Publications by authors named "Nicolai Miosge"

67 Publications

Regulation of Anti-Apoptotic SOD2 and BIRC3 in Periodontal Cells and Tissues.

Int J Mol Sci 2021 Jan 8;22(2). Epub 2021 Jan 8.

Department of Periodontology and Operative Dentistry, University Medical Center, University of Mainz, 55131 Mainz, Germany.

The aim of the study was to clarify whether orthodontic forces and periodontitis interact with respect to the anti-apoptotic molecules superoxide dismutase 2 (SOD2) and baculoviral IAP repeat-containing protein 3 (BIRC3). SOD2, BIRC3, and the apoptotic markers caspases 3 (CASP3) and 9 (CASP9) were analyzed in gingiva from periodontally healthy and periodontitis subjects by real-time PCR and immunohistochemistry. SOD2 and BIRC3 were also studied in gingiva from rats with experimental periodontitis and/or orthodontic tooth movement. Additionally, SOD2 and BIRC3 levels were examined in human periodontal fibroblasts incubated with and/or subjected to mechanical forces. Gingiva from periodontitis patients showed significantly higher SOD2, BIRC3, CASP3, and CASP9 levels than periodontally healthy gingiva. SOD2 and BIRC3 expressions were also significantly increased in the gingiva from rats with experimental periodontitis, but the upregulation of both molecules was significantly diminished in the concomitant presence of orthodontic tooth movement. In vitro, SOD2 and BIRC3 levels were significantly increased by , but this stimulatory effect was also significantly inhibited by mechanical forces. Our study suggests that SOD2 and BIRC3 are produced in periodontal infection as a protective mechanism against exaggerated apoptosis. In the concomitant presence of orthodontic forces, this protective anti-apoptotic mechanism may get lost.
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http://dx.doi.org/10.3390/ijms22020591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827060PMC
January 2021

Donor variation and sex hormone receptors in periodontal ligament cells.

Arch Oral Biol 2021 Feb 9;122:105026. Epub 2020 Dec 9.

Tissue Regeneration Group, Department of Orthodontics, University Medical Center, Goettingen, Germany.

Objective: This study evaluated the gene expression and protein synthesis of sex hormone receptors in human periodontal ligament cells (PDLCs) in relation to donor- and tooth-specific factors with the aim to clarify the debate about sex hormone receptors in PDLCs.

Design: The expression patterns of estrogen receptors (genes: ESR1 and ESR2; proteins: ERα and ERβ), androgen receptor (AR) and progesterone receptor (PR) were investigated in the context of immortalization status, previous orthodontic tooth movement (OTM), donor age, sex and hormonal stimulation in PDLCs from 14 healthy donors (male: n = 8, female: n = 6; adolescents: n = 8, adults: n = 6) using quantitative real-time polymerase chain reaction, Western blot and immunocytochemistry.

Results: For ERβ, the full-length isoform ERβ1 and truncated variants were detected. For ERα, the expected isoform ERα66 was not observed, but a novel isoform ERα36 was detected. Immortalization status, previous OTM and donor age had no impact on ESR1 and ESR2 expression. Estradiol stimulation for 24 h doubled the ratio of ESR2/ESR1 in PDLCs from female but not male donors, indicating sex-specific patterns of receptor expression. AR and PR demonstrated insufficient protein synthesis in PDLCs.

Conclusions: The data revealed a pivotal role for and complex interplay between ERα and ERβ in human PDLCs regardless of variable donor characteristics. Therefore, PDLC biology might be altered in patients of each age group and both sexes due to hormonal changes. This should be kept in mind during periodontic and orthodontic treatment of patients with special hormonal status.
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http://dx.doi.org/10.1016/j.archoralbio.2020.105026DOI Listing
February 2021

SMURF1 and SMURF2 in Progenitor Cells from Articular Cartilage and Meniscus during Late-Stage Osteoarthritis.

Cartilage 2020 Oct 22:1947603520967069. Epub 2020 Oct 22.

Oral Biology and Tissue Regeneration Work Group, University Medical Center Goettingen, Göttingen, Germany.

Objective: The aim of this study was to investigate the roles of SMURF1 and SMURF2 in progenitor cells from the human knee in late-stage osteoarthritis (OA).

Design: We applied immunohistochemistry, immunocytochemistry, RNAi, lentiviral transfection, and Western blot analysis. We obtained chondrogenic progenitor cells (CPCs) from the articular cartilage and meniscus progenitor cells (MPCs) from the nonvascularized part of the meniscus.

Results: SMURF1 and SMURF2 appeared in both osteoarthritic tissues. CPCs and MPCs exhibited comparable amounts of these proteins, which influence the balance between RUNX2 and SOX9. The overexpression of SMURF1 reduced the levels of RUNX2, SOX9, and TGFBR1. The overexpression of SMURF2 also reduced the levels of RUNX2 and TGFBR1, while SOX9 levels were not affected. The knockdown of SMURF1 had no effect on RUNX2, SOX9, or TGFBR1. The knockdown of SMURF2 enhanced RUNX2 and SOX9 levels in CPCs. The respective protein levels in MPCs were not affected.

Conclusions: This study shows that SMURF1 and SMURF2 are regulatory players for the expression of the major regulator transcription factors RUNX2 and SOX9 in CPCs and MPCs. Our novel findings may help elucidate new treatment strategies for cartilage regeneration.
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http://dx.doi.org/10.1177/1947603520967069DOI Listing
October 2020

Decreased Expression of the Human Urea Transporter SLC14A1 in Bone is Induced by Cytokines and Stimulates Adipogenesis of Mesenchymal Progenitor Cells.

Exp Clin Endocrinol Diabetes 2020 Sep 20;128(9):582-595. Epub 2020 Jan 20.

Clinic of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany.

