Virtual teaching for medical students during SARS-CoV-2 pandemic - Pfeil, A.; Franz, M.; Hoffmann, T.; Klemm, P.; Oelzner, P.; Muller-Ladner, U.; Lange, U.; Wolf, G.; Schett, Georg; Simon, David; Kleyer, Arnd; Hueber, Axel (Clinical and Experimental Rheumatology, 2021)
CRIS-Team WoS Importer:2022-02-11

Vitamin D receptor regulates TGF-? signalling in systemic sclerosis - Zerr, Pawel; Vollath, Stefan; Palumbo-Zerr, Katrin; Tomcik, Michal; Huang, Jingang; Distler, Alfiya; Beyer, Christian; Dees, Clara; Gela, Kolja; Distler, Oliver; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2015)
Vitamin D receptor (VDR) is a member of the nuclear receptor superfamily. Its ligand, 1,25-(OH)2D, is a metabolically active hormone derived from vitamin D3. The levels of vitamin D3 are decreased in patients with systemic sclerosis (SSc). Here, we aimed to analyse the role of VDR signalling in fibrosis.VDR expression was analysed in SSc skin, experimental fibrosis and human fibroblasts. VDR signalling was modulated by siRNA and with the selective agonist paricalcitol. The effects of VDR on Smad signalling were analysed by reporter assays, target gene analyses and coimmunoprecipitation. The effects of paricalcitol were evaluated in the models of bleomycin-induced fibrosis and fibrosis induced by overexpression of a constitutively active transforming growth factor-? (TGF-?) receptor I (TBRI(CA)).VDR expression was decreased in fibroblasts of SSc patients and murine models of SSc in a TGF-?-dependent manner. Knockdown of VDR enhanced the sensitivity of fibroblasts towards TGF-?. In contrast, activation of VDR by paricalcitol reduced the stimulatory effects of TGF-? on fibroblasts and inhibited collagen release and myofibroblast differentiation. Paricalcitol stimulated the formation of complexes between VDR and phosphorylated Smad3 in fibroblasts to inhibit Smad-dependent transcription. Preventive and therapeutic treatment with paricalcitol exerted potent antifibrotic effects and ameliorated bleomycin- as well as TBRI(CA)-induced fibrosis.We characterise VDR as a negative regulator of TGF-?/Smad signalling. Impaired VDR signalling with reduced expression of VDR and decreased levels of its ligand may thus contribute to hyperactive TGF-? signalling and aberrant fibroblast activation in SSc.
EVALuna2:12977

Vitamin k-dependent proteins in skeletal development and disease - Stock, Michael; Schett, Georg (International Journal of Molecular Sciences, 2021)
Vitamin K and Vitamin K-dependent proteins (VKDPs) are best known for their pivotal role in blood coagulation. Of the 14 VKPDs identified in humans to date, 6 play also important roles in skeletal biology and disease. Thus, osteocalcin, also termed bone Gla-protein, is the most abundant non-collagenous protein in bone. Matrix Gla protein and Ucma/GRP on the other hand are highly abundant in cartilage. Furthermore, periostin, protein S, and growth arrest specific 6 protein (GAS 6) are expressed in skeletal tissues. The roles for these VKDPs are diverse but include the control of calcification and turnover of bone and cartilage. Vitamin K plays an important role in osteoporosis and serum osteocalcin levels are recognized as a promising marker for osteoporosis. On the other hand, matrix Gla protein and Ucma/GRP are associated with osteoarthritis. This review focuses on the roles of these three VKDPs, osteocalcin, matrix Gla protein and Ucma/GRP, in skeletal development and disease but will also summarize the roles the other skeletal VKDPs (periostin, protein S and GAS6) in skeletal biology.
CRIS-Team Scopus Importer:2021-09-10
Keywords: GRP; Matrix Gla protein; Osteocalcin; Ucma; Vitamin K; Vitamin K-dependent proteins

