LPS-stimulated Inflammatory Environment Inhibits BMP-2-induced Osteoblastic Differentiation Through Crosstalk Between TLR4/MyD88/NF-κB and BMP/Smad Signaling

Overview

Journal Stem Cells Dev

Date 2013 Sep 21

PMID 24050190

Citations 44

Authors

Ru-Lin Huang

Yuwen Yuan

Gang-Ming Zou

Guangwang Liu

Jun Tu

Qingfeng Li

Affiliations

Soon will be listed here.

Abstract

Bone morphogenetic protein-2 (BMP-2) is a novel differentiation factor that is capable of inducing osteoblast differentiation and bone formation, making it an attractive option in treatment of bone defects, fractures, and spine fusions. Inflammation, which was a common situation during bone healing, is recognized to inhibit osteogenic differentiation and bone formation. However, the effect of inflammation on BMP-2-induced osteoblastic differentiation remains ambiguous. In this study, we showed that an inflammatory environment triggered by lipopolysaccharide (LPS) in vitro would suppress BMP-2-induced osteogenic differentiation of bone marrow mesenchymal stem cells, which represented by decreased alkaline phosphatase (ALPase) activity and down-regulated osteogenic genes. In addition, LPS activated nuclear factor-κB (NF-κB) via a TLR4/MyD88-dependent manner and inhibited BMP-2-induced phosphorylation and nuclear translocation of Smad1/5/8. The blocking of NF-κB signaling by pretreatment with specific inhibitors such as BAY-11-7082, TPCK and PDTC, or by transfection with plasmids encoding p65 siRNA or IκBα siRNA could significantly reverse the inhibitory effect of LPS on BMP-2-induced BMP/Smad signaling and osteogenic differentiation. By contrast, even without stimulation of LPS, overexpression of p65 gene showed obvious inhibitory effects on BMP-2-induced BMP/Smad signaling and ALPase activity. These data indicate that the LPS-mediated inflammatory environment inhibits BMP-2-induced osteogenic differentiation, and that the crosstalk between TLR4/MyD88/NF-κB and BMP/Smad signaling negatively modulates the osteoinductive capacity of BMP-2.

Citing Articles

Phlorofucofuroeckol-A: A Natural Compound with Potential to Attenuate Inflammatory Diseases Caused by Airborne Fine Dust.

Lee E, Yim S, Kang S, Ahn B, Kim C, Lee M Medicina (Kaunas). 2025; 61(1).

PMID: 39859147 PMC: 11767036. DOI: 10.3390/medicina61010165.

Triple-Combination Therapy with a Multifunctional Yolk-Shell Nanozyme Au@CeO Loaded with Dimethyl Fumarate for Periodontitis.

Li T, Shu M, Zhu C, Liu Q, Li Y, Wang R Adv Sci (Weinh). 2024; 12(7):e2413891.

PMID: 39716921 PMC: 11831482. DOI: 10.1002/advs.202413891.

Inhibition of lipopolysaccharide-induced NF-κB maintains osteogenesis of dental pulp and periodontal ligament stem cells.

Sandra F, Sudiono J, Chouw A, Celinna M, Dewi N, Djamil M Braz Oral Res. 2024; 38:e037.

PMID: 38747824 PMC: 11376659. DOI: 10.1590/1807-3107bor-2024.vol38.0037.

The role of toll-like receptors in orchestrating osteogenic differentiation of mesenchymal stromal cells and osteoimmunology.

Liu X, Zhou Z, Zeng W, Zeng Q, Zhang X Front Cell Dev Biol. 2023; 11:1277686.

PMID: 37941898 PMC: 10629627. DOI: 10.3389/fcell.2023.1277686.

Remodeling periodontal osteoimmune microenvironment through MAPK/NFκB phosphorylation pathway of macrophage via intelligent ROS scavenging.

Qiu X, Peng H, Zhao Y, Yu Y, Yang J, Liu C Hum Cell. 2023; 36(6):1991-2005.

PMID: 37695495 DOI: 10.1007/s13577-023-00979-3.

References

Montzka K, Fuhrmann T, Muller-Ehmsen J, Woltje M, Brook G . Growth factor and cytokine expression of human mesenchymal stromal cells is not altered in an in vitro model of tissue damage. Cytotherapy. 2010; 12(7):870-80. DOI: 10.3109/14653249.2010.501789. View

Yamashita M, Otsuka F, Mukai T, Otani H, Inagaki K, Miyoshi T . Simvastatin antagonizes tumor necrosis factor-alpha inhibition of bone morphogenetic proteins-2-induced osteoblast differentiation by regulating Smad signaling and Ras/Rho-mitogen-activated protein kinase pathway. J Endocrinol. 2008; 196(3):601-13. DOI: 10.1677/JOE-07-0532. View

Hess K, Ushmorov A, Fiedler J, Brenner R, Wirth T . TNFalpha promotes osteogenic differentiation of human mesenchymal stem cells by triggering the NF-kappaB signaling pathway. Bone. 2009; 45(2):367-76. DOI: 10.1016/j.bone.2009.04.252. View