The human urea transporter SLC14A1 (HUT11/UT-B) has been suggested as a marker for the adipogenic differentiation of bone cells with a relevance for bone diseases. We investigated the function of SLC14A1 in different cells models from bone environment. SLC14A1 expression and cytokine production was investigated in bone cells obtained from patients with osteoporosis. Gene and protein expression of SLC14A1 was studied during adipogenic or osteogenic differentiation of human mesenchymal progenitor cells (hMSCs) and of the single-cell-derived hMSC line (SCP-1), as well as in osteoclasts and chondrocytes. Localization was determined by histochemical methods and functionality by urea transport experiments. Expression of SLC14A1 mRNA was lower in cells from patients with osteoporosis that produced high levels of cytokines. Accordingly, when adding a combination of cytokines to SCP-1 SLC14A1 mRNA expression decreased. SLC14A1 mRNA expression decreased after both osteogenic and more pronounced adipogenic stimulation of hMSCs and SCP-1 cells. The highest SLC14A1 expression was determined in undifferentiated cells, lowest in chondrocytes and osteoclasts. Downregulation of SLC14A1 by siRNA resulted in an increased expression of interleukin-6 and interleukin-1 beta as well as adipogenic markers. Urea influx through SLC14A1 increased expression of osteogenic markers, adipogenic markers were suppressed. SLC14A1 protein was localized in the cell membrane and the cytoplasm. Summarizing, the SLC14A1 urea transporter affects early differentiation of hMSCs by diminishing osteogenesis or by favoring adipogenesis, depending on its expression level. Therefore, SLC14A1 is not unequivocally an adipogenic marker in bone. Our findings suggest an involvement of SLC14A1 in bone metabolism and inflammatory processes and disease-dependent influences on its expression.
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http://dx.doi.org/10.1055/a-1084-3888DOI Listing
September 2020

Molecular phenotyping of the surfaceome of migratory chondroprogenitors and mesenchymal stem cells using biotinylation, glycocapture and quantitative LC-MS/MS proteomic analysis.

Sci Rep 2019 06 21;9(1):9018. Epub 2019 Jun 21.

Centre for Sport, Exercise and Osteoarthritis Research Versus Arthritis, Queen's Medical Centre, Nottingham, NG7 2UH, United Kingdom.

The complement of cell surface proteins, collectively referred to as the surfaceome, is a useful indicator of normal differentiation processes, and the development of pathologies such as osteoarthritis (OA). We employed biochemical and proteomic tools to explore the surfaceome and to define biomarkers in chondrogenic progenitor cells (CPC) derived from human OA knee articular cartilage. These cells have great therapeutic potential, but their unexplored biology limits their clinical application. We performed biotinylation combined with glycocapture and high throughput shotgun proteomics to define the surface proteome of human bone marrow mesenchymal stem cells (MSCs) and human CPCs. We prepared cell surface protein-enriched fractions from MSCs and CPCs, and then a proteomic approach was used to compare and evaluate protein changes between undifferentiated MSCs and CPCs. 1256 proteins were identified in the study, of which 791 (63%) were plasma membrane, cell surface or extracellular matrix proteins. Proteins constituting the surfaceome were annotated and categorized. Our results provide, for the first time, a repository of quantitative proteomic data on the surfaceome of two closely related cell types relevant to cartilage biology and OA. These results may provide novel insights into the transformation of the surfaceome during chondrogenic differentiation and phenotypic changes during OA development.
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http://dx.doi.org/10.1038/s41598-019-44957-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588563PMC
June 2019

High Mobility Group Box 1 Protein in Osteoarthritic Knee Tissue and Chondrogenic Progenitor Cells: An Ex Vivo and In Vitro Study.

Cartilage 2019 Mar 26:1947603519835897. Epub 2019 Mar 26.

1 Tissue Regeneration and Oral Biology Work Group, Department of Prosthodontics, Georg August University, Gottingen, Germany.

Objective: In osteoarthritis (OA), a loss of healthy cartilage extracellular matrix (ECM) results in cartilage degeneration. Attracting chondrogenic progenitor cells (CPCs) to injury sites and stimulating them toward chondrogenic expression profiles is a regenerative approach in OA therapy. High mobility group box 1 protein (HMGB1) is associated with chemoattractant and proinflammatory effects in various pathological processes. Here, we investigate the migratory effects of HMGB1 in knee OA and CPCs for the first time.

Design: Immunohistochemistry, immunoblotting, and immunocytochemistry were performed to identify HMGB1 and its receptors, receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4) in OA knee tissue, chondrocytes, and CPCs. In situ hybridization for HMGB1 mRNA was performed in CPCs ex vivo. The chemoattractant effects of HMGB1 on CPCs were analyzed in cell migration assays.

Results: HMGB1 expression in OA tissue and OA chondrocytes was higher than in healthy specimens and cells. HMGB1, RAGE, and TLR4 were expressed in CPCs and chondrocytes. In situ hybridization revealed HMGB1 mRNA in CPCs after migration into OA knee tissue, and immunohistochemistry confirmed HMGB1 expression at the protein level. Stimulation via HMGB1 significantly increased the migration of CPCs.

Conclusions: Our results show the chemoattractant role of HMGB1 in knee OA. HMGB1 is released by chondrocytes and has migratory effects on CPCs. These effects might be mediated via RAGE and TLR4. The in vitro and ex vivo results of this study need to be confirmed in vivo.
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http://dx.doi.org/10.1177/1947603519835897DOI Listing
March 2019

The Influence of TGF-β3, EGF, and BGN on SOX9 and RUNX2 Expression in Human Chondrogenic Progenitor Cells.

J Histochem Cytochem 2019 02 15;67(2):117-127. Epub 2018 Nov 15.

Tissue Regeneration Work Group, Department of Prosthodontics.

Osteoarthritis (OA) is the most common chronic joint disease and leads to the degradation of the extracellular matrix by an imbalance between anabolic and catabolic processes. TGF-β3 (transforming growth factor beta-3) and epidermal growth factor (EGF) influence the osteochondrogenic potential of chondrocytes. In this study, we compared the expression of mediators and receptors in the TGF-β3 and EGF pathways, as well as biglycan (BGN), in healthy and diseased chondrocytes. Furthermore, we used chondrogenic progenitor cells (CPCs) for in vitro stimulation and knockdown experiments to elucidate the effects of TGF-β3 and EGF on the chondrogenic potential. Our results demonstrate that the expression of TGF-beta receptor type-1 (TGFBRI) and epidermal growth factor receptor (EGFR) is altered in diseased chondrocytes as well as in CPCs. Moreover, TGF-β3 and EGF stimulation influenced the expression levels of BGN, SRY (sex determining region Y)-box 9 (SOX9), and Runt-related transcription factor 2 (RUNX2) in CPCs. Therefore, changes in TGFBRI and EGFR expression likely contribute to the degenerative and regenerative effects seen in late stages of OA.
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http://dx.doi.org/10.1369/0022155418811645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354316PMC
February 2019

Cytotoxic effects to mouse and human gingival fibroblasts of a nanohybrid ormocer versus dimethacrylate-based composites.

