling. Int J Mol Med 37:901–910. https://doi.org/10.3892/ijmm.2016.2490
Kim YH, Lee YS, Choi EM (2011) Linarin isolated from Buddleja officinalis prevents hydrogen peroxide-induced dysfunction in osteoblastic MC3T3-E1 cells. Cell Immunol 268:112–116. https://doi.org/10.1016/j.cellimm.2011.02.002
Chen X, Ren S, Zhu G, Wang Z, Wen X (2017) Emodin suppresses cadmium-induced osteoporosis by inhibiting osteoclast formation. Environ Toxicol Pharmacol 54:162–168. https://doi.org/10.1016/j.etap.2017.07.007
Karim K, Giribabu N, Salleh N (2021) Marantodes pumilum (Blume) Kuntze (Kacip Fatimah) leaves aqueous extract prevents downregulation of Wnt/β-catenin pathway and upregulation of apoptosis in osteoblasts of estrogen-deficient, diabetes-induced rats. J Ethnopharmacol 280:114236. https://doi.org/10.1016/j.jep.2021.114236
Giribabu N, Karim K, Kilari EK, Salleh N (2017) Phyllanthus niruri leaves aqueous extract improves kidney functions, ameliorates kidney oxidative stress, inflammation, fibrosis and apoptosis and enhances kidney cell proliferation in adult male rats with diabetes mellitus. J Ethnopharmacol 205:123–137. https://doi.org/10.1016/j.jep.2017.05.002
Shahzad H, Giribabu N, Karim K, Kassim NM, Muniandy S, Salleh N (2017) Combinatorial effects of quercetin and sex-steroids on fluid and electrolytes’(Na+, cl-, HCO3-) secretory mechanisms in the uterus of ovariectomised female Sprague-Dawley rats. PLoS One 12:e0172765. https://doi.org/10.1371/journal.pone.0172765
Bechu A, Liao J, Huang C, Ahn C, McKeague M, Ghoshal S, Moores A (2021) Cadmium-containing quantum dots used in electronic displays: implications for toxicity and environmental transformations. ACS Appl Nano Mater 4(8):8417–8428. https://doi.org/10.1021/acsanm.1c01659
Satarug S, Vesey DA, Gobe GC (2017) Current health risk assessment practice for dietary cadmium: data from different countries. Food Chem Toxicol 106:430–445. https://doi.org/10.1016/j.fct.2017.06.013
Rencuzogullari N, Erdogan S (2007) Oral administration of lycopene reverses cadmium-suppressed body weight loss and lipid peroxidation in rats. Biol Trace Elem Res 118:175–183. https://doi.org/10.1007/s12011-007-0027-7
de Buffrénil V, Quilhac A (2021) Basic processes in bone growth. Vertebrate Skeletal Histol Paleohistol:193–220
Rodríguez J, Mandalunis PM (2018) A review of metal exposure and its effects on bone health. J Toxicol 2018:4854152. https://doi.org/10.1155/2018/4854152
Martin TJ, Sims NA (2015) RANKL/OPG; critical role in bone physiology. Rev Endocrine and Metabolic Disorders 16:131–139. https://doi.org/10.1007/s11154-014-9308-6
Qi S, He J, Han H, Zheng H, Jiang H, Hu CY, Zhang Z, Li X (2019) Anthocyanin-rich extract from black rice (Oryza sativa L. japonica) ameliorates diabetic osteoporosis in rats. Food Funct 10:5350–5360. https://doi.org/10.1039/c9fo00681h
Qi SS, Shao ML, Sun Z, Chen SM, Hu YJ, Wang HT, Wei TK, Li XS, Zheng HX (2021) Lycopene ameliorates diabetic osteoporosis via anti-inflammatory, anti-oxidation, and increasing osteoprotegerin/RANKL expression ratio. J Funct Foods 83:104539. https://doi.org/10.1016/j.jff.2021.104539
Domazetovic V, Marcucci G, Iantomasi T, Brandi ML, Vincenzini MT (2017) Oxidative stress in bone remodeling: role of antioxidants. Clinical cases in mineral and bone metabolism : the official journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal Diseases 14:209–216. https://doi.org/10.11138/ccmbm/2017.14.1.209
Winiarska-Mieczan A (2018) Protective effect of tea against lead and cadmium-induced oxidative stress-a review. Biometals 31:909–926. https://doi.org/10.1007/s10534-018-0153-z
