transforming-growth-factor-beta and Epidermolysis-Bullosa

Systemic skin-selective therapeutics would be a major advancement in the treatment of diseases affecting the entire skin, such as recessive dystrophic epidermolysis bullosa (RDEB), which is caused by mutations in the COL7A1 gene and manifests in transforming growth factor-β (TGF-β)-driven fibrosis and malignant transformation. Homing peptides containing a C-terminal R/KXXR/K motif (C-end rule [CendR] sequence) activate an extravasation and tissue penetration pathway for tumor-specific drug delivery. We have previously described a homing peptide CRKDKC (CRK) that contains a cryptic CendR motif and homes to angiogenic blood vessels in wounds and tumors, but it cannot penetrate cells or tissues. In this study, we demonstrate that removal of the cysteine from CRK to expose the CendR sequence confers the peptide novel ability to home to normal skin. Fusion of the truncated CRK (tCRK) peptide to the C terminus of an extracellular matrix protein decorin (DCN), a natural TGF-β inhibitor, resulted in a skin-homing therapeutic molecule (DCN-tCRK). Systemic DCN-tCRK administration in RDEB mice led to inhibition of TGF-β signaling in the skin and significant improvement in the survival of RDEB mice. These results suggest that DCN-tCRK has the potential to be utilized as a novel therapeutic compound for the treatment of dermatological diseases such as RDEB.

Topics: Animals; Biomarkers; Disease Models, Animal; Epidermolysis Bullosa; Fibrosis; Immunohistochemistry; Mice; Mice, Knockout; Neuropilin-1; Peptides; Protein Binding; Protein Interaction Domains and Motifs; Recombinant Fusion Proteins; Skin; Transforming Growth Factor beta; Wound Healing

Kindlin-1 is an integrin tail binding protein that controls integrin activation. Mutations in the FERMT-1 gene, which encodes for Kindlin-1, lead to Kindler syndrome in man, which is characterized by skin blistering, premature skin aging and skin cancer of unknown etiology. Here we show that loss of Kindlin-1 in mouse keratinocytes recapitulates Kindler syndrome and also produces enlarged and hyperactive stem cell compartments, which lead to hyperthickened epidermis, ectopic hair follicle development and increased skin tumor susceptibility. Mechanistically, Kindlin-1 controls keratinocyte adhesion through β1-class integrins and proliferation and differentiation of cutaneous epithelial stem cells by promoting α(v)β(6) integrin-mediated transforming growth factor-β (TGF-β) activation and inhibiting Wnt-β-catenin signaling through integrin-independent regulation of Wnt ligand expression. Our findings assign Kindlin-1 the previously unknown and essential task of controlling cutaneous epithelial stem cell homeostasis by balancing TGF-β-mediated growth-inhibitory signals and Wnt-β-catenin-mediated growth-promoting signals.

Topics: Animals; Antigens, Neoplasm; beta Catenin; Blister; Carrier Proteins; Cell Adhesion; Cell Proliferation; Disease Models, Animal; Epidermolysis Bullosa; Hair Follicle; Integrin beta1; Integrins; Keratinocytes; Mice; Mice, Transgenic; Periodontal Diseases; Photosensitivity Disorders; Signal Transduction; Skin; Skin Neoplasms; Stem Cells; Transforming Growth Factor beta; Wnt Proteins; Wnt Signaling Pathway

Kindler syndrome (KS) in humans is a severe skin blistering disease associated with inflammation and increased risk of epidermal squamous cell carcinoma (SCC). This disease is known to be caused by loss-of-function mutations in Kindlin-1, a focal adhesion β-integrin binding protein. Thus far, it has been unclear what specific signaling events occur in KS keratinocytes to promote tumorigenesis, especially since loss of β-integrins and focal adhesion complexes has been previously shown to prevent or delay tumor formation. In the April issue of Nature Medicine, Rognoni and colleagues generate a transgenic mouse lacking Kindlin-1 in the epidermis to model the key features of KS, and show that Kindlin-1 regulates Wnt and TGFβ signaling independent of β-integrins. These β1-integrin-independent functions of Kindlin-1 may contribute to the increased SCC risk in KS patients.

Topics: Animals; Blister; Carrier Proteins; Cell Proliferation; Epidermolysis Bullosa; Keratinocytes; Periodontal Diseases; Photosensitivity Disorders; Skin; Stem Cells; Transforming Growth Factor beta; Wnt Proteins