Clin Oral Investig 2019 Jan 30;23(1):133-139. Epub 2018 Mar 30.

Tissue Regeneration and Oral Biology Work Group, Department of Prosthodontics, Georg August University, Robert-Koch-Str. 40, 37075, Goettingen, Germany.

Objectives: Tooth-colored composites have emerged as a standard restorative material in caries therapy and have largely replaced materials such as silver amalgam or glass ionomer cements. In addition to their superior esthetics and desirable mechanical properties, composites also comprise negative characteristics, such as wear, shrinkage, and an adverse biocompatibility. Modifications of classic resin-based dental composites have been developed to overcome these shortcomings. For example, ormocers are innovative inorganic-organic hybrid polymers that form a siloxane network modified by the incorporation of organic groups. Recently, a new ormocer, Admira Fusion (VOCO), was introduced to composite technology. The absence of cytotoxic matrix monomers leads to the hypothesis that ormocers have improved biocompatibility compared to resin-based dental restorative materials.

Materials And Methods: The aim of this study was to compare the cytotoxic effects of Admira Fusion to a nanohybrid composite (GrandioSO, VOCO) and a nanofiller composite (Filtek Supreme XTE, 3M Espe) on the standard dermal mouse fibroblasts (L929) and human gingival fibroblasts (GF-1) via a Cell Counting Kit-8 (CCK-8) assay.

Results: Admira Fusion was significantly less cytotoxic than GrandioSO and Filtek Supreme XTE to both the standard mouse dermal fibroblasts (L929) and human gingival fibroblasts.

Conclusions: Compared to other resin-based dental restorative materials, the ormocer (Admira Fusion) possesses a superior biocompatibility in vitro. Future research studies are needed to confirm our results.

Clinical Significance: Clinically, dental practitioners and their patients might benefit from Admira Fusion in terms of reduced adverse biologic reactions compared to resin-based dental restorative materials.
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http://dx.doi.org/10.1007/s00784-018-2419-9DOI Listing
January 2019

A new albumin-depletion strategy improves proteomic research of gingival crevicular fluid from periodontitis patients.

Clin Oral Investig 2018 Apr 9;22(3):1375-1384. Epub 2017 Oct 9.

Max Planck Institute for Biophysical Chemistry, Bioanalytical Mass Spectrometry Group, Am Fassberg 11, 37077, Goettingen, Germany.

Objectives: Gingival crevicular fluid (GCF), the inflammatory infiltrate within the crevicular sulcus, is of great importance for diverse processes in the oral cavity and has a high impact in oral sciences. It is assumed to serve as a source of biomarkers for systemic or periodontal diseases and mediators of orthodontic tooth movement. In order to characterize the protein content of the GCF in an unbiased and complete approach, we employed mass spectrometry (MS), which allows not only the identification, but also the quantification of these proteins. In samples obtained from patients suffering from periodontitis, this method is often limited due to the presence of highly abundant serum albumin deriving from serum. The aim of this investigation was to employ a protein precipitation procedure for the efficient depletion of serum albumin from GCF samples.

Materials And Methods: GFC samples collected from five adult periodontitis patients were fractionated by trichloroacetic acid/acetone precipitation and the resulting soluble and pelleted fractions were analyzed by SDS-PAGE and high-resolution mass spectrometry.

Results: Trichloroacetic acid/acetone precipitation was successfully employed as a protein precipitation procedure for the efficient depletion of serum albumin from GCF samples. Careful analysis revealed that the precipitation step reduced the serum albumin content efficiently, and increased subsequent protein identifications by 32%. Three hundred seventeen proteins could only be identified with this new approach.

Conclusion: The increased coverage of the GCF proteome will help improve our understanding of molecular mechanisms in the periodontium during pathogenesis of periodontitis.

Clinical Relevance: Our new albumin depletion strategy combined with high-resolution mass spectrometry can be used to effectively monitor the molecular signals of the periodontium.
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http://dx.doi.org/10.1007/s00784-017-2213-0DOI Listing
April 2018

Fibulins and matrilins are novel structural components of the periodontium in the mouse.

Arch Oral Biol 2017 Oct 13;82:216-222. Epub 2017 Jun 13.

Georg August University, Tissue Regeneration and Oral Biology Work Group, Department of Prosthodontics, Robert-Koch-Str. 40, 37075, Goettingen, Germany. Electronic address:

Periodontitis refers to inflammatory disease of the periodontal structures (the gingiva, dental cementum, periodontal ligament (PDL) and alveolar bone) that ultimately leads to their destruction. Whereas collagens are well-examined main components of the periodontium, little is known about the other structural proteins that make up this tissue. The aim of this study was to identify new extracellular matrix (ECM) components, including fibulins and matrilins, in the periodontium of mice. After sacrificing 14 mice (Sv/129 strain), jaws were prepared. Each tissue sample contained a molar and its surrounding alveolar bone. Immunohistochemistry was carried out on paraffin-embedded sections. Our results show that mice exhibit fibulin-3, -4 and -5 and matrilin-1, -2, -3 and -4 in PDL and in blood vessels of alveolar bone and PDL as well as in the pericellular matrix of osteocytes and cementocytes. In dental cementum, only fibulin-4 is expressed. For the first time, we show that fibulin-3, -4 and -5 and matrilin-1, -2, -3 and -4 are essential components of the periodontal tissues. Our findings indicate an association of these proteins with collagens and oxytalan fibers that might be of future interest in regenerative periodontitis therapy.
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http://dx.doi.org/10.1016/j.archoralbio.2017.06.008DOI Listing
October 2017

Mapping the secretome of human chondrogenic progenitor cells with mass spectrometry.

Ann Anat 2017 Jul 30;212:4-10. Epub 2017 Mar 30.

University Medical Center Göttingen, Tissue Regeneration Work Group, Robert-Koch-Straße 40, 37075 Göttingen, Germany.