What Are the Peripheral Blood Determinants for Increased Osteoclast Formation in the Various Inflammatory Diseases Associated With Bone Loss? - De Vries, Teun J.; El Bakkali, Ismail; Kamradt, Thomas; Schett, Georg; Jansen, Ineke D. C.; D'Amelio, Patrizia (Frontiers in Immunology, 2019)
Local priming of osteoclast precursors (OCp) has long been considered the main and obvious pathway that takes place in the human body, where local bone lining cells and RANKL-expressing osteocytes may facilitate the differentiation of OCp. However, priming of OCp away from bone, such as in inflammatory tissues, as revealed in peripheral blood, may represent a second pathway, particularly relevant in individuals who suffer from systemic bone loss such as prevalent in inflammatory diseases. In this review, we used a systematic approach to review the literature on osteoclast formation in peripheral blood in patients with inflammatory diseases associated with bone loss. Only studies that compared inflammatory (bone) disease with healthy controls in the same study were included. Using this core collection, it becomes clear that experimental osteoclastogenesis using peripheral blood from patients with bone loss diseases in prevalent diseases such as rheumatoid arthritis, osteoporosis, periodontitis, and cancer-related osteopenia unequivocally point toward an intrinsically increased osteoclast formation and activation. In particular, such increased osteoclastogenesis already takes place without the addition of the classical osteoclastogenesis cytokines M-CSF and RANKL in vitro. We show that T-cells and monocytes as OCp are the minimal demands for such unstimulated osteoclast formation. In search for common and disease-specific denominators of the diseases with inflammation-driven bone loss, we demonstrate that altered T-cell activity and a different composition-such as the CD14+CD16+ vs. CD14+CD16- monocytes-and priming of OCp with increased M-CSF, RANKL, and TNF-alpha levels in peripheral blood play a role in increased osteoclast formation and activity. Future research will likely uncover the barcodes of the OCp in the various inflammatory diseases associated with bone loss.
CRIS-Team WoS Importer:2019-04-02

What Characterizes Osteoarthritis: Ultrasound-Detected Inflammation but Not Osteophytes Is More Common in Hand Osteoarthritis Than in Painless Bony Enlargements - Gasperi, Nina; Adinolfi, Antonella; Kleyer, Arnd; Hagen, Melanie; Gasperi, Christiane; Weger, Martin; Kiechl, Stefan; Willeit, Johann; Schett, Georg; Iagnocco, Annamaria; Gasperi, Arno; Mayr, Agnes; et al. (2018)
EVALuna2:34958

What constitutes the fat signal detected by MRI in the spine of patients with ankylosing spondylitis? A prospective study based on biopsies obtained during planned spinal osteotomy to correct hyperkyphosis or spinal stenosis - Baraliakos, Xenofon; Boehm, Heinrich; Bahrami, Reza; Samir, Ahmed; Schett, Georg; Luber, Markus; Ramming, Andreas; Braun, Juergen (Annals of the Rheumatic Diseases, 2019)
Objective: Study the MRI signal of fatty lesions (FL) by immunohistological analysis of vertebral body biopsies of patients with ankylosing spondylitis (AS) compared with degenerative disc disease (DDD). Methods: Biopsies obtained during planned surgery from vertebral edges where MRI signals of FL was detected were stained with H&E. Immunofluorescence (IF) staining was performed to quantify osteoblasts and osteoclasts. Bone marrow (BM) composition, grade of cellularity and quantification of cells were analysed on six randomly chosen high-power fields (HPF; 0.125 mm2) at 200-fold magnification per patient by two experienced researchers in a blinded manner. Results: Biopsies of 21 patients with AS and 18 with DDD were analysed. Adipocytes were found in the BM of 19 patients with AS (90.5%) versus 5 with DDD (27.8%) (p<0.001), while inflammatory infiltrates were found in in the BM of 8 patients with AS (38.1%) versus 14 with DDD (77.8%) (p=0.035) and fibrosis in 6 patients with AS (28.6%) versus 4 with DDD (22.2%) (p=n.s.). The most frequently detected cells were adipocytes in AS (43.3%) versus DDD (16.1%, p=0.002) and inflammatory mononuclear cells in DDD (55%) versus AS (11.0%, p=0.001). Using IF staining, there was more osteoblastic than osteoclastic activity (6.9 vs 0.17 cells/HPF) in FL as compared with inflammatory BM (1.3 vs 7.4 cells/HPF), respectively. Conclusion: MRI FL correspond to presence of adipocytes, resulting to change of cellular homeostasis towards diminution of osteoclasts in the BM of patients with AS. The cross-talk between the different cell types and osteitis, fat and new bone formation needs further study.
CRIS-Team Scopus Importer:2019-06-04
Keywords: axial spondyloarthritis; biopsy; fatty lesions; magnetic resonance imaging

