Bone Morphogenetic Protein 4 is Involved in Cadmium-associated Bone Damage

Overview

Journal Toxicol Sci

Publisher Oxford University Press

Specialty Toxicology

Date 2022 Dec 1

PMID 36453845

Authors

Yu Wan

Li-Jun Mo

Lu Wu

Dong-Li Li

Jia Song

You-Kun Hu

Hai-Bin Huang

Qin-Zhi Wei

Da-Peng Wang

Jian-Min Qiu

Zi-Ji Zhang

Qi-Zhan Liu

Xing-Fen Yang

Affiliations

Soon will be listed here.

Abstract

Cadmium (Cd) is a well-characterized bone toxic agent and can induce bone damage via inhibiting osteogenic differentiation. Bone morphogenetic protein (BMP)/SMAD signaling pathway can mediate osteogenic differentiation, but the association between Cd and BMP/SMAD signaling pathway is yet to be illuminated. To understand what elements of BMPs and SMADs are affected by Cd to influence osteogenic differentiation and if BMPs can be the biomarkers of which Cd-induced osteoporosis, human bone marrow mesenchymal stem cells (hBMSCs) were treated with cadmium chloride (CdCl2) in vitro to detect the expression of BMPs and SMADs, and 134 subjects were enrolled to explore if the BMPs can be potential biomarkers of Cd-associated bone damage. Our results showed that Cd exposure significantly promoted the adipogenic differentiation of hBMSCs and inhibited its osteogenic differentiation by inhibiting the expression of BMP-2/4, SMAD4, and p-SMAD1/5/9 complex. And mediation analyses yielded that BMP-4 mediated 39.32% (95% confidence interval 7.47, 85.00) of the total association between the Cd and the risk of Cd-associated bone damage. Moreover, during differentiation, BMP-4 had the potential to enhance mineralization compared with CdCl2 only group. These results reveal that BMP-4 can be a diagnostic biomarker and therapeutic target for Cd-associated bone damage.

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References

Haddouti E, Randau T, Hilgers C, Masson W, Pflugmacher R, Burger C . Vertebral Bone Marrow-Derived Mesenchymal Stromal Cells from Osteoporotic and Healthy Patients Possess Similar Differentiation Properties In Vitro. Int J Mol Sci. 2020; 21(21). PMC: 7663957. DOI: 10.3390/ijms21218309. View

Luu H, Song W, Luo X, Manning D, Luo J, Deng Z . Distinct roles of bone morphogenetic proteins in osteogenic differentiation of mesenchymal stem cells. J Orthop Res. 2007; 25(5):665-77. DOI: 10.1002/jor.20359. View

Peng Y, Kang Q, Luo Q, Jiang W, Si W, Liu B . Inhibitor of DNA binding/differentiation helix-loop-helix proteins mediate bone morphogenetic protein-induced osteoblast differentiation of mesenchymal stem cells. J Biol Chem. 2004; 279(31):32941-9. DOI: 10.1074/jbc.M403344200. View

Dalmo E, Johansson P, Niklasson M, Gustavsson I, Nelander S, Westermark B . Growth-Inhibitory Activity of Bone Morphogenetic Protein 4 in Human Glioblastoma Cell Lines Is Heterogeneous and Dependent on Reduced SOX2 Expression. Mol Cancer Res. 2020; 18(7):981-991. DOI: 10.1158/1541-7786.MCR-19-0638. View

Zhang Y, Musci T, Derynck R . The tumor suppressor Smad4/DPC 4 as a central mediator of Smad function. Curr Biol. 1997; 7(4):270-6. DOI: 10.1016/s0960-9822(06)00123-0. View

Parrow N, Fleming R . Bone morphogenetic proteins as regulators of iron metabolism. Annu Rev Nutr. 2014; 34:77-94. PMC: 7713507. DOI: 10.1146/annurev-nutr-071813-105646. View

Yu Y, Yang J, Chapman-Sheath P, Walsh W . TGF-beta, BMPS, and their signal transducing mediators, Smads, in rat fracture healing. J Biomed Mater Res. 2002; 60(3):392-7. DOI: 10.1002/jbm.1289. View

