Mary Goldring, PhD

Research

Laboratory of Cartilage Biology

Mary B. Goldring, PhD., is Senior Scientist and the former Co-Director of the Tissue Engineering Regeneration and Repair Program in the Research Division at Hospital for Special Surgery. Her research has focused on the molecular regulation of extracellular matrix remodeling with special attention to cartilage biology. Her major contributions include:

• The identification of the molecular mechanisms involved in the cellular response to inflammatory cytokines pertinent to the pathogenesis of osteoarthritis and rheumatoid arthritis
• The development of in vitro models, including human chondrocyte cell lines, for the study of chondrocyte biology
• The characterization of transcription factors regulating collagen gene expression in chondrocytes and fibroblasts
• The identification of novel mediators of cartilage development and homeostasis that are deregulated during osteoarthritis

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 promote 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.

Current Research

The current focus of Dr. Goldring’s laboratory is on 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.  Her laboratory has found that there are common mediators of these processes in human OA cartilage that are also involved in mechanotransduction, 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.

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;Elf3^fl/fl) or overexpressed in cartilage and synovium (ComptTA;TRE-Elf3). Current efforts are profiling gene expression (RNAseq) and microRNAs over the course of disease initiation and progression in novel mouse strains, generated in collaboration with Dr. Kenneth Marcu (Stony Brook University), 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. Mechanistic studies involve in vitro experiments using tissues and cells derived from the mouse strains and human samples retrieved from surgical procedures.

Collaborative work is ongoing with Dr. Carl Blobel (HSS) to understand the roles of ADAM17 and iRhom2 in the DMM model and with Dr. Marjolein van der Meulen (Cornell University, Ithaca) and Dr. Mathias Bostrom (HSS) to examine examining the impact of a non-invasive tibial loading model on osteoarthritic changes in cartilage and bone different mouse strains. Collaborative studies with Dr. HI Roach’s group (Southampton, UK) have also identified epigenetic regulation via alterations in the methylation status of specific CpG sites in the promoters of MMP13, IL1B, NOS2, and COL9A1, associated with aberrant gene expression in osteoarthritic cartilage.

Research Team

Miguel Otero, PhD (Assistant Scientist)
Kirsty L. Culley, PhD (Postdoctoral Fellow)
Elisa Wondimu (WCMC graduate student)

Vinny Craveiro, Kirsty Culley, Miguel Otero, Gary Dixon, Mary Goldring, Justin, Quinn, Elisabeth

Kirsty Culley, Justin Quinn, Jun Chang, Elisabeth Wondimu, Miguel Otero, Eleonora Olivotto, Marta Favero

Jun Chang, Kirsty Culley, Haruka Kaneko, Darren Plumb, Miguel Otero, Jonathan Coico, Cecilia Dragomir

Marta Favero, Darren Plumb, Cecilia Dragomir, Ko Hashimoto, Miguel Otero

Kaneyuki Tsuchimochi, Miguel Otero, Cecilia Dragomir, Darren Plumb, Jinghong Chen

Former Lab Members

Postdoctoral Fellows and Visiting Scholars:
Darren A. Plumb, PhD
Ko Hashimoto, MD, PhD
Marta Favero, MD, PhD
Eleonora Olivotto, PhD
Haruka Kaneko, MD, PhD
Karim El Hachem, MD
Anna Stevens, MD, PhD
Kaneyuki Tsuchimochi, MD, PhD
Jinghong Chen, PhD
Stefan Toegel, PhD, MPharmS
Philipp G. Maass, PhD
Jessica Andres Bergos (Universidad Complutense de Madrid, Spain)
Selene Perez Garcia (Universidad Complutense de Madrid, Spain)
Peter R. Martin (University of East Anglia, UK)

Research Staff

Cecilia Dragomir, M.D. (Research Coordinator)
Justin Quinn (Research Technician)
Jun Chang (Research Technician)
Jonathan Coico (Research Technician)

Students

Vinny Craveiro (HHMI/OREF medical student, co-mentored with Mathias Bostrom, MD)
Gary Dixon (rotating WCMC graduate student)
Catrina Johnson (Gateways to the Laboratory Summer Program for Pre-MD/PhD Students)
Alyssa Bagadion (rotating WCMC graduate student)

Collaborators

Carl Blobel, MD PhD(HSS)
Marjolein van der Meulen, PhD  (Cornell University, Ithaca)
Kenneth B. Marcu, PhD, Stony Brook University, Stony Brook, New York
Yefu Li, M.D., PhD, Harvard School of Dental Medicine, Boston, MA
Roland Wolkowicz, PhD, Department of Cell & Molecular Biology, San Diego State University
Hui (Herb) B. Sun, PhD, Department of Orthopaedic Surgery, Albert Einstein College of Medicine
Richard Oreffo, DPhil and H. I. (Trudy) Roach, PhD, (deceased) Bone and Joint Research Group, University of Southampton, UK