WHICH CELLS CORRESPOND TO THE TYPICAL SIGNALS FOR FATTY AND INFLAMMATORY LESIONS SEEN IN MAGNETIC RESONANCE IMAGING IN ANKYLOSING SPONDYLITIS? A PROSPECTIVE STUDY USING BIOPSY MATERIAL OBTAINED DURING SPINAL SURGERY - Baraliakos, X.; Boehm, H.; Samir, A.; Schett, Georg; Braun, J. (2016)
EVALuna2:13493

WHICH CELLS CORRESPOND TO TYPICAL SIGNALS FOR FATTY AND INFLAMMATORY LESIONS SEEN ON MRI IN AS? - Baraliakos, X.; Boehm, H.; Samir, A.; Schett, Georg; Braun, J. (2016)
EVALuna2:13470

Why does the gout attack stop? A roadmap for the immune pathogenesis of gout - Schett, Georg; Schauer, Christine; Hoffmann, Markus; Herrmann, Martin (RMD Open, 2015)
Gout is one of the most severe and frequent rheumatic diseases. Clinical manifestations of gout arise from uric acid crystal deposition in the musculoskeletal tissue. At high concentrations of uric acid in the body (hyperuricaemia), needle-shaped monosodium urate (MSU) crystals are formed. The structures are ingested by neutrophils and monocytes and thereby trigger robust activation of the inflammasome, an intracellular protein complex mounting an inflammatory response. Inflammasome activation builds interleukin-1, which acts as a proinflammatory mediator and induces vasodilation, recruitment of additional leucocytes and the expression of proinflammatory cytokines and chemokines. This process is associated with the clinical manifestation of an acute gout attack. Such attacks, however, stop rather rapidly and the process of resolution of inflammation in gout is now better defined. Neutrophils having ingested MSU crystals undergo a specific form of cell death called NETosis, which is characterised by the formation of neutrophil extracellular traps (NETs). During this process, DNA is extruded, allowing the dense packaging of MSU crystals as well as the degradation of proinflammatory cytokines, thereby allowing the stopping of the inflammatory process. Reactive oxygen species are essential for forming NETs and for allowing the resolution of inflammation in gout. This process of NETosis is critical for understanding tophaceous gout, since tophi are composed of NETs and densely packed MSU crystals.
EVALuna2:13175

Why remission is not enough: underlying disease mechanisms in RA that prevent cure - Schett, Georg; Tanaka, Yoshiya; Isaacs, John D. (Nature Reviews Rheumatology, 2020)
Cure is the aspirational aim for the treatment of all diseases, including chronic inflammatory conditions such as rheumatoid arthritis (RA); however, it has only been during the twenty-first century that remission, let alone cure, has been a regularly achievable target in RA. Little research has been carried out on how to cure RA, and the term ‘cure’ still requires definition for this disease. Even now, achieving a cure seems to be a rare occurrence among individuals with RA. Therefore, this Review is aimed at addressing the obstacles to the achievement of cure in RA. The differences between remission and cure in RA are first defined, followed by a discussion of the underlying factors (referred to as drivers) that prevent the achievement of cure in RA by triggering sustained immune activation and effector cytokine production. Such drivers include adaptive immune system activation, mesenchymal tissue priming and so-called ‘remote’ (non-immune and non-articular) factors. Strategies to target these drivers are also presented, with an emphasis on the development of strategies that could complement currently used cytokine inhibition and thereby improve the likelihood of curing RA.
CRIS-Team Scopus Importer:2020-12-25

WNT16 antagonises excessive canonical WNT activation and protects cartilage in osteoarthritis - Nalesso, Giovanna; Thomas, Bethan Lynne; Sherwood, Joanna Claire; Yu, Jing; Addimanda, Olga; Eldridge, Suzanne Elizabeth; Thorup, Anne-Sophie; Dale, Leslie; Schett, Georg; Zwerina, Jochen; Eltawil, Noha; Pitzalis, Costantino; et al. (Annals of the Rheumatic Diseases, 2017)
Both excessive and insufficient activation of WNT signalling results in cartilage breakdown and osteoarthritis. WNT16 is upregulated in the articular cartilage following injury and in osteoarthritis. Here, we investigate the function of WNT16 in osteoarthritis and the downstream molecular mechanisms.Osteoarthritis was induced by destabilisation of the medial meniscus in wild-type and WNT16-deficient mice. Molecular mechanisms and downstream effects were studied in vitro and in vivo in primary cartilage progenitor cells and primary chondrocytes. The pathway downstream of WNT16 was studied in primary chondrocytes and using the axis duplication assay in Xenopus.WNT16-deficient mice developed more severe osteoarthritis with reduced expression of lubricin and increased chondrocyte apoptosis. WNT16 supported the phenotype of cartilage superficial-zone progenitor cells and lubricin expression. Increased osteoarthritis in WNT16-deficient mice was associated with excessive activation of canonical WNT signalling. In vitro, high doses of WNT16 weakly activated canonical WNT signalling, but, in co-stimulation experiments, WNT16 reduced the capacity of WNT3a to activate the canonical WNT pathway. In vivo, WNT16 rescued the WNT8-induced primary axis duplication in Xenopus embryos.In osteoarthritis, WNT16 maintains a balanced canonical WNT signalling and prevents detrimental excessive activation, thereby supporting the homeostasis of progenitor cells.
EVALuna2:13281

