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Pathobiochemical impact of human xylosyltransferase-I in bone homeostasis

Subject Area Toxicology, Laboratory Medicine
Cell Biology
Term from 2016 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 316628156
 
Final Report Year 2025

Final Report Abstract

Human xylosyltransferase-I (XT-I) catalyzes the initial and rate-determining step of proteoglycan (PG) biosynthesis and is therefore substantially involved in the formation of a functional extracellular matrix (ECM). The enzymatic XT-I activity is proportional to PG glycosylation and can be used as a non-invasive biomarker for fibrotic tissue remodeling processes. Human pathogenic XYLT1 mutations lead to XYLT1 deficiency and are causative for skeletal dysplasia Desbuquois dysplasia type 2 (DBQD2). A better understanding of the molecular and cellular mechanisms of XT-I regulation is essential to determine whether XT-I could be a suitable therapeutic target in the future. In the first funding period, the mechanistic aspects of XT-I regulation and its involvement in fibroproliferative processes were characterized in more detail using the example of dermal fibrosis and scleroderma (SSc). Activin A, miRNA-29b and miRNA-145 were identified as XT- I inducers, and celastrol and amphotericin B were described as XT-I inhibitors. Furthermore, XYLT1-deficient normal human dermal fibroblasts (NHDF) were generated for the first time using CRISPR/Cas9 technology. The XYLT1-deficient NHDF were characterized by aberrant ECM composition and integrity, but also showed atypical cellular properties in terms of increased senescence and myofibroblast differentiation. The results obtained thus not only provide new key insights into the signaling pathways involved in XT-I regulation, but also demonstrate the high pathophysiological relevance of XYLT1-deficiency. The functional characterization of XT-I in bone metabolism was thus addressed in the second funding period. Using CRISPR/Cas9-based generation and differentiation of XYLT1-deficient human mesenchymal stem cells (hMSC), clinical manifestations of DBQD2 affecting bones and joints were analyzed at the cellular level for the first time. XYLT1-deficiency was characterized by an aberrant chondrocyte cartilage matrix, premature chondrocyte maturation, reduced osteogenic matrix mineralization and reduced resorption activity of osteoclasts associated with premature induction of osteoclastogenesis. Although no features of cellular senescence were detected in the generated XYLT1-deficient hMSC, the putative association of cellular senescence and XT-I regulation defined the function of XT-I as an anti-fibrotic mediator in the acute senescence of dermal wound healing. In the long term, the results of our project will contribute to the development of therapeutic intervention options for XT-I-associated diseases.

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