Tissue engineering offers promising perspectives in the therapy of osteoarthritis. In the context of cell-based therapy, chondrogenic progenitor cells (CPCs) may be used to regenerate defects in cartilage tissue. An in-depth characterization of the secretome of CPCs is a prerequisite to this approach. In this study, a method was developed for the qualitative and quantitative analysis of the secretome of undifferentiated and differentiated CPCs. Secreted proteins from cells grown in two-dimensional as well as three-dimensional alginate cultures were extracted and analyzed by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Quantitation was achieved by internal standardization using stable isotope-labeled amino acids in cell culture (SILAC). Qualitative analysis of CPC secretomes revealed ECM-components, signal proteins and growth factors most of which were also found in healthy cartilage. A quantitative comparison revealed significantly upregulated proteins with regenerative potential during differentiation, while proteins involved in catabolic metabolism were significantly downregulated. The development of methods for qualitative and quantitative analysis of the secretome of CPCs by mass spectrometry provides a foundation for the investigation of progenitor or stem cells from other sources.
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http://dx.doi.org/10.1016/j.aanat.2017.03.003DOI Listing
July 2017

Distinct functions of the dual leucine zipper kinase depending on its subcellular localization.

Cell Signal 2016 Apr 9;28(4):272-83. Epub 2016 Jan 9.

Department of Pharmacology, University of Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany; Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; Institute of Pharmacy, University of Hamburg, Bundesstr. 45, 20146 Hamburg, Germany. Electronic address:

The dual leucine zipper kinase DLK induces β-cell apoptosis by inhibiting the transcriptional activity conferred by the β-cell protective transcription factor cAMP response element binding protein CREB. This action might contribute to β-cell loss and ultimately diabetes. Within its kinase domain DLK shares high homology with the mixed lineage kinase (MLK) 3, which is activated by tumor necrosis factor (TNF) α and interleukin (IL)-1β, known prediabetic signals. In the present study, the regulation of DLK in β-cells by these cytokines was investigated. Both, TNFα and IL-1β induced the nuclear translocation of DLK. Mutations within a putative nuclear localization signal (NLS) prevented basal and cytokine-induced nuclear localization of DLK and binding to the importin receptor importin α, thereby demonstrating a functional NLS within DLK. DLK NLS mutants were catalytically active as they phosphorylated their down-stream kinase c-Jun N-terminal kinase to the same extent as DLK wild-type but did neither inhibit CREB-dependent gene transcription nor transcription conferred by the promoter of the anti-apoptotic protein BCL-xL. In addition, the β-cell apoptosis-inducing effect of DLK was severely diminished by mutation of its NLS. In a murine model of prediabetes, enhanced nuclear DLK was found. These data demonstrate that DLK exerts distinct functions, depending on its subcellular localization and thus provide a novel level of regulating DLK action. Furthermore, the prevention of the nuclear localization of DLK as induced by prediabetic signals with consecutive suppression of β-cell apoptosis might constitute a novel target in the therapy of diabetes mellitus.
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http://dx.doi.org/10.1016/j.cellsig.2016.01.002DOI Listing
April 2016

Laminins and Nidogens in the Pericellular Matrix of Chondrocytes: Their Role in Osteoarthritis and Chondrogenic Differentiation.

Am J Pathol 2016 Feb 10;186(2):410-8. Epub 2015 Dec 10.

Department of Prosthodontics, Tissue Regeneration Work Group, Georg August University, Göttingen, Germany. Electronic address:

The aim of this study was to investigate the role of laminins and nidogen-2 in osteoarthritis (OA) and their potential to support chondrogenic differentiation. We applied immunohistochemistry, electron microscopy, siRNA, quantitative RT-PCR, Western blot, and proteome analysis for the investigation of cartilage tissue and isolated chondrocytes in three-dimensional culture obtained from patients with late-stage knee OA and nidogen-2 knockout mice. We demonstrate that subunits of laminins appear in OA cartilage and that nidogen-2-null mice exhibit typical osteoarthritic features. Chondrogenic progenitor cells (CPCs) produced high levels of laminin-α1, laminin-α5, and nidogen-2 in their pericellular matrix, and laminin-α1 enhanced collagen type II and reduced collagen type I expression by cultured CPCs. Nidogen-2 increased SOX9 gene expression. Knockdown of nidogen-2 reduced SOX9 expression, whereas it up-regulated RUNX2 expression. This study reveals that the influence of the pericellular matrix on CPCs is important for the expression of the major regulator transcription factors, SOX9 and RUNX2. Our novel findings that laminins and nidogen-2 drive CPCs toward chondrogenesis may help in the elucidation of new treatment strategies for cartilage tissue regeneration.
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http://dx.doi.org/10.1016/j.ajpath.2015.10.014DOI Listing
February 2016

Interleukin 17 inhibits progenitor cells in rheumatoid arthritis cartilage.

Eur J Immunol 2016 Feb 14;46(2):440-5. Epub 2015 Dec 14.

Department of Nephrology and Rheumatology, University Medical Center, Goettingen, Germany.

Mesenchymal stem cells are known to exert immunomodulatory effects in inflammatory diseases. Immuneregulatory cells lead to progressive joint destruction in rheumatoid arthritis (RA). Proinflammatory cytokines, such as tumour necrosis factor α (TNF-α) and interleukins (ILs) are the main players. Here, we studied progenitor cells from RA cartilage (RA-CPCs) that are positive for IL-17 receptors to determinate the effects of inflammation on their chondrogenic potenial. IL-17A/F reduced the chondrogenic potential of these cells via the upregulation of RUNX2 protein and enhanced IL-6 protein and MMP3 mRNA levels. Blocking antibodies against IL-17 positively influenced their repair potential. Furthermore, treating the RA-CPCs with the anti-human IL-17 antibody secukinumab or the anti-TNF-α antibody adalimumab reduced the proinflammatory IL-6 protein level and positively influenced the secretion of anti-inflammatory IL-10 protein. Additionally, adalimumab and secukinumab in particular reduced RUNX2 protein to promote chondrogenesis. The amelioration of inflammation, particularly via IL-17 antagonism, might be a new therapeutic approach for enhancing intrinsic cartilage repair mechanisms in RA patients.
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http://dx.doi.org/10.1002/eji.201545910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064647PMC
February 2016

Human migratory meniscus progenitor cells are controlled via the TGF-β pathway.

Stem Cell Reports 2014 Nov 25;3(5):789-803. Epub 2014 Sep 25.

