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Reduced Iron in Diabetic Wounds: An Oxidative Stress-Dependent Role for STEAP3 in Extracellular Matrix Deposition and Remodeling

Wilkinson, Holly N.; Upson, Sophie E.; Banyard, Kayleigh L.; Knight, Robert; Mace, Kimberly A.; Hardman, Matthew J.

Authors

Sophie E. Upson

Kayleigh L. Banyard

Robert Knight

Kimberly A. Mace



Abstract

Iron is crucial for maintaining normal bodily function with well-documented roles in erythropoiesis, hemostasis, and inflammation. Despite this, little is known about the temporal regulation of iron during wound healing, or how iron contributes to wound biology and pathology. In this study, we profiled tissue iron levels across a healing time-course, identifying iron accumulation during late-stage repair. Diabetic murine wounds displayed significantly reduced iron levels, delayed extracellular matrix deposition, and dysregulation of iron gene expression. In vitro studies revealed important cellular roles for iron, promoting both the deposition and remodeling of extracellular proteins. Functional studies identified oxidative stress-dependent upregulation of the iron-converting metalloreductase, STEAP3, as a key mediator of extracellular matrix production. Taken together, these data reveal a mechanistic role for iron in facilitating the remodeling stage of wound healing. Indeed, targeting tissue iron could be a promising future strategy to tackle the development and progression of chronic wounds.

Citation

Wilkinson, H. N., Upson, S. E., Banyard, K. L., Knight, R., Mace, K. A., & Hardman, M. J. (2019). Reduced Iron in Diabetic Wounds: An Oxidative Stress-Dependent Role for STEAP3 in Extracellular Matrix Deposition and Remodeling. Journal of Investigative Dermatology, 139(11), 2368-2377.e7. https://doi.org/10.1016/j.jid.2019.05.014

Journal Article Type Article
Acceptance Date May 23, 2019
Online Publication Date Jun 7, 2019
Publication Date Nov 1, 2019
Deposit Date Jun 20, 2019
Publicly Available Date Dec 8, 2019
Journal Journal of Investigative Dermatology
Print ISSN 0022-202x
Electronic ISSN 1523-1747
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 139
Issue 11
Pages 2368-2377.e7
DOI https://doi.org/10.1016/j.jid.2019.05.014
Keywords Cell Biology; Biochemistry; Molecular Biology; Dermatology
Public URL https://hull-repository.worktribe.com/output/2018862
Publisher URL https://www.sciencedirect.com/science/article/pii/S0022202X19316331

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