WNT5A PROMOTES FIBROBLAST ACTIVATION AND TISSUE FIBROSIS BY ROR2/RYK DEPENDENT ACTIVATION OF PCP-SIGNALING - Chen, Chih-Wei; Lin, N. -Y.; Zhang, Yun; Huang, J.; Palumbo-Zerr, K.; Schambony, Alexandra; Beyer, Christian; Schett, Georg; Distler, Jörg (2016)
EVALuna2:13488

WNT5A Promotes Tissue Fibrosis By Wnt/PCP-Dependent Activation of Latent TGF-beta - Chen, Chih-Wei; Thuong Trinh-Minh,; Lin, Neng-Yu; Zhang, Yun; Groeber, Florian; Beyer, Christian; Schett, Georg; Distler, Jörg (2017)
EVALuna2:33430

XIAP AS NOVEL INTEGRATOR OF TGF BETA SIGNALLING AND CANONICAL WNT SIGNALLING IN TISSUE FIBROSIS - Bergmann, C.; Hallenberger, L.; Merlevede, B.; Brandt, Adrian; Dees, Clara; Chen, Chih-Wei; Stock, Michael; Beyer, Christian; Distler, O.; Schett, Georg; Distler, Jörg (2018)
EVALuna2:34997

X-linked inhibitor of apoptosis protein (XIAP) inhibition in systemic sclerosis (SSc) - Bergmann, Christina; Hallenberger, Ludwig; Chenguiti Fakhouri, Sara; Chenguiti Fakhouri, Sara; Merlevede, Benita; Brandt, Adrian; Dees, Clara; Zhu, Honglin; Zehender, Ariella; Zhou, Xiang; Schwab, Annemarie; Chen, Chih-Wei; et al. (Annals of the Rheumatic Diseases, 2021)
X-linked inhibitor of apoptosis protein (XIAP) is a multifunctional protein with important functions in apoptosis, cellular differentiation and cytoskeletal organisation and is emerging as potential target for the treatment of various cancers. The aim of the current study was to investigate the role of XIAP in the pathogenesis of systemic sclerosis (SSc). The expression of XIAP in human skin samples of patients with SSc and chronic graft versus host disease (cGvHD) and healthy individuals was analysed by quantitative PCR, immunofluorescence (IF) and western blot. XIAP was inactivated by siRNA-mediated knockdown and pharmacological inhibition. The effects of XIAP inactivation were analysed in cultured fibroblasts and in the fibrosis models bleomycin-induced and topoisomerase-I-(topoI)-induced fibrosis and in Wnt10b-transgenic mice. The expression of XIAP, but not of other inhibitor of apoptosis protein family members, was increased in fibroblasts in SSc and sclerodermatous cGvHD. Transforming growth factor beta (TGF-β) induced the expression of XIAP in a SMAD3-dependent manner. Inactivation of XIAP reduced WNT-induced fibroblast activation and collagen release. Inhibition of XIAP also ameliorated fibrosis induced by bleomycin, topoI and overexpression of Wnt10b in well-tolerated doses. The profibrotic effects of XIAP were mediated via WNT/β-catenin signalling. Inactivation of XIAP reduces binding of β-catenin to TCF to in a TLE-dependent manner to block WNT/β-catenin-dependent transcription. Our data characterise XIAP as a novel link between two core pathways of fibrosis. XIAP is overexpressed in SSc and cGvHD in a TGF-β/SMAD3-dependent manner and in turn amplifies the profibrotic effects of WNT/β-catenin signalling on fibroblasts via transducin-like enhancer of split 3. Targeted inactivation of XIAP inhibits the aberrant activation of fibroblasts in murine models of SSc.
CRIS-Team Scopus Importer:2021-05-07
Keywords: fibroblasts; pulmonary fibrosis; scleroderma; systemic