Tissue Regeneration Work Group, Department of Prosthodontics, Medical Faculty, Georg-August-University, 37075 Goettingen, Germany. Electronic address:

Degeneration of the knee joint during osteoarthritis often begins with meniscal lesions. Meniscectomy, previously performed extensively after meniscal injury, is now obsolete because of the inevitable osteoarthritis that occurs following this procedure. Clinically, meniscus self-renewal is well documented as long as the outer, vascularized meniscal ring remains intact. In contrast, regeneration of the inner, avascular meniscus does not occur. Here, we show that cartilage tissue harvested from the avascular inner human meniscus during the late stages of osteoarthritis harbors a unique progenitor cell population. These meniscus progenitor cells (MPCs) are clonogenic and multipotent and exhibit migratory activity. We also determined that MPCs are likely to be controlled by canonical transforming growth factor β (TGF-β) signaling that leads to an increase in SOX9 and a decrease in RUNX2, thereby enhancing the chondrogenic potential of MPC. Therefore, our work is relevant for the development of novel cell biological, regenerative therapies for meniscus repair.
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http://dx.doi.org/10.1016/j.stemcr.2014.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4235742PMC
November 2014

Cartilage repair in vivo: the role of migratory progenitor cells.

Curr Rheumatol Rep 2014 Nov;16(11):461

Tissue Regeneration Work Group, Department of Prosthodontics, Georg August University, Robert-Koch-Str. 40, 37075, Göttingen, Germany.

The most common diseases of the joints and its tissues are osteoarthritis and rheumatoid arthritis, with osteoarthritis being anticipated to be the fourth leading cause of disability by the year 2020. To date, no truly causal therapies are available, and this has promoted tissue engineering attempts mainly involving mesenchymal stem cells. The goal of all tissue repairs would be to restore a fully functional tissue, here a hyaline articular cartilage. The hyaline cartilage is the most affected in osteoarthritis, where altered cell-matrix interactions gradually destroy tissue integrity. In rheumatoid arthritis, the inflammatory aspect is more important, and the cartilage tissue is destroyed by the invasion of tumor-like pannus tissue arising from the inflamed synovia. Furthermore, the fibrocartilage of the meniscus is clearly involved in the initiation of osteoarthritis, especially after trauma. Recent investigations have highlighted the role of migratory progenitor cells found in diseased tissues in situ. In osteoarthritis and rheumatoid arthritis, these chondrogenic progenitor cells are involved in regeneration efforts that are largely unsuccessful in diseased cartilage tissue. However, these progenitor cells are interesting targets for a cell-based regenerative therapy for joint diseases.
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http://dx.doi.org/10.1007/s11926-014-0461-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169867PMC
November 2014

The growth plate's response to load is partially mediated by mechano-sensing via the chondrocytic primary cilium.

Cell Mol Life Sci 2015 Feb 2;72(3):597-615. Epub 2014 Aug 2.

Institute of Biochemistry and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University, P.O. Box 12, 76100, Rehovot, Israel.

Mechanical load plays a significant role in bone and growth-plate development. Chondrocytes sense and respond to mechanical stimulation; however, the mechanisms by which those signals exert their effects are not fully understood. The primary cilium has been identified as a mechano-sensor in several cell types, including renal epithelial cells and endothelium, and accumulating evidence connects it to mechano-transduction in chondrocytes. In the growth plate, the primary cilium is involved in several regulatory pathways, such as the non-canonical Wnt and Indian Hedgehog. Moreover, it mediates cell shape, orientation, growth, and differentiation in the growth plate. In this work, we show that mechanical load enhances ciliogenesis in the growth plate. This leads to alterations in the expression and localization of key members of the Ihh-PTHrP loop resulting in decreased proliferation and an abnormal switch from proliferation to differentiation, together with abnormal chondrocyte morphology and organization. Moreover, we use the chondrogenic cell line ATDC5, a model for growth-plate chondrocytes, to understand the mechanisms mediating the participation of the primary cilium, and in particular KIF3A, in the cell's response to mechanical stimulation. We show that this key component of the cilium mediates gene expression in response to mechanical stimulation.
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http://dx.doi.org/10.1007/s00018-014-1690-4DOI Listing
February 2015

Purinergic signalling is required for calcium oscillations in migratory chondrogenic progenitor cells.

Pflugers Arch 2015 Feb 21;467(2):429-42. Epub 2014 May 21.

Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032, Debrecen, Hungary.

Osteoarthritis (OA) is the most common form of chronic musculoskeletal disorders. A migratory stem cell population termed chondrogenic progenitor cells (CPC) with in vitro chondrogenic potential was previously isolated from OA cartilage. Since intracellular Ca(2+) signalling is an important regulator of chondrogenesis, we aimed to provide a detailed understanding of the Ca(2+) homeostasis of CPCs. In this work, CPCs immortalised by lentiviral administration of the human telomerase reverse transcriptase (hTERT) and grown in monolayer cultures were studied. Expressions of all three IP3Rs were confirmed, but no RyR subtypes were detected. Ca(2+) oscillations observed in CPCs were predominantly dependent on Ca(2+) release and store replenishment via store-operated Ca(2+) entry; CPCs express both STIM1 and Orai1 proteins. Expressions of adenosine receptor mRNAs were verified, and adenosine elicited Ca(2+) transients. Various P2 receptor subtypes were identified; P2Y1 can bind ADP; P2Y4 is targeted by UTP; and ATP may evoke Ca(2+) transients via detected P2X subtypes, as well as P2Y1 and P2Y2. Enzymatic breakdown of extracellular nucleotides by apyrase completely abrogated Ca(2+) oscillations, suggesting that an autocrine/paracrine purinergic mechanism may drive Ca(2+) oscillations in these cells. As CPCs possess a broad spectrum of functional molecular elements of Ca(2+) signalling, Ca(2+)-dependent regulatory mechanisms can be supposed to influence their differentiation potential.
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http://dx.doi.org/10.1007/s00424-014-1529-8DOI Listing
February 2015

Norepinephrine inhibition of mesenchymal stem cell and chondrogenic progenitor cell chondrogenesis and acceleration of chondrogenic hypertrophy.

Arthritis Rheumatol 2014 Sep;66(9):2472-81

University Hospital Regensburg, Regensburg, Germany.

Objective: Mesenchymal progenitor cell chondrogenesis is the biologic platform for the generation or regeneration of cartilage, but the external influence of the sympathetic nervous system on this process is not yet known. Sympathetic nerve fibers are present in articular tissue, and the sympathetic nervous system influences the musculoskeletal system by, for example, increasing osteoclastogenesis. This study was initiated to explore the role of the sympathetic neurotransmitter norepinephrine (NE) in mesenchymal stem cell (MSC)-dependent and cartilage progenitor cell (CPC)-dependent chondrogenesis.

