Aldosterone and Ligands of Elastin Receptor Trigger the Common Signaling Pathway Resulting in Deposition of New Elastic Fibers by Fibroblasts Derived from Patients with Severe Stretch Marks and Dermal Scars
Thomas F. Mitts, M.D.1, Aleksander Hinek, M.D., PhD2.
1Human Matrix Sciences, LLC, Visalia, CA, USA, 2University of Toronto, Hospital for Sick Children, Toronto, ON, Canada.
We have recently established that mineralo-corticosteroid aldosterone triggers the up-regulation in collagen and elastin deposition by cardiac stromal cells and modulate formation of resilient post-infarct scars. Since the skin fibroblasts also express MR, we now tested whether aldosterone would also modulate deposition of the skin matrix. Our studies employed cultures of human skin fibroblasts and organ cultures of skin explants derived from normal individuals and patients with stretch marks and dermal scars. We found that treatment of normal skin fibroblasts with aldosterone (10-50nM) in addition to stimulation of collagen-I gene expression, also induced a dose dependent increase in levels of elastin mRNA and a consequent increase in deposition of insoluble elastin assembled in elastic fibers. We also found that pre-treatment of cells with a MR antagonist, spironolactone (2µM), which inhibited the aldosterone-induced collagen-I expression, intensified the stimulatory effect of aldosterone elastin gene expression and a net deposition of elastin. A similar pro-elastogenic effect of aldosterone, intensified by spironolactone has been also observed in cultured skin explants derived from stretch marks and dermal scars. These data suggested that aldosterone, stimulates elastogenesis via the MR-independent pathway. Moreover, we have established that this pro-elastogenic, MR-independent action of aldosterone involves facilitation of intracellular signals induced by the insulin-growth factor receptor-I (IGF-IR). Additionally, we have also established that the potent pro-elastogenic effect of our novel peptide constructs containing the elastin receptor ligand domains (EBPLs), also depends on the downstream cross-activation of IGF-IR-mediated signaling. Because, both aldosterone (applied with and without spironolactone) and EBPLs enhanced a net elastogenesis, even in cultures of fibroblasts and skin explants derived from patients with severe stretch marks and dermal scar tissue, we postulate that combination of these two factors should be considered in therapies aimed at boosting elastic fibers formation in adult human skin. Preliminary clinical data demonstrating beneficial effects of these compounds applied in the topical creams endorse our claim.