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Search Results: 1 - 10 of 1469 matches for " Jochen Ringe "
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Tissue engineering in the rheumatic diseases
Jochen Ringe, Michael Sittinger
Arthritis Research & Therapy , 2009, DOI: 10.1186/ar2572
Abstract: Diseases like rheumatoid arthritis (RA) or degenerative arthritis (osteoarthritis, OA) are accompanied by a progressive reduction of extracellular matrices (ECMs) in joint cartilage and bone and, eventually, loss of joint function and excessive morbidity. Current pharmacological treatment of RA focuses on alleviating symptoms and/or modifying the disease process. Despite recent success in controlling pain and inflammation, marginal cartilage regeneration has been observed. Obviously, suppression of inflammation is not sufficient to restore joint structure and function. Probably, cartilage repair may be achieved only by triggering local cartilage tissue responses leading to recovery of chondrocyte remodelling. An imbalance in joint cartilage, subchondral bone, and synovial membrane remodelling is one important characteristic of OA. Despite many OA research efforts, treatment strategies are poor and restricted to relieving the symptoms, to different surgical procedures (including techniques stimulating self-repair of the joint) [1,2], or to endo-prothetic joint replacement.In the last decade, tissue engineering approaches for the repair of joint cartilage and bone defects have reached the clinic. Here, autologous cells are transplanted as cell suspension or in combination with supportive scaffolds into the defect site or, since 2007, are in situ recruited to the defect site due to the implantation of scaffolds combined with cell attractants. Meanwhile, the scope of clinical application for tissue engineering was expanded to OA diseased joint cartilage [3,4].Besides clinically applied tissue-specific chondrocytes, undifferentiated mesenchymal stem cells (MSCs) are of special interest as cell candidates. In particular, bone marrow MSCs are comprehensively characterized and represent promising candidates [5]. They are easy to isolate and expand, they differentiate into various tissues like cartilage [6] and bone [7], and therefore they are able to regenerate osteochondra
Chondrogenic differentiation potential of osteoarthritic chondrocytes and their possible use in matrix-associated autologous chondrocyte transplantation
Tilo Dehne, Camilla Karlsson, Jochen Ringe, Michael Sittinger, Anders Lindahl
Arthritis Research & Therapy , 2009, DOI: 10.1186/ar2800
Abstract: Articular chondrocytes from patients with OA undergoing total knee replacement (Mankin Score > 3, Ahlb?ck Score > 2) and from patients undergoing ACT, here referred to as normal donors (ND), were isolated applying protocols used for ACT. Their chondrogenic differentiation potential was evaluated both in high-density pellet and scaffold (Hyaff-11) cultures by histological proteoglycan assessment (Bern Score) and immunohistochemistry for collagen types I and II. Chondrocytes cultured in monolayer and scaffolds were subjected to gene expression profiling using genome-wide oligonucleotide microarrays. Expression data were verified by using real-time PCR.Chondrocytes from ND and OA donors demonstrated accumulation of comparable amounts of cartilage matrix components, including sulphated proteoglycans and collagen types I and II. The mRNA expression of cartilage markers (ACAN, COL2A1, COMP, CRTL1, SOX9) and genes involved in matrix synthesis (BGN, CILP2, COL9A2, COL11A1, TIMP4) was highly induced in 3D cultures of chondrocytes from both donor groups. Genes associated with hypertrophic or OA cartilage (ALPL, COL1A1, COL3A1, COL10A1, MMP13, POSTN, PTH1R, RUNX2) were not significantly regulated between the two groups of donors. The expression of 661 genes, including COMP, FN1, and SOX9, was differentially regulated between OA and ND chondrocytes cultured in monolayer. During scaffold culture, the differences diminished between the OA and ND chondrocytes, and only 184 genes were differentially regulated.Only few genes were differentially expressed between OA and ND chondrocytes in Hyaff-11 culture. The risk of differentiation into hypertrophic cartilage does not seem to be increased for OA chondrocytes. Our findings suggest that the chondrogenic capacity is not significantly affected by OA, and OA chondrocytes fulfill the requirements for matrix-associated ACT.The regenerative capacity of articular cartilage is very limited and injuries that do not penetrate the subchondral b