Methods: Using human MSCs or CPCs, chondrogenic differentiation was induced in the presence of NE, the specific β-adrenergic receptor (β-AR) agonist isoproterenol, and the specific β-AR antagonist nadolol. We studied sympathetic nerve fibers, tyrosine hydroxylase (TH) expression, catecholamine biosynthesis, and synovial fluid levels in human joints, as well as cartilage-specific matrix deposition during differentiation.

Results: TH+ sympathetic nerve fibers were present in the synovial tissue, meniscus, and subchondral bone marrow. In addition, synovial fluid from patients with knee trauma demonstrated high concentrations of NE. During MSC or CPC chondrogenesis, β-AR were expressed. Chondrogenic aggregates treated with NE or isoproterenol synthesized lower amounts of type II collagen and glycosaminoglycans. NE and isoproterenol treatment dose-dependently increased the levels of cartilage hypertrophy markers (type X collagen and matrix metalloproteinase 13). Nadolol reversed the inhibition of chondrogenesis and the up-regulation of cartilage hypertrophy.

Conclusion: Our findings demonstrate NE-dependent inhibition of chondrogenesis and acceleration of hypertrophic differentiation. By inhibiting cartilage repair, these sympathetic influences can be important after joint trauma. These findings may be a basis for novel neurochondrogenic therapeutic options.
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http://dx.doi.org/10.1002/art.38695DOI Listing
September 2014

Collagen receptors integrin alpha2beta1 and discoidin domain receptor 1 regulate maturation of the glomerular basement membrane and loss of integrin alpha2beta1 delays kidney fibrosis in COL4A3 knockout mice.

Matrix Biol 2014 Feb 27;34:13-21. Epub 2014 Jan 27.

Clinic of Nephrology and Rheumatology, University Medicine Goettingen, Goettingen, Germany. Electronic address:

Maturation of the glomerular basement membrane (GBM) is essential for maintaining the integrity of the renal filtration barrier. Impaired maturation causes proteinuria and renal fibrosis in the type IV collagen disease Alport syndrome. This study evaluates the role of collagen receptors in maturation of the GBM, matrix accumulation and renal fibrosis by using mice deficient for discoidin domain receptor 1 (DDR1), integrin subunit α2 (ITGA2), and type IV collagen α3 (COL4A3). Loss of both collagen receptors DDR1 and integrin α2β1 delays maturation of the GBM: due to a porous GBM filtration barrier high molecular weight proteinuria that more than doubles between day 60 and day 100. Thereafter, maturation of the GBM causes proteinuria to drop down to one tenth until day 200. Proteinuria and the porous GBM cause accumulation of glomerular and tubulointerstitial matrix, which both decrease significantly after GBM-maturation until day 250. In parallel, in a disease with impaired GBM-maturation such as Alport syndrome, loss of integrin α2β1 positively delays renal fibrosis: COL4A3(-/-)/ITGA2(-/-) double knockouts exhibited reduced proteinuria and urea nitrogen compared to COL4A3(-/-)/ITGA2(+/-) and COL4A3(-/-)/ITGA2(+/+) mice. The double knockouts lived 20% longer and showed less glomerular and tubulointerstitial extracellular matrix deposition than the COL4A3(-/-) Alport mice with normal integrin α2β1 expression. Electron microscopy illustrated improvements in the glomerular basement membrane structure. MMP2, MMP9, MMP12 and TIMP1 were expressed at significantly higher levels (compared to wild-type mice) in COL4A3(-/-)/ITGA2(+/+) Alport mice, but not in COL4A3(+/+)/ITGA2(-/-) mice. In conclusion, the collagen receptors DDR1 and integrin α2β1 contribute to regulate GBM-maturation and to control matrix accumulation. As demonstrated in the type IV collagen disease Alport syndrome, glomerular cell-matrix interactions via collagen receptors play an important role in the progression of renal fibrosis.
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http://dx.doi.org/10.1016/j.matbio.2014.01.006DOI Listing
February 2014

A discoidin domain receptor 1 knock-out mouse as a novel model for osteoarthritis of the temporomandibular joint.

Cell Mol Life Sci 2014 Mar 4;71(6):1081-96. Epub 2013 Aug 4.

Oral Biology and Tissue Regeneration Work Group, Department of Prosthodontics, Medical Faculty, Georg-August-University, Robert Koch Straße 40, 37075, Goettingen, Germany.

Discoidin domain receptor 1 (DDR-1)-deficient mice exhibited a high incidence of osteoarthritis (OA) in the temporomandibular joint (TMJ) as early as 9 weeks of age. They showed typical histological signs of OA, including surface fissures, loss of proteoglycans, chondrocyte cluster formation, collagen type I upregulation, and atypical collagen fibril arrangements. Chondrocytes isolated from the TMJs of DDR-1-deficient mice maintained their osteoarthritic characteristics when placed in culture. They expressed high levels of runx-2 and collagen type I, as well as low levels of sox-9 and aggrecan. The expression of DDR-2, a key factor in OA, was increased. DDR-1-deficient chondrocytes from the TMJ were positively influenced towards chondrogenesis by a three-dimensional matrix combined with a runx-2 knockdown or stimulation with extracellular matrix components, such as nidogen-2. Therefore, the DDR-1 knock-out mouse can serve as a novel model for temporomandibular disorders, such as OA of the TMJ, and will help to develop new treatment options, particularly those involving tissue regeneration.
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http://dx.doi.org/10.1007/s00018-013-1436-8DOI Listing
March 2014

Current concepts in stem cell therapy for articular cartilage repair.

Expert Opin Biol Ther 2013 Apr 16;13(4):541-8. Epub 2013 Jan 16.

Georg August University, Tissue Regeneration Work Group, Department of Prosthodontics, Goettingen, Germany.

Introduction: Hyaline articular cartilage is the connective tissue responsible for frictionless joint movement. Its degeneration ultimately results in complete loss of joint function in the late stages of osteoarthritis. Intrinsic repair is compromised, and cartilage tissue regeneration is difficult. However, new options are available to repair cartilage tissue by applying ESCs, MSCs and CPCs.

Areas Covered: In this review, the authors shed light on the different concepts currently under investigation for cartilage repair.

Expert Opinion: So far, there is no way to derive a chondrogenic lineage from stem cells that forms functional hyaline cartilage tissue in vivo. One alternative might be to enhance the chondrogenic potential of repair cells, which are already present in diseased cartilage tissue. CPCs found in diseased cartilage tissue in situ are biologically driven toward the osteochondrogenic lineage and can be directed toward chondrogenesis at least in vitro.
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http://dx.doi.org/10.1517/14712598.2013.758707DOI Listing
April 2013

Plasma leakage through glomerular basement membrane ruptures triggers the proliferation of parietal epithelial cells and crescent formation in non-inflammatory glomerular injury.

