Giuseppina Mancino1, Annarita Sibilio1, Cristina Luongo2, Emery Di Cicco1, Caterina Miro2, Annunziata Gaetana Cicatiello1, Annarita Nappi2, Serena Sagliocchi1, Raffaele Ambrosio3, Maria Angela De Stefano1, Daniela Di Girolamo1, Tommaso Porcelli1, Melania Murolo1, Federica Saracino1, Giuseppe Perruolo4, Pietro Formisano4, Mariano Stornaiuolo5, Monica Dentice1,6. 1. Department of Clinical Medicine and Surgery, Research Unit (URT) Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Council of Research (CNR); University of Naples "Federico II," Naples, Italy. 2. Department of Public Health, and Research Unit (URT) Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Council of Research (CNR); University of Naples "Federico II," Naples, Italy. 3. IRCCS SDN, Naples, Italy. 4. Department of Department of Translational Medicine, Research Unit (URT) Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Council of Research (CNR); University of Naples "Federico II," Naples, Italy. 5. Department of Pharmacy; Research Unit (URT) Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Council of Research (CNR); University of Naples "Federico II," Naples, Italy. 6. CEINGE-Biotecnologie Avanzate Scarl, Naples, Italy.
Abstract
Background: Thyroid hormones (THs) are key regulators of development, tissue differentiation, and maintenance of metabolic balance in virtually every cell of the body. Accordingly, severe alteration of TH action during fetal life leads to permanent deficits in humans. The skin is among the few adult tissues expressing the oncofetal protein type 3 deiodinase (D3), the TH inactivating enzyme. Here, we demonstrate that D3 is dynamically regulated during epidermal ontogenesis. Methods: To investigate the function of D3 in a postdevelopmental context, we used a mouse model of conditional epidermal-specific D3 depletion. Loss of D3 resulted in tissue hypoplasia and enhanced epidermal differentiation in a cell-autonomous manner. Results: Accordingly, wound healing repair and hair follicle cycle were altered in the D3-depleted epidermis. Further, in vitro ablation of D3 in primary culture of keratinocytes indicated that various markers of stratified epithelial layers were upregulated, thereby confirming the pro-differentiative action of D3 depletion and the consequent increased intracellular triiodothyronine levels. Notably, loss of D3 reduced the clearance of systemic TH in vivo, thereby demonstrating the critical requirement for epidermal D3 in the maintenance of TH homeostasis. Conclusion: In conclusion, our results show that the D3 enzyme is a key TH-signaling component in the skin, thereby providing a striking example of a physiological context for deiodinase-mediated TH metabolism, as well as a rationale for therapeutic manipulation of deiodinases in pathophysiological contexts.
Background: Thyroid hormones (THs) are key regulators of development, tissue differentiation, and maintenance of metabolic balance in virtually every cell of the body. Accordingly, severe alteration of TH action during fetal life leads to permanent deficits in humans. The skin is among the few adult tissues expressing the oncofetal protein type 3 deiodinase (D3), the TH inactivating enzyme. Here, we demonstrate that D3 is dynamically regulated during epidermal ontogenesis. Methods: To investigate the function of D3 in a postdevelopmental context, we used a mouse model of conditional epidermal-specific D3 depletion. Loss of D3 resulted in tissue hypoplasia and enhanced epidermal differentiation in a cell-autonomous manner. Results: Accordingly, wound healing repair and hair follicle cycle were altered in the D3-depleted epidermis. Further, in vitro ablation of D3 in primary culture of keratinocytes indicated that various markers of stratified epithelial layers were upregulated, thereby confirming the pro-differentiative action of D3 depletion and the consequent increased intracellular triiodothyronine levels. Notably, loss of D3 reduced the clearance of systemic TH in vivo, thereby demonstrating the critical requirement for epidermal D3 in the maintenance of TH homeostasis. Conclusion: In conclusion, our results show that the D3 enzyme is a key TH-signaling component in the skin, thereby providing a striking example of a physiological context for deiodinase-mediated TH metabolism, as well as a rationale for therapeutic manipulation of deiodinases in pathophysiological contexts.