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Ermann, Joerg

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Ermann

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Joerg

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Ermann, Joerg

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2015 - 20185

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Author's Publications: search.filters.isAuthorOfPublication.b00051f8-9dd7-4578-854e-891e110941e8

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Now showing 1 - 5 of 5
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    Histone demethylase LSD1 regulates bone mass by controlling WNT7B and BMP2 signaling in osteoblasts
    (Nature Publishing Group UK, 2018) Sun, Jun; Ermann, Joerg; Niu, Ningning; Yan, Guang; Yang, Yang; Shi, Yujiang; Zou, Weiguo
    Multiple regulatory mechanisms control osteoblast differentiation and function to ensure unperturbed skeletal formation and remodeling. In this study we identify histone lysine-specific demethylase 1(LSD1/KDM1A) as a key epigenetic regulator of osteoblast differentiation. Knockdown of LSD1 promoted osteoblast differentiation of human mesenchymal stem cells (hMSCs) in vitro and mice lacking LSD1 in mesenchymal cells displayed increased bone mass secondary to accelerated osteoblast differentiation. Mechanistic in vitro studies revealed that LSD1 epigenetically regulates the expression of WNT7B and BMP2. LSD1 deficiency resulted in increased BMP2 and WNT7B expression in osteoblasts and enhanced bone formation, while downregulation of WNT7B- and BMP2-related signaling using genetic mouse model or small-molecule inhibitors attenuated bone phenotype in vivo. Furthermore, the LSD1 inhibitor tranylcypromine (TCP) could increase bone mass in mice. These data identify LSD1 as a novel regulator of osteoblast activity and suggest LSD1 inhibition as a potential therapeutic target for treatment of osteoporosis.
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    Author Correction: Towards an arthritis flare-responsive drug delivery system
    (Nature Publishing Group UK, 2018) Joshi, Nitin; Yan, Jing; Levy, Seth; Bhagchandani, Sachin; Slaughter, Kai V.; Sherman, Nicholas E.; Amirault, Julian; Wang, Yufeng; Riegel, Logan; He, Xueyin; Rui, Tan Shi; Valic, Michael; Vemula, Praveen; Miranda, Oscar R.; Levy, Oren; Gravallese, Ellen M.; Aliprantis, Antonios; Ermann, Joerg; Karp, Jeffrey
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    XBP1-Independent UPR Pathways Suppress C/EBP-β Mediated Chondrocyte Differentiation in ER-Stress Related Skeletal Disease
    (Public Library of Science, 2015) Cameron, Trevor L.; Bell, Katrina M.; Gresshoff, Irma L.; Sampurno, Lisa; Mullan, Lorna; Ermann, Joerg; Glimcher, Laurie H.; Boot-Handford, Raymond P.; Bateman, John F.
    Schmid metaphyseal chondrodysplasia (MCDS) involves dwarfism and growth plate cartilage hypertrophic zone expansion resulting from dominant mutations in the hypertrophic zone collagen, Col10a1. Mouse models phenocopying MCDS through the expression of an exogenous misfolding protein in the endoplasmic reticulum (ER) in hypertrophic chondrocytes have demonstrated the central importance of ER stress in the pathology of MCDS. The resultant unfolded protein response (UPR) in affected chondrocytes involved activation of canonical ER stress sensors, IRE1, ATF6, and PERK with the downstream effect of disrupted chondrocyte differentiation. Here, we investigated the role of the highly conserved IRE1/XBP1 pathway in the pathology of MCDS. Mice with a MCDS collagen X p.N617K knock-in mutation (ColXN617K) were crossed with mice in which Xbp1 was inactivated specifically in cartilage (Xbp1CartΔEx2), generating the compound mutant, C/X. The severity of dwarfism and hypertrophic zone expansion in C/X did not differ significantly from ColXN617K, revealing surprising redundancy for the IRE1/XBP1 UPR pathway in the pathology of MCDS. Transcriptomic analyses of hypertrophic zone cartilage identified differentially expressed gene cohorts in MCDS that are pathologically relevant (XBP1-independent) or pathologically redundant (XBP1-dependent). XBP1-independent gene expression changes included large-scale transcriptional attenuation of genes encoding secreted proteins and disrupted differentiation from proliferative to hypertrophic chondrocytes. Moreover, these changes were consistent with disruption of C/EBP-β, a master regulator of chondrocyte differentiation, by CHOP, a transcription factor downstream of PERK that inhibits C/EBP proteins, and down-regulation of C/EBP-β transcriptional co-factors, GADD45-β and RUNX2. Thus we propose that the pathology of MCDS is underpinned by XBP1 independent UPR-induced dysregulation of C/EBP-β-mediated chondrocyte differentiation. Our data suggest that modulation of C/EBP-β activity in MCDS chondrocytes may offer therapeutic opportunities.
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    An inflammation-targeting hydrogel for local drug delivery in inflammatory bowel disease
    (American Association for the Advancement of Science (AAAS), 2015-08-12) Zhang, Sufeng; Ermann, Joerg; Succi, Marc; Zhou, Allen; Hamilton, Matthew; Cao, Bonnie; Korzenik, Joshua; Glickman, Jonathan; Vemula, Praveen K.; Glimcher, Laurie; Traverso, Giovanni; Langer, Robert; Karp, Jeffrey
    A hydrogel binds to inflamed tissues, delivering therapeutics locally and reducing systemic drug exposure in mouse models of inflammatory bowel disease.
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    Towards an arthritis flare-responsive drug delivery system
    (Nature Publishing Group UK, 2018) Joshi, Nitin; Yan, Jing; Levy, Seth; Bhagchandani, Sachin; Slaughter, Kai V.; Sherman, Nicholas E.; Amirault, Julian; Wang, Yufeng; Riegel, Logan; He, Xueyin; Rui, Tan Shi; Valic, Michael; Vemula, Praveen; Miranda, Oscar R.; Levy, Oren; Gravallese, Ellen M.; Aliprantis, Antonios; Ermann, Joerg; Karp, Jeffrey
    Local delivery of therapeutics for the treatment of inflammatory arthritis (IA) is limited by short intra-articular half-lives. Since IA severity often fluctuates over time, a local drug delivery method that titrates drug release to arthritis activity would represent an attractive paradigm in IA therapy. Here we report the development of a hydrogel platform that exhibits disassembly and drug release controlled by the concentration of enzymes expressed during arthritis flares. In vitro, hydrogel loaded with triamcinolone acetonide (TA) releases drug on-demand upon exposure to enzymes or synovial fluid from patients with rheumatoid arthritis. In arthritic mice, hydrogel loaded with a fluorescent dye demonstrates flare-dependent disassembly measured as loss of fluorescence. Moreover, a single dose of TA-loaded hydrogel but not the equivalent dose of locally injected free TA reduces arthritis activity in the injected paw. Together, our data suggest flare-responsive hydrogel as a promising next-generation drug delivery approach for the treatment of IA.