Zheng HX, Chen DJ, Zu YX, Wang EZ, Qi SS (2020) Chondroitin sulfate prevents STZ induced diabetic osteoporosis through decreasing blood glucose, antioxidative stress, anti-inflammation and OPG/RANKL expression regulation. Int J Mol Sci 21:5303. https://doi.org/10.3390/ijms21155303
Chen X, Bi M, Yang J, Cai J, Zhang H, Zhu Y, Zheng Y, Liu Q, Shi G, Zhang Z (2021) Cadmium exposure triggers oxidative stress, necroptosis, Th1/Th2 imbalance and promotes inflammation through the TNF-α/NF-κB pathway in swine small intestine. J Hazard Mater 421:126704. https://doi.org/10.1016/j.jhazmat.2021.126704
Yelumalai S, Giribabu N, Karim K, Omar SZ, Salleh NB (2019) In vivo administration of quercetin ameliorates sperm oxidative stress, inflammation, preserves sperm morphology and functions in streptozotocin-nicotinamide induced adult male diabetic rats. Arch Med Sci : AMS 15:240–249. https://doi.org/10.5114/aoms.2018.81038
Jihen EH, Imed M, Fatima H, Abdelhamid K (2009) Protective effects of selenium (se) and zinc (Zn) on cadmium (cd) toxicity in the liver of the rat: effects on the oxidative stress. Ecotoxicol Environ Saf 72:1559–1564. https://doi.org/10.1016/j.ecoenv.2008.12.006
Hong G, Zhou L, Shi X, He W, Wang H, Wei Q, Chen P, Qi L, Tickner J, Lin L, Xu J (2017) Bajijiasu abrogates osteoclast differentiation via the suppression of RANKL signaling pathways through NF-κB and NFAT. Int J Mol Sci 18. https://doi.org/10.3390/ijms18010203
Iotsova V, Caamaño J, Loy J, Yang Y, Lewin A, Bravo R (1997) Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2. Nat Med 3:1285–1289. https://doi.org/10.1038/nm1197-1285
Douglass JD, Dorfman MD, Fasnacht R, Shaffer LD, Thaler JP (2017) Astrocyte IKKβ/NF-κB signaling is required for diet-induced obesity and hypothalamic inflammation. Mol Metab 6:366–373. https://doi.org/10.1016/j.molmet.2017.01.010
Zhang Y, Li Y, Zhang J, Qi X, Cui Y, Yin K, Lin H (2021) Cadmium induced inflammation and apoptosis of porcine epididymis via activating RAF1/MEK/ERK and NF-κB pathways. Toxicol Appl Pharmacol 415:115449. https://doi.org/10.1016/j.taap.2021.115449
Chen X, Zhang S, Xuan Z, Ge D, Chen X, Zhang J, Wang Q, Wu Y, Liu B (2017) The phenolic fraction of Mentha haplocalyx and its constituent linarin ameliorate inflammatory response through inactivation of NF-κB and MAPKs in lipopolysaccharide-induced RAW264.7 cells. Molecules (Basel, Switzerland) 22. https://doi.org/10.3390/molecules22050811
Wang J, Fu B, Lu F, Hu X, Tang J, Huang L (2018) Inhibitory activity of linarin on osteoclastogenesis through receptor activator of nuclear factor κB ligand-induced NF-κB pathway. Biochem Biophys Res Commun 495:2133–2138. https://doi.org/10.1016/j.bbrc.2017.12.091
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We are really grateful to HOD of the Department of Orthopaedics for the help in technical and instrumental support.
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This study was funded by Xi’an Health and Family Planning Commission 2019 “Science and Technology +” Action Plan — Social Development Demonstration Project.
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YY, RC, and JL performed the experiments and collected data. YY, RC, and PZ drafted the manuscript. JF assisted in data collection. XW, YC, and PZ were assisted in data analysis. YY, RC, and BD assisted in the experimental design and edited the manuscript. All authors reviewed and approved the final manuscript.
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Yang, Y., Cheng, R., Liu, J. et al. Linarin Protects against Cadmium-Induced Osteoporosis Via Reducing Oxidative Stress and Inflammation and Altering RANK/RANKL/OPG Pathway. Biol Trace Elem Res 200, 3688–3700 (2022). https://doi.org/10.1007/s12011-021-02967-w
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DOI: https://doi.org/10.1007/s12011-021-02967-w