Dose Effect of Tumor Necrosis Factor-alpha on in Vitro Osteogenic Differentiation of Mesenchymal Stem Cells on Biodegradable Polymeric Microfiber Scaffolds

Overview

Journal Biomaterials

Specialty Biomedical Engineering

Date 2009 Dec 8

PMID 19963268

Citations 24

Authors

Paschalia M Mountziaris

Stephanie N Tzouanas

Antonios G Mikos

Affiliations

Soon will be listed here.

Abstract

This study presents a first step in the development of a bone tissue engineering strategy to trigger enhanced osteogenesis by modulating inflammation. This work focused on characterizing the effects of the concentration of a pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-alpha), on osteogenic differentiation of mesenchymal stem cells (MSCs) grown in a 3D culture system. MSC osteogenic differentiation is typically achieved in vitro through a combination of osteogenic supplements that include the anti-inflammatory corticosteroid dexamethasone. Although simple, the use of dexamethasone is not clinically realistic, and also hampers in vitro studies of the role of inflammatory mediators in wound healing. In this study, MSCs were pre-treated with dexamethasone to induce osteogenic differentiation, and then cultured in biodegradable electrospun poly(epsilon-caprolactone) (PCL) scaffolds, which supported continued MSC osteogenic differentiation in the absence of dexamethasone. Continuous delivery of 0.1 ng/mL of recombinant rat TNF-alpha suppressed osteogenic differentiation of rat MSCs over 16 days, which was likely the result of residual dexamethasone antagonizing TNF-alpha signaling. Continuous delivery of a higher dose, 5 ng/mL TNF-alpha, stimulated osteogenic differentiation for a few days, and 50 ng/mL TNF-alpha resulted in significant mineralized matrix deposition over the course of the study. These findings suggest that the pro-inflammatory cytokine TNF-alpha stimulates osteogenic differentiation of MSCs, an effect that can be blocked by the presence of anti-inflammatory agents like dexamethasone, with significant implications on the interplay between inflammation and tissue regeneration.

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References

Gomes M, Bossano C, Johnston C, Reis R, Mikos A . In vitro localization of bone growth factors in constructs of biodegradable scaffolds seeded with marrow stromal cells and cultured in a flow perfusion bioreactor. Tissue Eng. 2006; 12(1):177-88. DOI: 10.1089/ten.2006.12.177. View

Young S, Patel Z, Kretlow J, Murphy M, Mountziaris P, Baggett L . Dose effect of dual delivery of vascular endothelial growth factor and bone morphogenetic protein-2 on bone regeneration in a rat critical-size defect model. Tissue Eng Part A. 2009; 15(9):2347-62. PMC: 2792218. DOI: 10.1089/ten.tea.2008.0510. 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

Prockop D . Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997; 276(5309):71-4. DOI: 10.1126/science.276.5309.71. View

Balga R, Wetterwald A, Portenier J, Dolder S, Mueller C, Hofstetter W . Tumor necrosis factor-alpha: alternative role as an inhibitor of osteoclast formation in vitro. Bone. 2006; 39(2):325-35. DOI: 10.1016/j.bone.2006.02.056. View

Paula-Silva F, Ghosh A, Silva L, Kapila Y . TNF-alpha promotes an odontoblastic phenotype in dental pulp cells. J Dent Res. 2009; 88(4):339-44. PMC: 3144054. DOI: 10.1177/0022034509334070. View

Pham Q, Sharma U, Mikos A . Electrospinning of polymeric nanofibers for tissue engineering applications: a review. Tissue Eng. 2006; 12(5):1197-211. DOI: 10.1089/ten.2006.12.1197. View

Gerstenfeld L, Cho T, Kon T, Aizawa T, Tsay A, Fitch J . Impaired fracture healing in the absence of TNF-alpha signaling: the role of TNF-alpha in endochondral cartilage resorption. J Bone Miner Res. 2003; 18(9):1584-92. DOI: 10.1359/jbmr.2003.18.9.1584. View

Rhen T, Cidlowski J . Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N Engl J Med. 2005; 353(16):1711-23. DOI: 10.1056/NEJMra050541. View

10.

Guo R, Yamashita M, Zhang Q, Zhou Q, Chen D, Reynolds D . Ubiquitin ligase Smurf1 mediates tumor necrosis factor-induced systemic bone loss by promoting proteasomal degradation of bone morphogenetic signaling proteins. J Biol Chem. 2008; 283(34):23084-92. PMC: 2517001. DOI: 10.1074/jbc.M709848200. View

11.

Gerstenfeld L, Cullinane D, Barnes G, Graves D, Einhorn T . Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. J Cell Biochem. 2003; 88(5):873-84. DOI: 10.1002/jcb.10435. View

12.

Pape H, Schmidt R, Rice J, van Griensven M, Das Gupta R, Krettek C . Biochemical changes after trauma and skeletal surgery of the lower extremity: quantification of the operative burden. Crit Care Med. 2000; 28(10):3441-8. DOI: 10.1097/00003246-200010000-00012. View

13.

Hecht J, Kuhl H, Haas S, Bauer S, Poustka A, Lienau J . Gene identification and analysis of transcripts differentially regulated in fracture healing by EST sequencing in the domestic sheep. BMC Genomics. 2006; 7:172. PMC: 1578570. DOI: 10.1186/1471-2164-7-172. View

14.

Pham Q, Sharma U, Mikos A . Electrospun poly(epsilon-caprolactone) microfiber and multilayer nanofiber/microfiber scaffolds: characterization of scaffolds and measurement of cellular infiltration. Biomacromolecules. 2006; 7(10):2796-805. DOI: 10.1021/bm060680j. View

15.

Gerstenfeld L, Cho T, Kon T, Aizawa T, Cruceta J, Graves B . Impaired intramembranous bone formation during bone repair in the absence of tumor necrosis factor-alpha signaling. Cells Tissues Organs. 2001; 169(3):285-94. DOI: 10.1159/000047893. View

16.

Kon T, Cho T, Aizawa T, Yamazaki M, Nooh N, Graves D . Expression of osteoprotegerin, receptor activator of NF-kappaB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing. J Bone Miner Res. 2001; 16(6):1004-14. DOI: 10.1359/jbmr.2001.16.6.1004. View

17.

Ding J, Ghali O, Lencel P, Broux O, Chauveau C, Devedjian J . TNF-alpha and IL-1beta inhibit RUNX2 and collagen expression but increase alkaline phosphatase activity and mineralization in human mesenchymal stem cells. Life Sci. 2009; 84(15-16):499-504. DOI: 10.1016/j.lfs.2009.01.013. View

18.

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

19.

Iqbal J, Sun L, Kumar T, Blair H, Zaidi M . Follicle-stimulating hormone stimulates TNF production from immune cells to enhance osteoblast and osteoclast formation. Proc Natl Acad Sci U S A. 2006; 103(40):14925-30. PMC: 1595452. DOI: 10.1073/pnas.0606805103. View

20.

Taichman R, Hauschka P . Effects of interleukin-1 beta and tumor necrosis factor-alpha on osteoblastic expression of osteocalcin and mineralized extracellular matrix in vitro. Inflammation. 1992; 16(6):587-601. DOI: 10.1007/BF00919342. View