Differential gene expression profiling of human bone marrow-derived mesenchymal stem cells during adipogenic development
Adriane Menssen, Thomas H?upl, Michael Sittinger, Bruno Delorme, Pierre Charbord, Jochen Ringe
BMC Genomics , 2011, DOI: 10.1186/1471-2164-12-461
Abstract: The mesenchymal stem cell character of human MSC cultures was proven by cell morphology, by flow cytometry analysis and by the ability of the cells to develop into the osteo-, chondro- and adipogenic lineage. Moreover we were able to detect 184 adipogenic candidate genes (85 with increased, 99 with decreased expression) that were differentially expressed during adipogenic development of MSC and/or between MSC and fat tissue in a highly significant way (p < 0.00001). Subsequently, groups of up- or down-regulated genes were formed and analyzed with biochemical and cluster tools. Among the 184 genes, we identified already known transcription factors such as PPARG, C/EBPA and RTXA. Several of the genes could be linked to corresponding biochemical pathways like the adipocyte differentiation, adipocytokine signalling, and lipogenesis pathways. We also identified new candidate genes possibly related to adipogenesis, such as SCARA5, coding for a receptor with a putative transmembrane domain and a collagen-like domain, and MRAP, encoding an endoplasmatic reticulum protein.Comparing differential gene expression profiles of human MSC and native fat cells or tissue allowed us to establish a comprehensive differential kinetic gene expression network of adipogenesis. Based on this, we identified known and unknown genes and biochemical pathways that may be relevant for adipogenic differentiation. Our results encourage further and more focused studies on the functional relevance of particular adipogenic candidate genes.Human mesenchymal stem cells (MSC) are easy to isolate from bone marrow aspirates. In cell culture, they can be expanded as clones showing multilineage differentiation potential [1,2]. It is well known that human MSC differentiate when cultured under appropriate conditions into adipocytes, osteoblasts or chondrocytes [1,3].Human adipocyte development can be studied in vitro starting from MSC cultures, which can be induced to follow the process of adipogenesis [4]. Ho
Crosstalks between integrin alpha 5 and IGF2/IGFBP2 signalling trigger human bone marrow-derived mesenchymal stromal osteogenic differentiation
Zahia Hamidouche, Olivia Fromigué, Jochen Ringe, Thomas H?upl, Pierre J Marie
BMC Cell Biology , 2010, DOI: 10.1186/1471-2121-11-44
Abstract: Microarray analysis and validation experiments showed that the expression of IGF2 and IGFBP2 was increased together with integrin alpha5 (ITGA5) during dexamethasone-induced osteoblast differentiation in human MSCs. This effect was functional since we found that IGF2 and IGFBP2 enhanced the expression of osteoblast phenotypic markers and in vitro osteogenic capacity of hMSCs. Interestingly, we showed that downregulation of endogenous ITGA5 using specific shRNA decreased IGF2 and IGFBP2 expression in hMSCs. Conversely, ITGA5 overexpression upregulated IGF2 and IGFBP2 expression in hMSCs, which indicates tight crosstalks between these molecules. Consistent with this concept, activation of endogenous ITGA5 using a specific antibody that primes the integrin, or a peptide that specifically activates ITGA5 increased IGF2 and IGFBP2 expression in hMSCs. Finally, we showed that pharmacological inhibition of FAK/ERK1/2-MAPKs or PI3K signalling pathways that are enhanced by ITGA5 activation, blunted IGF2 and IGFBP2 expression in hMSCs.The results show that ITGA5 is a key mediator of IGF2 and IGFBP2 expression that promotes osteoblast differentiation in human MSCs, and reveal that crosstalks between ITGA5 and IGF2/IGFBP2 signalling are important mechanisms that trigger osteogenic differentiation in human bone marrow derived mesenchymal stromal cells.Mesenchymal stromal cells (MSCs) can differentiate into chondroblasts, adipocytes or osteoblasts under appropriate stimulation [1-3]. Adult human MSCs (hMSCs) are therefore an important source for tissue repair and therapy in regenerative medicine [4,5]. Expanding the osteogenic capacity of hMSCs is thus of major interest for improving the osteogenic potential of hMSCs for optimal bone regeneration [6]. The osteogenic differentiation of MSCs is characterized by the expression of timely expressed genes such as Runx2, alkaline phosphatase (ALP) and type I collagen (Col1A1) followed by extracellular matrix mineralization [7,8]. Severa