J Pathol 2012 Dec 26;228(4):482-94. Epub 2012 Jul 26.

Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Germany.

Glomerular crescents are most common in rapidly progressive glomerulonephritis but also occur in non-inflammatory chronic glomerulopathies; thus, factors other than inflammation should trigger crescent formation, eg vascular damage and plasma leakage. Here we report that Alport nephropathy in Col4A3-deficient Sv129 mice is complicated by diffuse and global crescent formation in which proliferating parietal epithelial cells are the predominant cell type. Laminin staining and transmission and acellular scanning electron microscopy of acellular glomeruli documented disruptions and progressive disintegration of the glomerular basement membrane in Col4A3-deficient mice. FITC-dextran perfusion further revealed vascular leakage from glomerular capillaries into Bowman's space, further documented by fibrin deposits in the segmental crescents. Its pathogenic role was validated by showing that the fibrinolytic activity of recombinant urokinase partially prevented crescent formation. In addition, in vitro studies confirmed an additional mitogenic potential of serum on murine and human parietal epithelial cells. Furthermore, loss of parietal cell polarity and unpolarized secretion of extracellular matrix components were evident within fibrocellular crescents. Among 665 human Alport nephropathy biopsies, crescent formation was noted in 0.4%. We conclude that glomerular vascular injury and GBM breaks cause plasma leakage which triggers a wound healing programme involving the proliferation of parietal cells and their loss of polarity. This process can trigger cellular and fibrocellular crescent formation even in the absence of cellular inflammation and rupture of the Bowman's capsule.
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http://dx.doi.org/10.1002/path.4046DOI Listing
December 2012

New insights into cartilage repair - the role of migratory progenitor cells in osteoarthritis.

Matrix Biol 2012 Apr 14;31(3):206-13. Epub 2012 Jan 14.

Tissue regeneration work group, Department of Prosthodontics, Georg August University, Goettingen, Germany.

Osteoarthritis is one of the most common musculo-skeletal diseases with a complex patholoy and a strong impact on cell biology, differentiation and migration behavior of mesenchymal stem cell-derived progenitor cells. In this review, we elucidate the influence of the pathologically altered extracellular matrix on progenitor cell behavior. Moreover, we discuss the modulation of progenitor cells especially of previously characterized chondrogenic progenitor cells (Koelling et al., 2009) in situ to enhance their regeneration potential. These options comprise the application of growth factors like fibroblast growth factor-2, a Runx-2 knock down and a contemporary anti-inflammatory therapy. This supports endogenous regeneration on behalf of the diseased osteoarthritic cartilage, which otherwise results mainly in an insufficient fibro-cartilaginous repair tissue. Furthermore, new results indicate a role of pericytes in osteoarthritis for these repair attempts. We discuss the biological mechanisms potentially leading to new therapeutic options in osteoarthritis to enhance regeneration in situ.
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http://dx.doi.org/10.1016/j.matbio.2012.01.007DOI Listing
April 2012

Absence of the basement membrane component nidogen 2, but not of nidogen 1, results in increased lung metastasis in mice.

J Histochem Cytochem 2012 Apr 19;60(4):280-9. Epub 2012 Jan 19.

Department of Dermatology, University Hospital Cologne, Cologne, Germany.

Nidogen 1 and 2 are ubiquitous basement membrane (BM) components. They show a divergent expression pattern in certain adult tissues with a prominent localization of nidogen 2 in blood vessel BMs. Deletion of either nidogen 1 or 2 in mice had no effect on BM formation, suggesting complementary functions. However, studies in these mice revealed isoform-specific functions with nidogen 1-deficient mice showing neurological abnormalities and wound-healing defects not seen in the absence of nidogen 2. To investigate this further nidogen 1- or 2-deficient mice were intravenously injected with B16 murine melanoma cells, and lung metastasis was analyzed. The authors could show that loss of nidogen 2, but not of nidogen 1, significantly promotes lung metastasis of melanoma cells. Histological and ultrastructural analysis of nidogen 1- and 2-deficient lungs did not reveal differences in morphology and ultrastructure of BMs, including vessel BMs. Furthermore, deposition and distribution of the major BM components were indistinguishable between the two mouse strains. Taken together, these results suggest that absence of nidogen 2 might result in subtle changes of endothelial BMs in the lung, which would allow faster passage of tumor cells through these BMs, leading to a higher metastasis rate and more larger tumors.
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http://dx.doi.org/10.1369/0022155412436586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3351237PMC
April 2012

The primary cilium as a dual sensor of mechanochemical signals in chondrocytes.

Cell Mol Life Sci 2012 Jul 13;69(13):2101-7. Epub 2012 Jan 13.

Department of Prosthodontics, Georg August University, Goettingen, Germany.

The primary cilium is an immotile, solitary, and microtubule-based structure that projects from cell surfaces into the extracellular environment. The primary cilium functions as a dual sensor, as mechanosensors and chemosensors. The primary cilia coordinate several essential cell signaling pathways that are mainly involved in cell division and differentiation. A primary cilium malfunction can result in several human diseases. Mechanical loading is sense by mechanosensitive cells in nearly all tissues and organs. With this sensation, the mechanical signal is further transduced into biochemical signals involving pathways such as Akt, PKA, FAK, ERK, and MAPK. In this review, we focus on the fundamental functional and structural features of primary cilia in chondrocytes and chondrogenic cells.
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http://dx.doi.org/10.1007/s00018-011-0911-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375420PMC
July 2012

Tumour necrosis factor-α drives Alport glomerulosclerosis in mice by promoting podocyte apoptosis.

J Pathol 2012 Jan 26;226(1):120-31. Epub 2011 Sep 26.

Nephrologisches Zentrum, University of München, Germany.

