New molecular medicine-based scar management strategies

Abstract

Keloids and hypertrophic scars are prevalent disabling conditions with still suboptimal treatments. Basic science and molecular-based medicine research have contributed to unravel new bench-to-bedside scar therapies and to dissect the complex signalling pathways involved. Peptides such as the transforming growth factor beta (TGF-β) superfamily, with Smads, Ski, SnoN, Fussels, endoglin, DS-Sily, Cav-1p, AZX100, thymosin-β4 and other related molecules may emerge as targets to prevent and treat keloids and hypertrophic scars. The aim of this review is to describe the basic complexity of these new molecular scar management strategies and point out new fibrosis research lines.

Keywords: Endoglin; FAP-alpha/DPPIV; Fussels; Keloid; Rapamycin; Review; Scar; Ski; SnoN; TGF-β.

Figure 1. COMPONENTS OF THE TGF-β SUPERFAMILY

*Note that there are also TGF-β4 and 5, but not in humans. TGF-β = Transforming growth factor beta; AMH= Antimüllerian hormone; BMPs= Bone morphogenetic proteins.

Figure 2

TGF-β-RELATED DISEASES.

Figure 3. SECRETION OF TGF-β

TGFβ is secreted from the cells in a latent inactivated form, which is then cleaved by furins and other convertases to form active signaling molecules. *Mechanisms to activate latent TGFβ-complexes are only partially understood and include proteases such as plasmin, calpain and matrix metalloproteinases, protein interactions with molecules such as thrombospondin and integrin αvβ6, physicochemical mechanisms such as pH, radiation and reactive oxygen species, and drugs such as antiestrogens, retinoids and glucocorticoids [25].

Figure 4

TGF-β SUPERFAMILY RECEPTORS.

Figure 5. TGF-β SUPERFAMILY RECEPTORS REGULATION

Phospho-relay from the constitutively active type II receptor to the type I receptor, and subsequently phosphorylation of R-Smads is essential to activate canonical TGFβ superfamily signaling [27]. This process is positively and negatively regulated at all stages of the pathway by various proteins, such as the immunophilin FKBP12 [15], TRIP-1 (the receptor interacting protein 1), the STRAP (Serine-threonine kinase receptor-associated protein), the TRAP-1 (TβRI-associated protein-1), the TLP (a TRAP-1-like-protein), the chaperone protein or Hot Shock Protein 90 (Hsp90), and the protein phosphatase 2A (PP2A), among others [27].

Figure 6. TGF-β SIGNALING PATHWAYS

There are two main pathways, Smad (or canonical) and the non-Smad (or non-canonical) pathway, mainly devoted to EMT (epithelial-to-mesenchymal transition) and apoptosis. Furthermore, there are crosstalks with other pathways, such as Wnt/Wg, Hh (Hedgehog), Notch, interleukins, IFN-γ, and TNF-α, among others.

Figure 7. CANONICAL TGF-β SIGNALING AND RECEPTORS

Each of these Smad4-R-Smad-transcription factor complexes recruits co-activators, repressors, and chromatin remodeling factors to selected sequence elements in the regulatory regions of specific target genes [15].