ABSTRACT
The EDA gene encodes ectodysplasin A (Eda), which if mutated causes X-linked hypohidrotic ectodermal dysplasia (XLHED) disease in humans. Ocular surface changes occur in XLHED patients whereas its underlying mechanism remains elusive. In this study, we found Eda was highly expressed in meibomian glands, and it was detected in human tears but not serum. Corneal epithelial integrity was defective and the thickness was reduced in the early postnatal stage of Eda mutant Tabby mice. Corneal epithelial cell proliferation decreased and the epithelial wound healing was delayed in Tabby mice, whereas it was restored by exogenous Eda. Eda exposure promoted mouse corneal epithelial wound healing during organ culture, whereas scratch wound assay showed that it did not affect human corneal epithelial cell line migration. Epidermal growth factor receptor (EGFR), phosphorylated EGFR (p-EGFR), and phosphorylated ERK1/2 (p-ERK) were down-regulated in Tabby mice corneal epithelium. Eda treatment up-regulated the expression of Ki67, EGFR, p-EGFR, and p-ERK in human corneal epithelial cells in a dose-dependent manner. In conclusion, Eda protein can be secreted from meibomian glands and promotes corneal epithelial cell proliferation through regulation of the EGFR signaling pathway. Eda release into the tears plays an essential role in the maintenance of corneal epithelial homeostasis.
Subject(s)
Ectodermal Dysplasia 1, Anhidrotic/metabolism , Ectodysplasins/metabolism , Epithelium, Corneal/metabolism , Eyelid Diseases/metabolism , Meibomian Glands/metabolism , Adolescent , Adult , Animals , Cell Line , Cell Movement/drug effects , Cell Proliferation/drug effects , Ectodermal Dysplasia 1, Anhidrotic/drug therapy , Ectodermal Dysplasia 1, Anhidrotic/pathology , Ectodermal Dysplasia 1, Anhidrotic/physiopathology , Ectodysplasins/genetics , Ectodysplasins/pharmacology , Ectodysplasins/therapeutic use , Epithelium, Corneal/drug effects , Epithelium, Corneal/injuries , Epithelium, Corneal/pathology , ErbB Receptors/metabolism , Eyelid Diseases/pathology , Eyelid Diseases/physiopathology , Female , Humans , Male , Meibomian Glands/pathology , Meibomian Glands/physiopathology , Mice, Mutant Strains , Organ Culture Techniques , Phosphorylation , Protein Processing, Post-Translational , Recombinant Proteins/metabolism , Recombinant Proteins/pharmacology , Recombinant Proteins/therapeutic use , Signal Transduction , Tears/metabolism , Wound Healing/drug effects , Young AdultSubject(s)
Ectodermal Dysplasia 1, Anhidrotic/genetics , Skin/pathology , Tacrolimus , Vitiligo/complications , Administration, Topical , Adolescent , Contraindications , Ectodermal Dysplasia 1, Anhidrotic/complications , Ectodermal Dysplasia 1, Anhidrotic/drug therapy , Follow-Up Studies , Humans , Immunosuppressive Agents/administration & dosage , Male , Skin/drug effects , Tacrolimus/administration & dosage , Time Factors , Vitiligo/diagnosis , Young AdultABSTRACT
The TNF family ligand ectodysplasin A (EDA) regulates the induction, morphogenesis and/or maintenance of skin-derived structures such as teeth, hair, sweat glands and several other glands. Deficiencies in the EDA - EDA receptor (EDAR) signalling pathway cause hypohidrotic ectodermal dysplasia (HED). This syndrome is characterized by the absence or malformation of several skin-derived appendages resulting in hypotrychosis, hypodontia, heat-intolerance, dry skin and dry eyes, susceptibility to airways infections and crusting of various secretions. The EDA-EDAR system is an important effector of canonical Wnt signalling in developing skin appendages. It functions by stimulating NF-κB-mediated transcription of effectors or inhibitors of the Wnt, Sonic hedgehog (SHH), fibroblast growth factor (FGF) and transforming growth factor beta (TGFß) pathways that regulate interactions within or between epithelial and mesenchymal cells and tissues. In animal models of Eda-deficiency, soluble EDAR agonists can precisely correct clinically relevant symptoms with low side effects even at high agonist doses, indicating that efficient negative feedback signals occur in treated tissues. Hijacking of the placental antibody transport system can help deliver active molecules to developing foetuses in a timely manner. EDAR agonists may serve to treat certain forms of ectodermal dysplasia.