Die Rolle von Astacin-ähnlichen Metalloproteasen in physiologischer Wundheilung und Vernarbung
Zusammenfassung der Projektergebnisse
Regulated proteolysis is essential for tissue homeostasis. Proteolytic activity is required both for the degradation of the extracellular matrix as well as its deposition and build up. In this project we investigated the role of the emerging family of metalloproteinases, called astacinlike proteinases (ALPs), in skin homeostasis, normal and pathological wound healing. The ALPs are composed of two subfamilies: the bone morphogenetic protein-1/tolloid-like proteinases (BTPs) and the meprins. Our study using mouse models and patient material supported the role of BTPs as essential players in skin wound healing. Further analyses directed to the genetic skin fragility disorder recessive dystrophic epidermolysis bullosa (RDEB), which manifests in progressive scarring and soft tissue fibrosis, disclosed the potential specific involvement of dysregulated BTP activity in RDEB fibrosis. Further studies have been initiated to identify BTP activity-derived biomarkers of RDEB fibrosis. Direct targeting of BTP activity to limit fibrosis in RDEB is challenging given the essential role of BTPs in wound healing and the large wound burden associated with RDEB. The main focus on our studies was on the much less explored meprins. The meprins comprise meprin α and meprin β. Although they were known to be expressed in skin, limited details about their tissue distribution and their function in skin homeostasis were known. Given the reports of increased meprin activity in fibrotic conditions a role of meprin activity in dermal scarring and fibrosis was expected. Using a translational approach we could show that meprins are primarily expressed in the epidermis of the skin and intriguingly in RDEB fibrosis is associated with generally lower levels of meprins. Wound healing analyses showed that meprin α appears to limit regeneration and fibrosis reactions. Future studies will address the general applicability of these findings and interrogate if enhancing meprin α activity or processes downstream its activity could be an option for fibrosis management. Epidermal meprin β promoted wound closure. By developing a mouse model with cell- and tissue-specific expression of meprin β we could confirm that meprin β over-expression in the dermis of skin did not evoke fibrosis. However, increased meprin β in keratinocytes led to profound changes of epidermal activity. We could identify targets of meprin β in the epidermis of skin. Importantly, our results indicated that elevated meprin β activity could be involved in the pathogenesis of epidermal blistering and skin peeling conditions. Thus, targeting of meprin β activity using small molecules could potentially be effective to treat a large group of diseases with alter epidermal activity. Our project has allowed for the increased understanding of meprins in skin physiology. Although quantitatively minor proteins in skin they both fill selective functions in skin homeostasis and regeneration that can be therapeutically explored.
Projektbezogene Publikationen (Auswahl)
- Analysis of the functional consequences of targeted exon deletion in COL7A1 reveals prospects for dystrophic epidermolysis bullosa therapy. Mol. Ther. 2016;24(7):1302–11
Bornert O, Kühl T, Bremer J, van den Akker PC, Pasmooij AM, Nyström A
(Siehe online unter https://doi.org/10.1038/mt.2016.92) - Collagen VII Half-Life at the Dermal-Epidermal Junction Zone: Implications for Mechanisms and Therapy of Genodermatoses. J. Invest. Dermatol. 2016;136(6):1116–23
Kühl T, Mezger M, Hausser I, Guey LT, Handgretinger R, Bruckner-Tuderman L, et al
(Siehe online unter https://doi.org/10.1016/j.jid.2016.02.002) - Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin β and promotes transendothelial cell migration. FASEB J. 2017; 31(3):1226-1237
Bedau T, Peters F, Prox J, Arnold P, Schmidt F, Finkernagel M, Köllmann S, Wichert R, Otte A, Ohler A, Stirnberg M, Lucius R, Koudelka T, Tholey A, Biasin V, Pietrzik CU, Kwapiszewska G, Becker-Pauly C
(Siehe online unter https://doi.org/10.1096/fj.201601113R) - Identification of tissue damage, extracellular matrix remodeling and bacterial challenge as common mechanisms associated with high-risk cutaneous squamous cell carcinomas. Matrix Biol. 2018;66:1–21
Föll MC, Fahrner M, Gretzmeier C, Thoma K, Biniossek ML, Kiritsi D, et al
(Siehe online unter https://doi.org/10.1016/j.matbio.2017.11.004) - Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa. Proc. Natl. Acad. Sci. U.S.A. 2018;115(4):E705–14
Nyström A, Bornert O, Kühl T, Gretzmeier C, Thriene K, Dengjel J, et al
(Siehe online unter https://doi.org/10.1073/pnas.1709111115) - Inhibitors of BMP-1/tolloid-like proteinases: efficacy, selectivity and cellular toxicity. FEBS OpenBio, 2018; 8(12):2011-2021
Talantikite M, Lécorché P, Beau F, Damour O, Becker-Pauly C, Ho WB, Dive V, Vadon-Le Goff S, Moali C
(Siehe online unter https://doi.org/10.1002/2211-5463.12540) - Differences in Shedding of the Interleukin-11 Receptor by the Proteases ADAM9, ADAM10, ADAM17, Meprin α, Meprin β and MT1-MMP. Int J Mol Sci. 2019 Jul 26;20(15)
Sammel M, Peters F, Lokau J, Scharfenberg F, Werny L, Linder S, Garbers C, Rose-John S, Becker-Pauly C
(Siehe online unter https://doi.org/10.3390/ijms20153677) - Generation of rabbit polyclonal human and murine collagen VII monospecific antibodies: A useful tool for dystrophic epidermolysis bullosa therapy studies. Matrix Biology Plus. 2019;4:100017
Bornert O, Kocher T, Gretzmeier C, Liemberger B, Hainzl S, Koller U, et al
(Siehe online unter https://doi.org/10.1016/j.mbplus.2019.100017) - Tethering soluble meprin α in an enzyme complex to the cell surface affects IBD associated genes. FASEB J, 9(1):546
Peters F, Scharfenberg F, Colmorgen C, Armbrust F, Wichert R, Arnold P, Potempa B, Potempa J, Pietrzik CU, Häsler R, Rosenstiel P, Becker-Pauly C
(Siehe online unter https://doi.org/10.1096/fj.201802391R) - Proteomic profiling of fibroblasts isolated from chronic wounds identifies disease-relevant signaling pathways. J. Invest. Dermatol. 2020
Berberich B, Thriene K, Gretzmeier C, Kühl T, Bayer H, Athanasiou I, et al
(Siehe online unter https://doi.org/10.1016/j.jid.2020.02.040) - STAT3 targeting in dystrophic epidermolysis bullosa. Br. J. Dermatol. 2020;182(5):1279–81
Mittapalli VR, Kühl T, Kuzet SE, Gretzmeier C, Kiritsi D, Gaggioli C, et al.
(Siehe online unter https://doi.org/10.1111/bjd.18639)