Reverse Differentiation as a Gene Filtering Tool in Genome Expression Profiling of Adipogenesis for Fat Marker Gene Selection and Their Analysis
Mujib Ullah, Stefan Stich, Thomas H?upl, Jan Eucker, Michael Sittinger, Jochen Ringe
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0069754
Abstract: Background During mesenchymal stem cell (MSC) conversion into adipocytes, the adipogenic cocktail consisting of insulin, dexamethasone, indomethacin and 3-isobutyl-1-methylxanthine not only induces adipogenic-specific but also genes for non-adipogenic processes. Therefore, not all significantly expressed genes represent adipogenic-specific marker genes. So, our aim was to filter only adipogenic-specific out of all expressed genes. We hypothesize that exclusively adipogenic-specific genes change their expression during adipogenesis, and reverse during dedifferentiation. Thus, MSC were adipogenic differentiated and dedifferentiated. Results Adipogenesis and reverse adipogenesis was verified by Oil Red O staining and expression of PPARG and FABP4. Based on GeneChips, 991 genes were differentially expressed during adipogenesis and grouped in 4 clusters. According to bioinformatic analysis the relevance of genes with adipogenic-linked biological annotations, expression sites, molecular functions, signaling pathways and transcription factor binding sites was high in cluster 1, including all prominent adipogenic genes like ADIPOQ, C/EBPA, LPL, PPARG and FABP4, moderate in clusters 2–3, and negligible in cluster 4. During reversed adipogenesis, only 782 expressed genes (clusters 1–3) were reverted, including 597 genes not reported for adipogenesis before. We identified APCDD1, CHI3L1, RARRES1 and SEMA3G as potential adipogenic-specific genes. Conclusion The model system of adipogenesis linked to reverse adipogenesis allowed the filtration of 782 adipogenic-specific genes out of total 991 significantly expressed genes. Database analysis of adipogenic-specific biological annotations, transcription factors and signaling pathways further validated and valued our concept, because most of the filtered 782 genes showed affiliation to adipogenesis. Based on this approach, the selected and filtered genes would be potentially important for characterization of adipogenesis and monitoring of clinical translation for soft-tissue regeneration. Moreover, we report 4 new marker genes.
Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration
Kristin Andreas, Thomas H?upl, Carsten Lübke, Jochen Ringe, Lars Morawietz, Anja Wachtel, Michael Sittinger, Christian Kaps
Arthritis Research & Therapy , 2009, DOI: 10.1186/ar2605
Abstract: An interactive in vitro cultivation system composed of human chondrocyte alginate cultures and conditioned supernatant of SV40 T-antigen immortalised human synovial fibroblasts was used. Chondrocyte alginate cultures were stimulated with supernatant of RA synovial fibroblasts, of healthy donor synovial fibroblasts, and of RA synovial fibroblasts that have been antirheumatically treated with disease-modifying antirheumatic drugs (DMARDs) (azathioprine, gold sodium thiomalate, chloroquine phosphate, and methotrexate), nonsteroidal anti-inflammatory drugs (NSAIDs) (piroxicam and diclofenac), or steroidal anti-inflammatory drugs (SAIDs) (methylprednisolone and prednisolone). Chondrocyte gene expression profile was analysed using microarrays. Real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay were performed for validation of microarray data.Genome-wide expression analysis revealed 110 RA-related genes in human chondrocytes: expression of catabolic mediators (inflammation, cytokines/chemokines, and matrix degradation) was induced, and expression of anabolic mediators (matrix synthesis and proliferation/differentiation) was repressed. Potential marker genes to define and influence cartilage/chondrocyte integrity and regeneration were determined and include already established genes (COX-2, CXCR-4, IL-1RN, IL-6/8, MMP-10/12, and TLR-2) and novel genes (ADORA2A, BCL2-A1, CTGF, CXCR-7, CYR-61, HSD11B-1, IL-23A, MARCKS, MXRA-5, NDUFA4L2, NR4A3, SMS, STS, TNFAIP-2, and TXNIP). Antirheumatic treatment with SAIDs showed complete and strong reversion of RA-related gene expression in human chondrocytes, whereas treatment with NSAIDs and the DMARD chloroquine phosphate had only moderate to minor effects. Treatment with the DMARDs azathioprine, gold sodium thiomalate, and methotrexate efficiently reverted chondrocyte RA-related gene expression toward the 'healthy' level. Pathways of cytokine-cytokine receptor interaction, transforming grow