Chronic renal failure involves the progressive loss of renal parenchymal cells. For example, Alport syndrome develops from mutated type IV collagen that fosters the digestion of glomerular basement membranes and podocyte loss, followed by progressive glomerulosclerosis, ie Alport nephropathy. Here we show that autosomal recessive Alport nephropathy in collagen 4a3-deficient mice is associated with increased intrarenal expression of the pro-apoptotic cytokine tumour necrosis factor-alpha (TNF-α) in glomerular cells including podocytes as well as in infiltrating leukocytes. We therefore hypothesized that TNF-α contributes to Alport glomerulosclerosis by inducing podocyte apoptosis. To address this issue, we treated 4-week-old collagen 4a3-deficient mice with either vehicle or the TNF-α antagonist etanercept for a period of 5 weeks. Etanercept treatment prolonged mean survival from 68 to 81 days as compared to vehicle-treated mice. The beneficial effect of etanercept on survival was associated with a significant improvement of the glomerulosclerosis score, proteinuria, and the glomerular filtration rate at 9 weeks of age. Etanercept treatment specifically reduced the numbers of apoptotic podocytes, increased total podocyte counts, and increased the renal mRNA expression of nephrin and podocin without affecting markers of renal inflammation. TNF-α-induced podocyte loss is a previously unrecognized pathological mechanism of Alport glomerulosclerosis, and TNF-α blockade might be a therapeutic option to delay the progression of Alport nephropathy and potentially of other forms of glomerulosclerosis.
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http://dx.doi.org/10.1002/path.2979DOI Listing
January 2012

Fibrillin-3 expression in human development.

Matrix Biol 2011 Jan 21;30(1):43-52. Epub 2010 Oct 21.

Faculty of Medicine, Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada.

Fibrillin proteins are the major components of extracellular microfibrils found in many connective tissues. Fibrillin-1 and fibrillin-2 are well studied and mutations in these proteins cause a number of fibrillinopathies including Marfan syndrome and congenital contractural arachnodactyly, respectively. Fibrillin-3 was more recently discovered and is much less well characterized. Fibrillin-1 is expressed throughout life, whereas fibrillins-2 and -3 are thought to be primarily present during development. Here, we report detailed fibrillin-3 expression patterns in early human development. A polyclonal antiserum against a C-terminal recombinant half of human fibrillin-3 was produced in rabbit. Anti-fibrillin-3 antibodies were affinity-purified and antibodies cross-reacting with the other fibrillins were removed by absorption resulting in specific anti-fibrillin-3 antibodies. Immunohistochemical analyses with these purified antibodies demonstrate that fibrillin-3 is temporally expressed in numerous tissues relatively evenly from the 6th to the 12th gestational week. Fibrillin-3 was found spatially expressed in perichondrium, perineurium, perimysium, skin, developing bronchi, glomeruli, pancreas, kidney, heart and testis and at the prospective basement membranes in developing epithelia and endothelia. Double immunohistochemical analyses showed that all fibrillins are globally expressed in the same organs, with a number of differences on the tissue level in cartilage, perichondrium and developing bronchi. These results suggest that fibrillin-3, compared to the other fibrillins, fulfills both overlapping and distinct functions in human development.
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http://dx.doi.org/10.1016/j.matbio.2010.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961473PMC
January 2011

Bacterial CpG-DNA accelerates Alport glomerulosclerosis by inducing an M1 macrophage phenotype and tumor necrosis factor-α-mediated podocyte loss.

Kidney Int 2011 Jan 20;79(2):189-98. Epub 2010 Oct 20.

Nephrologisches Zentrum, Medizinische Poliklinik der LMU, University of München, München, Germany.

Loss of function mutations in the α3 or α4 chain of type IV collagen cause Alport nephropathy, characterized by progressive glomerulosclerosis. While studying the mechanisms that determine disease progression, we found that the evolution of kidney disease in Col4a3-deficient mice was associated with an influx of immune cell subsets including nonactivated macrophages. This suggested that intrarenal inflammation might accelerate Alport nephropathy. A possible mechanism might be the well-known enhancement of immune recognition by bacterial products. We found that exposure to bacterial endotoxin from 4 to 6 weeks of age did not affect disease progression, whereas an equipotent dose of cytosine-guanine (CpG)-DNA, a synthetic mimic of bacterial DNA, accelerated all aspects of Alport nephropathy and reduced the overall lifespan of Col4a3-deficient mice. This effect was associated with a significant increase of renal CD11b+/Ly6C(hi) macrophages, intrarenal production of inducible nitric oxide synthase, tumor necrosis factor (TNF)-α, interleukin-12, and CXCL10, and loss of podocytes. TNF-α was essential for acceleration of Alport nephropathy, as etanercept (a soluble TNF-α receptor) entirely abrogated the CpG-DNA effect. Thus, systemic exposure to CpG-DNA induces classically activated (M1) macrophages that enhance intrarenal inflammation and disease progression. Hence, factors that modulate the phenotype of renal macrophages can affect the progression of Alport nephropathy and, potentially, other types of chronic kidney diseases.
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http://dx.doi.org/10.1038/ki.2010.373DOI Listing
January 2011

Integrin α2-deficient mice provide insights into specific functions of collagen receptors in the kidney.

Fibrogenesis Tissue Repair 2010 Sep 22;3:19. Epub 2010 Sep 22.

Department of Nephrology and Rheumatology, Georg-August-University Goettingen, Goettingen, Germany.

Background: Integrins are important cellular receptors for collagens. Within the glomerulus, podocytes regulate the integrity of the glomerular basement membrane (GBM) by sensing the presence of collagen and regulating collagen IV synthesis. The present study evaluates the role of integrin α2 (ITGA2) in cell-matrix interaction.

Methods And Results: ITGA2-deficient mice had normal renal function but moderate proteinuria and enhanced glomerular and tubulointerstitial matrix deposition. Electron microscopy demonstrated irregular podocyte-matrix interaction, causing pathological protrusions towards the urinary (podocyte) side of the GBM. These characteristic subepithelial bulges mimic the renal phenotype of mice, which are deficient in another collagen receptor, discoidin domain receptor (DDR)1. Using immunogold staining, ITGA2 expression was found to localize to the basolateral site of the podocyte foot processes. ITGA2-deficient mice overexpressed transforming growth factor (TGF)β and connective tissue growth factor (CTGF) compared with wild-type mice. Using in situ hybridization, tubular cells were found to be the primary site of TGFβ synthesis and podocytes the source of CTGF in ITGA2-deficient mice.

Conclusion: These findings support our hypothesis that both these collagen receptors (ITGA2 and DDR1) play a similar role within the kidney. Further, cell-matrix interaction via collagen receptors seems to be crucial for maintenance of normal GBM architecture and function. Targeting collagen receptors such as ITGA2 might be a new form of treatment for progressive fibrotic diseases.
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http://dx.doi.org/10.1186/1755-1536-3-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2954872PMC
September 2010