Discovery about the Effects of Glucocorticoids in Wound Closure Could Open Wider Possibilities
Even after years of careful research pointed investigators toward a novel pathway involved in wound healing, Marjana Tomic-Canic, Ph.D., and her team were still surprised. The specific molecule and the potential scope of applications to other autoimmune and inflammatory processes beyond the skin were both unexpected.
Glucocorticoid hormones are naturally synthesized in a body and have important biological roles including stress-response. In addition, many dermatologists and other physicians commonly prescribe glucocorticoids for their anti-inflammatory effects, but unanswered questions remain. Their specific mechanism of action and ways to mitigate potential side effects with prolonged use, including impaired wound healing, are unknown.
Lead study author Ivan Jozic, Ph.D., Tomic-Canic and their colleagues sought answers to these questions. They discovered that glucocorticoids can drive overgrowth of tissue including the one around the edges of a wound and inhibit healing by blocking the movement of keratinocytes.
“The notion that an anti-inflammatory signal mediated by cortisol, which is normally triggered by wounding, converts into a pathological growth signal that leads to overgrowth of the tissue and, at the same time, blocks cell migration, is a fundamental new insight into the pathophysiology of wound healing,” said Tomic-Canic, professor of dermatology and Director of the Wound Healing and Regenerative Medicine Research Program at the University of Miami Miller School of Medicine.
One of the surprises of the study, which is published in the Journal of Investigative Dermatology, is the identity of this bad actor. “Cortisol was the last molecule to be suspected for the hyperproliferation of keratinocytes,” Tomic-Canic said.
The investigators uncovered the new signaling pathway by studying skin, retinal and bronchial human epithelial cells and fibroblasts. They found that glucocorticoids rapidly signal from cell membrane, triggering a “Wnt-like pathway.” This signaling cascade includes membranous glucocorticoid receptor (mbGR), phospholipase C (PLC) and protein kinase C (PKC) that activates ?-catenin to become nuclear and act as a transcription factor. Components of a Wnt pathway are key regulators of cell differentiation and proliferation. Deregulation of Wnt signaling is implicated in many skin, cardiovascular and neuronal diseases, as well as various forms of cancer.
So even though cortisol can spur hyperproliferation of keratinocytes, the mbGR/PLC/PKC pathway can inhibit their migration into a wound and inhibit healing.
“The concept that a stress signal [cortisol] can convert into a growth signal [Wnt] is paradigm changing and was certainly a surprise,” Tomic-Canic said.
Interestingly, the researchers found the same pathway in fibroblast cells, suggesting a wider role for this pathway, one that could someday lead to therapeutic targets for many other inflammatory-driven conditions. “The impact may be tremendous,” Tomic-Canic said, “if one takes into account the relative abundance of glucocorticoid receptors and PKC signaling in tissues and systemic circulating presence of glucocorticoids, our discovery of PKC activation by mbGR provides new insights into mechanisms by which systemic and local corticosteroids may contribute to PKC-mediated effects and offer insights into pathophysiology of numerous diseases.”
For example, blocking mbGR signaling produced by endogenous cortisol can accelerate epithelialization and subsequent wound healing, “which suggests that selective targeting of mbGR may have therapeutic effects or may alleviate multiple side effects of prolonged glucocorticoid therapy,” Tomic-Canic said. “This introduces novel concepts that may result in using skin as a target organ to finely tune circulating cortisol levels in order to attenuate various inflammatory and autoimmune diseases.”
A 3M Fellowship from the Wound Healing Foundation granted to Jozic, a postdoctoral fellow, supported this research. The full findings appear in the Journal of Investigative Dermatology.