Professional Contributions and Honors

Dr. Goldring is the recipient of the 2009 University of Oregon, Clark Honors College Alumni Achievement Award, the 2014 Orthopaedic Research Society (ORS) Women’s Leadership Award, and the 2015 Osteoarthritis Research Society International (OARSI) Basic Science Research Award. She is Past President of the ORS and was a member of the Board of Directors of the OARSI. She has served as Co- Editor of Arthritis & Rheumatism and is currently Associate Editor of Journal of Cellular Physiology, Arthritis Research and Therapy, and Journal of Orthopedic Research. For the American College of Rheumatology, she has served as Chair of the Cartilage Biology Study Group, as Abstract Chair, and on the Annual Meeting Planning Committee and is currently on the ACR Committee on Publications. She served as Chair of the Arthritis Foundation Molecular Biology and Genetics Study Section and on study sections for NIH, OREF, DOD, and NASA. She is frequently invited to speak at national and international meetings and has been on the organizing committees of the 2005, 2007, and 2015 Cartilage Gordon Conferences.

Appointments

Languages

English

Selected Publications

Culley KL, Dragomir CL, Chang J, Wondimu EB, Coico J, Plumb DA, Otero M, Goldring MB: Mouse models of osteoarthritis: surgical model of posttraumatic osteoarthritis induced by destabilization of the medial meniscus. Methods Mol Biol 2015, 1226:143-173.

Leong DJ, Choudhury M, Hanstein R, Hirsh DM, Kim SJ, Majeska RJ, Schaffler MB, Hardin JA, Spray DC, Goldring MB et al: Green tea polyphenol treatment is chondroprotective, anti-inflammatory and palliative in a mouse post-traumatic osteoarthritis model. Arthritis Res Ther 2014, 16(6):508.

Imagawa K, de Andres MC, Hashimoto K, Itoi E, Otero M, Roach HI, Goldring MB, Oreffo RO: Association of reduced type IX collagen gene expression in human osteoarthritic chondrocytes with epigenetic silencing by DNA hypermethylation. Arthritis Rheumatol 2014, 66(11):3040-3051.

Zhao R, Wang A, Hall KC, Otero M, Weskamp G, Zhao B, Hill D, Goldring MB, Glomski K, Blobel CP: Lack of ADAM10 in endothelial cells affects osteoclasts at the chondro-osseus junction. J Orthop Res 2014, 32(2):224-230.

Olivotto E, Otero M, Astolfi A, Platano D, Facchini A, Pagani S, Flamigni F, Facchini A, Goldring MB, Borzi RM et al: IKKalpha/CHUK regulates extracellular matrix remodeling independent of its kinase activity to facilitate articular chondrocyte differentiation. PLoS One 2013, 8(9):e73024.

Hall KC, Hill D, Otero M, Plumb DA, Froemel D, Dragomir CL, Maretzky T, Boskey A, Crawford HC, Selleri L et al: ADAM17 controls endochondral ossification by regulating terminal differentiation of chondrocytes. Mol Cell Biol 2013, 33(16):3077-3090.

Ko FC, Dragomir C, Plumb DA, Goldring SR, Wright TM, Goldring MB, van der Meulen MC: In vivo cyclic compression causes cartilage degeneration and subchondral bone changes in mouse tibiae. Arthritis Rheum 2013, 65(6):1569-1578.

Hashimoto K, Otero M, Imagawa K, de Andres MC, Coico JM, Roach HI, Oreffo RO, Marcu KB, Goldring MB: Regulated transcription of human matrix metalloproteinase 13 (MMP13) and interleukin-1beta (IL1B) genes in chondrocytes depends on methylation of specific proximal promoter CpG sites. J Biol Chem 2013, 288(14):10061-10072.

Ritter SY, Subbaiah R, Bebek G, Crish J, Scanzello CR, Krastins B, Sarracino D, Lopez MF, Crow MK, Aigner T et al: Proteomic analysis of synovial fluid from the osteoarthritic knee: comparison with transcriptome analyses of joint tissues. Arthritis Rheum 2013, 65(4):981-992.

de Andres MC, Imagawa K, Hashimoto K, Gonzalez A, Roach HI, Goldring MB, Oreffo RO: Loss of methylation in CpG sites in the NF-kappaB enhancer elements of inducible nitric oxide synthase is responsible for gene induction in human articular chondrocytes. Arthritis Rheum 2013, 65(3):732-742.