Li Y, He X, Li Y, He J, Anderstam B, Andersson G . Nicotinamide phosphoribosyltransferase (Nampt) affects the lineage fate determination of mesenchymal stem cells: a possible cause for reduced osteogenesis and increased adipogenesis in older individuals. J Bone Miner Res. 2011; 26(11):2656-64. DOI: 10.1002/jbmr.480. View

Moerman E, Teng K, Lipschitz D, Lecka-Czernik B . Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: the role of PPAR-gamma2 transcription factor and TGF-beta/BMP signaling pathways. Aging Cell. 2004; 3(6):379-89. PMC: 1850101. DOI: 10.1111/j.1474-9728.2004.00127.x. View

10.

Wang H, Chen H, Chernick M, Li D, Ying G, Yang J . Selenomethionine exposure affects chondrogenic differentiation and bone formation in Japanese medaka (Oryzias latipes). J Hazard Mater. 2019; 387:121720. DOI: 10.1016/j.jhazmat.2019.121720. View

11.

Huang D, Hou X, Zhang D, Zhang Q, Yan C . Two novel polysaccharides from rhizomes of Cibotium barometz promote bone formation via activating the BMP2/SMAD1 signaling pathway in MC3T3-E1 cells. Carbohydr Polym. 2020; 231:115732. DOI: 10.1016/j.carbpol.2019.115732. View

12.

Hu L, Yin C, Zhao F, Ali A, Ma J, Qian A . Mesenchymal Stem Cells: Cell Fate Decision to Osteoblast or Adipocyte and Application in Osteoporosis Treatment. Int J Mol Sci. 2018; 19(2). PMC: 5855582. DOI: 10.3390/ijms19020360. View

13.

Matsumoto Y, Otsuka F, Takano-Narazaki M, Katsuyama T, Nakamura E, Tsukamoto N . Estrogen facilitates osteoblast differentiation by upregulating bone morphogenetic protein-4 signaling. Steroids. 2013; 78(5):513-20. DOI: 10.1016/j.steroids.2013.02.011. View

14.

Mamun M, Hosen M, Islam K, Khatun A, Alam M, Al-Bari M . Tridax procumbens flavonoids promote osteoblast differentiation and bone formation. Biol Res. 2015; 48:65. PMC: 4652438. DOI: 10.1186/s40659-015-0056-1. View

15.

Nambunmee K, Honda R, Nishijo M, Swaddiwudhipong W, Nakagawa H, Ruangyuttikarn W . Bone resorption acceleration and calcium reabsorption impairment in a Thai population with high cadmium exposure. Toxicol Mech Methods. 2009; 20(1):7-13. DOI: 10.3109/15376510903452941. View

16.

Ozkan Z, Deveci D, Onalan Etem E, Yuce H . Lack of effect of bone morphogenetic protein 2 and 4 gene polymorphisms on bone density in postmenopausal Turkish women. Genet Mol Res. 2010; 9(4):2311-6. DOI: 10.4238/vol9-4gmr922. View

17.

Rodriguez J, Mandalunis P . Effect of cadmium on bone tissue in growing animals. Exp Toxicol Pathol. 2016; 68(7):391-7. DOI: 10.1016/j.etp.2016.06.001. View

18.

Yu Y, Bliss J, Bruce W, Walsh W . Bone morphogenetic proteins and Smad expression in ovine tendon-bone healing. Arthroscopy. 2007; 23(2):205-10. DOI: 10.1016/j.arthro.2006.08.023. View

19.

Cheng H, Liu S, Li W, Zhao X, Zhao X, Cheng M . Arsenic trioxide regulates adipogenic and osteogenic differentiation in bone marrow MSCs of aplastic anemia patients through BMP4 gene. Acta Biochim Biophys Sin (Shanghai). 2015; 47(9):673-9. DOI: 10.1093/abbs/gmv065. View

20.

van den Wijngaard A, Mulder W, Dijkema R, Boersma C, Mosselman S, van Zoelen E . Antiestrogens specifically up-regulate bone morphogenetic protein-4 promoter activity in human osteoblastic cells. Mol Endocrinol. 2000; 14(5):623-33. DOI: 10.1210/mend.14.5.0463. View