Philipp Lachenmann: DELPHI Rationale


Albrecht Hasinger Lecture 2016

Mary B. Goldring, PhD

Hospital for Special Surgery and Weill Cornell Medical College, New York City, NY, USA

“The elusive search for a target in osteoarthritis therapy: Lessons from in vitro and in vivo models”

Mary Goldring

Mary B. Goldring, PhD, is Senior Scientist and Co-Director of the Tissue Engineering, Regeneration and Repair Program in the Research Division of the Hospital for Special Surgery and Professor of Cell and Developmental Biology, Weill Cornell Medical College in New York City. Her research on cartilage biology focuses on the molecular regulation of extracellular matrix remodeling. Her major contributions include the identification of the molecular and cellular mechanisms involved in the pathogenesis of osteoarthritis and rheumatoid arthritis and the development of in vitro models for the study of human chondrocyte biology. Current work involves relating findings in mouse models of osteoarthritis to aspects of the human disease.

On the occasion of the Albrecht Hasinger Lecture 2016, Mary B. Goldring will talk about The elusive search for a target in osteoarthritis therapy: Lessons from in vitro and in vivo models”:

“Osteoarthritis (OA) is a whole joint disease, in which thinning and loss of cartilage is a critical determinant in OA progression. The disruption of cartilage homeostasis due to multiple potential causes, related to aging, genetic predisposition, trauma, or metabolic disorder, is associated with profound phenotypic modifications of chondrocytes. Early changes involve disruption of the pericellular matrix through signaling events mediated by chondrocyte receptors such as discoidin domain receptor-2 (DDR-2) and syndecan-4. My laboratory studies the mechanisms of gene regulation by which stress- and inflammation-induced signals induce expression of matrix metalloproteinase 13 (MMP-13), the pivotal collagen-degrading proteinase that marks osteoarthritis progression, as well as other catabolic and anabolic responses in cartilage and other joint tissues. Common mediators of these processes in human OA cartilage are also involved in mechano-transduction, including the protein kinases, IKKs and MAPKs. These pathways converge on transcriptional regulation of MMP13, IL1B, and other key genes by NF-kB, Elf3, C/EBPb, Runx2, and hypoxia-inducible factor (HIF) 2a. Alterations in the methylation status of specific CpG sites in the promoters of MMP13, IL1B, NOS2, and COL9A1 are also associated with aberrant gene expression in OA cartilage. Current work involves relating findings in mouse models of osteoarthritis to aspects of the human disease by examining knockout and transgenic mouse strains in the context of a post-traumatic OA mouse model due to surgical destabilization of the medial meniscus (DMM). Novel mouse strains have been generated in which the cytokine-inducible transcription factor Elf3 is either knocked out specifically in cartilage (Col2a1Cre;Elf3fl/fl) or overexpressed in cartilage and synovium (Comp-tTA;TRE-Elf3). Current efforts are profiling gene expression (RNAseq) and microRNAs over the course of disease initiation and progression in novel mouse strains with inducible, cartilage-specific deletion of the NF-kB signaling kinases, IKKa and IKKb, compared to the Runx2+/- mouse, which is protected from DMM-OA, and the Col11a1+/- (Cho/+; chondrodysplasia) mouse that develops accelerated OA with aging. Since the chondrocytes in adult human cartilage are normally quiescent and maintain the matrix in a low turnover state, understanding how they undergo phenotypic modulation and participate in matrix destruction and abnormal repair in OA may lead to identification of critical targets for therapy to block cartilage damage and promote effective cartilage repair.” [Mary B. Goldring]

Festive Event on December 6, 2016, at 5:00 p.m.

The Albrecht Hasinger Lecture, which is funded by the Ernst Schering Foundation, takes place in conjunction with the award ceremony of the Avrion Mitchison Prize at the German Rheumatism Research Center (DRFZ).

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German Rheumatism Research Center Berlin
Campus Charité Mitte

Charitéplatz 1
10117 Berlin