Yamazaki M, Fukushima H, Shin M, Katagiri T, Doi T, Takahashi T . Tumor necrosis factor alpha represses bone morphogenetic protein (BMP) signaling by interfering with the DNA binding of Smads through the activation of NF-kappaB. J Biol Chem. 2009; 284(51):35987-95. PMC: 2791026. DOI: 10.1074/jbc.M109.070540. View

Lu Y, Yeh W, Ohashi P . LPS/TLR4 signal transduction pathway. Cytokine. 2008; 42(2):145-151. DOI: 10.1016/j.cyto.2008.01.006. View

Shaik-Dasthagirisaheb Y, Huang N, Baer M, Gibson 3rd F . Role of MyD88-dependent and MyD88-independent signaling in Porphyromonas gingivalis-elicited macrophage foam cell formation. Mol Oral Microbiol. 2012; 28(1):28-39. PMC: 3543481. DOI: 10.1111/omi.12003. View

Oeckinghaus A, Hayden M, Ghosh S . Crosstalk in NF-κB signaling pathways. Nat Immunol. 2011; 12(8):695-708. DOI: 10.1038/ni.2065. View

Mountziaris P, Mikos A . Modulation of the inflammatory response for enhanced bone tissue regeneration. Tissue Eng Part B Rev. 2008; 14(2):179-86. PMC: 2962857. DOI: 10.1089/ten.teb.2008.0038. View

Sonomoto K, Yamaoka K, Oshita K, Fukuyo S, Zhang X, Nakano K . Interleukin-1β induces differentiation of human mesenchymal stem cells into osteoblasts via the Wnt-5a/receptor tyrosine kinase-like orphan receptor 2 pathway. Arthritis Rheum. 2012; 64(10):3355-63. DOI: 10.1002/art.34555. View

10.

Feng X, Feng G, Xing J, Shen B, Li L, Tan W . TNF-α triggers osteogenic differentiation of human dental pulp stem cells via the NF-κB signalling pathway. Cell Biol Int. 2013; 37(12):1267-75. DOI: 10.1002/cbin.10141. View

11.

Rundle C, Wang H, Yu H, Chadwick R, Davis E, Wergedal J . Microarray analysis of gene expression during the inflammation and endochondral bone formation stages of rat femur fracture repair. Bone. 2005; 38(4):521-9. DOI: 10.1016/j.bone.2005.09.015. View

12.

Brown J, Wang H, Hajishengallis G, Martin M . TLR-signaling networks: an integration of adaptor molecules, kinases, and cross-talk. J Dent Res. 2010; 90(4):417-27. PMC: 3075579. DOI: 10.1177/0022034510381264. View

13.

Lacey D, Simmons P, Graves S, Hamilton J . Proinflammatory cytokines inhibit osteogenic differentiation from stem cells: implications for bone repair during inflammation. Osteoarthritis Cartilage. 2009; 17(6):735-42. DOI: 10.1016/j.joca.2008.11.011. View

14.

Ghosh S, Hayden M . New regulators of NF-kappaB in inflammation. Nat Rev Immunol. 2008; 8(11):837-48. DOI: 10.1038/nri2423. View

15.

Zhao L, Huang J, Zhang H, Wang Y, Matesic L, Takahata M . Tumor necrosis factor inhibits mesenchymal stem cell differentiation into osteoblasts via the ubiquitin E3 ligase Wwp1. Stem Cells. 2011; 29(10):1601-10. PMC: 3708970. DOI: 10.1002/stem.703. View

16.

Thomas M, Puleo D . Infection, inflammation, and bone regeneration: a paradoxical relationship. J Dent Res. 2011; 90(9):1052-61. PMC: 3169879. DOI: 10.1177/0022034510393967. View

17.

Bischoff D, Zhu J, Makhijani N, Kumar A, Yamaguchi D . Angiogenic CXC chemokine expression during differentiation of human mesenchymal stem cells towards the osteoblastic lineage. J Cell Biochem. 2007; 103(3):812-24. DOI: 10.1002/jcb.21450. View

18.

Matsumoto Y, Otsuka F, Takano M, Mukai T, Yamanaka R, Takeda M . Estrogen and glucocorticoid regulate osteoblast differentiation through the interaction of bone morphogenetic protein-2 and tumor necrosis factor-alpha in C2C12 cells. Mol Cell Endocrinol. 2010; 325(1-2):118-27. DOI: 10.1016/j.mce.2010.05.004. View

19.

Schett G . Effects of inflammatory and anti-inflammatory cytokines on the bone. Eur J Clin Invest. 2011; 41(12):1361-6. DOI: 10.1111/j.1365-2362.2011.02545.x. View

20.

Li Y, Li A, Strait K, Zhang H, Nanes M, Weitzmann M . Endogenous TNFalpha lowers maximum peak bone mass and inhibits osteoblastic Smad activation through NF-kappaB. J Bone Miner Res. 2007; 22(5):646-55. DOI: 10.1359/jbmr.070121. View