Otero M, Plumb DA, Tsuchimochi K, Dragomir CL, Hashimoto K, Peng H, Olivotto E, Bevilacqua M, Tan L, Yang Z et al: E74-like factor 3 (ELF3) impacts on matrix metalloproteinase 13 (MMP13) transcriptional control in articular chondrocytes under proinflammatory stress. J Biol Chem 2012, 287(5):3559-3572.

Otero M, Favero M, Dragomir C, Hachem KE, Hashimoto K, Plumb DA, Goldring MB: Human chondrocyte cultures as models of cartilage-specific gene regulation. Methods Mol Biol 2012, 806:301-336.

Xu L, Polur I, Servais JM, Hsieh S, Lee PL, Goldring MB, Li Y: Intact pericellular matrix of articular cartilage is required for unactivated discoidin domain receptor 2 in the mouse model. Am J Pathol 2011, 179(3):1338-1346.

Shimada H, Sakakima H, Tsuchimochi K, Matsuda F, Komiya S, Goldring MB, Ijiri K: Senescence of chondrocytes in aging articular cartilage: GADD45beta mediates p21 expression in association with C/EBPbeta in senescence-accelerated mice. Pathol Res Pract 2011, 207(4):225-231.

de Andres MC, Imagawa K, Hashimoto K, Gonzalez A, Goldring MB, Roach HI, Oreffo RO: Suppressors of cytokine signaling (SOCS) are reduced in osteoarthritis. Biochem Biophys Res Commun 2011, 407(1):54-59.

Imagawa K, de Andres MC, Hashimoto K, Pitt D, Itoi E, Goldring MB, Roach HI, Oreffo RO: The epigenetic effect of glucosamine and a nuclear factor-kappa B (NF-kB) inhibitor on primary human chondrocytes--implications for osteoarthritis. Biochem Biophys Res Commun 2011, 405(3):362-367.

Leong DJ, Li YH, Gu XI, Sun L, Zhou Z, Nasser P, Laudier DM, Iqbal J, Majeska RJ, Schaffler MB et al: Physiological loading of joints prevents cartilage degradation through CITED2. Faseb J 2011, 25(1):182-191.

Tsuchimochi K, Otero M, Dragomir CL, Plumb DA, Zerbini LF, Libermann TA, Marcu KB, Komiya S, Ijiri K, Goldring MB: GADD45beta enhances Col10a1 transcription via the MTK1/MKK3/6/p38 axis and activation of C/EBPbeta-TAD4 in terminally differentiating chondrocytes. J Biol Chem 2010, 285(11):8395-8407.

Hashimoto K, Oreffo RO, Gibson MB, Goldring MB, Roach HI: DNA demethylation at specific CpG sites in the IL1B promoter in response to inflammatory cytokines in human articular chondrocytes. Arthritis Rheum 2009, 60(11):3303-3313.

Ijiri K, Zerbini LF, Peng H, Otu HH, Tsuchimochi K, Otero M, Dragomir C, Walsh N, Bierbaum BE, Mattingly D et al: Differential expression of GADD45beta in normal and osteoarthritic cartilage: potential role in homeostasis of articular chondrocytes. Arthritis Rheum 2008, 58(7):2075-2087.

http://www.ncbi.nlm.nih.gov/pubmed/?term=Goldring+MB

http://www.ncbi.nlm.nih.gov/pubmed/?term=McGuire%20MB%5BAuthor%5D&cauthor=true&cauthor_uid=7178859

http://www.ncbi.nlm.nih.gov/pubmed/?term=McGuire+MK+with+Russell+RG

 

Recent Key Review Articles

 

Goldring MB, Berenbaum F: Emerging targets in osteoarthritis therapy. Curr Opin Pharmacol 2015, 22:51-63.

Houard X, Goldring MB, Berenbaum F: Homeostatic mechanisms in articular cartilage and role of inflammation in osteoarthritis. Curr Rheumatol Rep 2013, 15(11):375.

Loeser RF, Goldring SR, Scanzello CR, Goldring MB: Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum 2012, 64(6):1697-1707.

Goldring MB, Marcu KB: Epigenomic and microRNA-mediated regulation in cartilage development, homeostasis, and osteoarthritis. Trends Mol Med 2012, 18(2):109-118.

Goldring MB, Otero M: Inflammation in osteoarthritis. Curr Opin Rheumatol 2011, 23(5):471-478.

Goldring MB, Goldring SR: Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Ann N Y Acad Sci 2010, 1192:230-237.

Marcu KB, Otero M, Olivotto E, Borzi RM, Goldring MB: NF-kappaB signaling: multiple angles to target OA. Curr Drug Targets 2010, 11(5):599-613.

 

For more publications, please see the PubMed listing.