Key regulatory molecules of cartilage destruction in rheumatoid arthritis: an in vitro study
Kristin Andreas, Carsten Lübke, Thomas H?upl, Tilo Dehne, Lars Morawietz, Jochen Ringe, Christian Kaps, Michael Sittinger
Arthritis Research & Therapy , 2008, DOI: 10.1186/ar2358
Abstract: Human chondrocytes were cultured three-dimensionally for 14 days in alginate beads and subsequently stimulated for 48 hours with supernatants from SV40 T-antigen immortalized human synovial fibroblasts (SF) derived from a normal donor (NDSF) and from a patient with RA (RASF), respectively. To identify RA-related factors released from SF, supernatants of RASF and NDSF were analyzed with antibody-based protein membrane arrays. Stimulated cartilage-like cultures were used for subsequent gene expression profiling with oligonucleotide microarrays. Affymetrix GeneChip Operating Software and Robust Multi-array Analysis (RMA) were used to identify differentially expressed genes. Expression of selected genes was verified by real-time RT-PCR.Antibody-based protein membrane arrays of synovial fibroblast supernatants identified RA-related soluble mediators (IL-6, CCL2, CXCL1–3, CXCL8) released from RASF. Genome-wide microarray analysis of RASF-stimulated chondrocytes disclosed a distinct expression profile related to cartilage destruction involving marker genes of inflammation (adenosine A2A receptor, cyclooxygenase-2), the NF-κB signaling pathway (toll-like receptor 2, spermine synthase, receptor-interacting serine-threonine kinase 2), cytokines/chemokines and receptors (CXCL1–3, CXCL8, CCL20, CXCR4, IL-1β, IL-6), cartilage degradation (matrix metalloproteinase (MMP)-10, MMP-12) and suppressed matrix synthesis (cartilage oligomeric matrix protein, chondroitin sulfate proteoglycan 2).Differential transcriptome profiling of stimulated human chondrocytes revealed a disturbed catabolic–anabolic homeostasis of chondrocyte function and disclosed relevant pharmacological target genes of cartilage destruction. This study provides comprehensive insight into molecular regulatory processes induced in human chondrocytes during RA-related destruction of cartilage. The established model may serve as a human in vitro disease model of RA-related destruction of cartilage and may help to elucid
Therapie chronischer Schmerzen des Bewegungsapparates mit Opioiden
Ringe JD
Journal für Mineralstoffwechsel , 2002,
Abstract: Eine schmerzfreie Funktionsf higkeit des Bewegungsapparates ist ein hohes Gesundheitsgut. Den hohen Wert des "unbemerkten schmerzfreien Funktionierens" des lokomotorischen Systems wissen meist erst diejenigen richtig zu sch tzen, die an einer Erkrankung mit motorischen Einschr nkungen und Schmerzen leiden. Prim re Affektionen des Skeletts, der Gelenke oder der Muskulatur und ihrer Innervation k nnen zugrundeliegen. Die Diagnostik entsprechender Erkrankungen wird oft durch eine zu einseitige rheumatologische, osteologische, orthop dische oder neurologische Sicht erschwert. Es ist offensichtlich, da wichtige und intensive Wechselwirkungen zwischen Knochen, Gelenken und Muskulatur bestehen und eine ganzheitliche Sicht des Bewegungsapparates in vielen F llen hilfreich sein dürfte. Die praktische Erfahrung, da bei zahlreichen Erkrankungen des Bewegungsapparates die Patienten ihre Schmerzen nicht eindeutig als oss r, arthrogen oder myogen beschreiben k nnen, belegt die Notwendigkeit, den Bewegungsapparat als ein "Funktionssystem" zu betrachten. Andererseits betrifft bei vielen Erkrankungen das unspezifische Leitsymptom Schmerz mehrere Strukturen zugleich. Besonders schwere und in der Regel ohne Opiate nicht beherschbare Schmerzen des Bewegungsapparates treten bei metastatischen Skelettdestruktionen auf. In dieser übersicht soll jedoch die Therapie chronischer Schmerzen bei nichtmalignen Erkrankungen abgehandelt werden. Als zwei besonders h ufige und oft dramatische Beispiele werden die manifeste Osteoporose mit Wirbelfrakturen und die Osteoarthrose der Wirbels ule mit fortgeschrittenen degenerativen Ver nderungen dargestellt.
Osteoporose des alten Menschen: Pr vention und Therapie
Ringe JD
Journal für Mineralstoffwechsel , 2001,
Perspectives of combined treatment strategies in osteoporosis
Ringe JD
Journal für Menopause , 2000,
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