BMP-1/tolloid-like proteinases (BTPs) are major players in tissue morphogenesis, growth and repair. They act by promoting the deposition of structural extracellular matrix proteins and by controlling the activity of matricellular proteins and TGF-β superfamily growth factors. They have also been implicated in several pathological conditions such as fibrosis, cancer, metabolic disorders and bone diseases. Despite this broad range of pathophysiological functions, the putative existence of a specific endogenous inhibitor capable of controlling their activities could never be confirmed. Here, we show that procollagen C-proteinase enhancer-2 (PCPE-2), a protein previously reported to bind fibrillar collagens and to promote their BTP-dependent maturation, is primarily a potent and specific inhibitor of BTPs which can counteract their proteolytic activities through direct binding. PCPE-2 therefore differs from the cognate PCPE-1 protein and extends the possibilities to fine-tune BTP activities, both in physiological conditions and in therapeutic settings.

AbstractThe climbing passion flower Passiflora discophora features branched tendrils with multiple adhesive pads at their tips allowing it to attach to large-diameter supports and to flat surfaces. We conducted tensile tests to quantify the performance of this attachment system. We found that the force at failure varies with substrate, ontogenetic state (turgescent or senescent), and tendril size (i.e. tendril cross-sectional area and pad area). The tendrils proved to be well balanced in size and to attach firmly to a variety of substrates (force at failure up to 2N). Pull-off tests performed with tendrils grown on either epoxy, plywood, or beech bark revealed that senescent tendrils could still bear 24, 64, or 100% of the force measured for turgescent tendrils, respectively, thus providing long-lasting attachment at minimal physiological costs. The tendril main axis was typically the weakest part of the adhesive system, whereas the pad–substrate interface never failed. This suggests that the plants use the slight oversizing of adhesive pads as a strategy to cope with ‘unpredictable’ substrates. The pads, together with the spring-like main axis, which can, as shown, dissipate a large amount of energy when straightened, thus constitute a fail-safe attachment system.

Dystrophic epidermolysis bullosa (DEB) is an inherited skin disorder, characterized by mutations in the gene encoding for collagen VII. DEB manifests in chronic skin fragility with blistering at the dermal-epidermal junction. Unremitting injury and inflammation evoke progressive fibrosis of skin and other epithelia in DEB. Here, we aimed to understand consequences of this with respect to biomechanics, epidermal integrity and barrier function. To this end, we followed changes in skin biomechanics with age in DEB mice using atomic force microscopy and its consequences using lipidomics, followed by validating molecular analyses in human DEB donor skin. The papillary dermis as well as the basal epidermal layers progressively stiffened over time in chronically injured skin, which was accompanied by increased activation of basal keratinocytes. In contrast, the superficial stratum corneum of DEB skin that is naturally exposed to mechanical challenges became significantly softer over time compared to wild-type mouse counterparts. This went along with an altered stratum corneum lipid composition and a reduced barrier function, which was also noted in human fibrotic DEB skin. In vitro models suggested involvement of inflammation-independent triggers and pointed to dermal mechanical stiffness as a potential factor influencing these epidermal changes. Together our data indicate that an altered lipid matrix may cause stratum corneum softness and epidermal barrier deficiency in DEB. An impaired barrier may increase the susceptibility to skin damage and could further provoke dermal activation, inflammation and induction of fibrogenic processes or could foster the development of epidermal inflammation and itch in DEB patients.

Injury- and inflammation-driven progressive dermal fibrosis is a severe manifestation of recessive dystrophic epidermolysis bullosa-a genetic skin blistering disease caused by mutations in COL7A1. TGF-β activation plays a prominent part in progressing dermal fibrosis. However, the underlying mechanisms are not fully elucidated. TGF-β is secreted in a latent form, which has to be activated for its biological functions. In this study, we determined that recessive dystrophic epidermolysis bullosa fibroblasts have an enhanced capacity to activate the latent form. Mechanistic and functional assessment demonstrated that this process depends on multiple latent TGF-β activators, including TSP-1, RGD-binding integrins, matrix metalloproteinases, and ROS, which act in concert, in a self-perpetuating feedback loop to progress fibrosis. Importantly, our study also disclosed keratinocytes as prominent facilitators of fibrosis in recessive dystrophic epidermolysis bullosa. They stimulate microenvironmental latent TGF-β activation through enhanced production of the above mediators. Collectively, our study provides data on the molecular mechanism behind dysregulated TGF-β signaling in recessive dystrophic epidermolysis bullosa, which are much needed for the development of evidence-based fibrosis-delaying treatments.

Recessive dystrophic epidermolysis bullosa (RDEB), a genetic skin blistering disease, is a paradigmatic condition of tissue fragility-driven multi-organ fibrosis. Here, longitudinal analyses of the tissue proteome through the course of naturally developing disease in RDEB mice revealed that increased pro-inflammatory immunity associates with fibrosis evolution. Mechanistically, this fibrosis is a consequence of altered extracellular matrix organization rather than that of increased abundance of major structural proteins. In a humanized system of disease progression, we targeted inflammatory cell fibroblast communication with Ang-(1-7)-an anti-inflammatory heptapeptide of the renin-angiotensin system, which reduced the fibrosis-evoking aptitude of RDEB cells. In vivo, systemic administration of Ang-(1-7) efficiently attenuated progression of multi-organ fibrosis and increased survival of RDEB mice. Collectively, our study shows that selective down-modulation of pro-inflammatory immunity may mitigate injury-induced fibrosis. Furthermore, together with published data, our data highlight molecular diversity among fibrotic conditions. Both findings have direct implications for the design of therapies addressing skin fragility and fibrosis.

Skin consists of the epidermis and dermis, which are connected by a specialized basement membrane—the epidermal basement membrane. Both the epidermal basement membrane and the underlying interstitial extracellular matrix (ECM) created by dermal fibroblasts contain distinct network-forming macromolecules. These matrices play various roles in order to maintain skin homeostasis and integrity. Within this complex interplay of cells and matrices, cell surface receptors play essential roles not only for inside-out and outside-in signaling, but also for establishing mechanical and biochemical properties of skin. Already minor modulations of this multifactorial cross-talk can lead to severe and systemic diseases. In this review, major epidermal and dermal cell surface receptors will be addressed with respect to their interactions with matrix components as well as their roles in fibrotic, inflammatory or tumorigenic skin diseases.

Lectins are glycan-binding proteins with no catalytic activity and ubiquitously expressed in nature. Numerous bacteria use lectins to efficiently bind to epithelia, thus facilitating tissue colonisation. Wounded skin is one of the preferred niches for Pseudomonas aeruginosa, which has developed diverse strategies to impair tissue repair processes and promote infection. Here, we analyse the effect of the P. aeruginosa fucose-binding lectin LecB on human keratinocytes and demonstrate that it triggers events in the host, upon binding to fucosylated residues on cell membrane receptors, which extend beyond its role as an adhesion molecule. We found that LecB associates with insulin-like growth factor-1 receptor and dampens its signalling, leading to the arrest of cell cycle. In addition, we describe a novel LecB-triggered mechanism to down-regulate host cell receptors by showing that LecB leads to insulin-like growth factor-1 receptor internalisation and subsequent missorting towards intracellular endosomal compartments, without receptor activation. Overall, these data highlight that LecB is a multitask virulence factor that, through subversion of several host pathways, has a profound impact on keratinocyte proliferation and survival.