Mary Goldring, PhD

Appointments

Senior Scientist, HSS Research Division

Director, Laboratory for Cartilage Biology, Tissue Engineering Repair & Regeneration Program

Professor of Cell and Developmental Biology, Weill Cornell Medical College

 

Selected Publications

Ijiri K, Zerbini LF, Peng H, Otu HH, Tsuchimochi K, Otero M, Dragomir C, Walsh N, Bierbaum BE, Mattingly D, van Flandern G, Komiya S, Aigner T, Libermann TA, Goldring MB. Differential expression of GADD45bin normal and osteoarthritic cartilage: Potential role in homeostasis of articular chondrocytes. Arthritis Rheum 2008; 58:2075-2087.

Peng H, Tan L, Osaki M, Zhan Y, Ijiri K, Tsuchimochi K, Otero M, Wang H, Choy BK, Grall FT, Gu X, Libermann TA, Oettgen P, Goldring MB. ESE-1 is a potent repressor of type II collagen gene (COL2A1) transcription in human chondrocytes. J Cell Physiol 2008; 251: 562-573.

Xu L, Peng H, Glasson S, Lee PL, Hu K, Ijiri K, Olsen BR, Goldring MB, Li Y: Increased expression of the collagen receptor discoidin domain receptor 2 in articular cartilage as a key event in the pathogenesis of osteoarthritis. Arthritis Rheum 2007; 56:2663-2673

Goodwin JL, Farley ML, Swaim B, Goldring SR, Goldring MB, Bierbaum BE, Gray ML: Dual proline labeling protocol for individual "baseline" and "response" biosynthesis measurements in human articular cartilage. Osteoarthritis Cartilage 2008; 16:1263-1266.

Baldassarri M, Goodwin JS, Farley ML, Bierbaum BE, Goldring SR, Goldring MB, Burstein D, Gray ML: Relationship between cartilage stiffness and dGEMRIC index: correlation and prediction. J Orthop Res 2007; 25:904-912.

Ijiri K, Zerbini LF, Peng H, Correa RG, Lu B, Walsh N, Zhao Y, Taniguchi N, Huang XL, Otu H, Wang H, Wang JF, Komiya S, Ducy P, Rahman MU, Flavell RA, Gravallese E, Oettgen P, Libermann TA, Goldring MB. A novel role for GADD45b as a mediator of MMP-13 gene expression during chondrocyte terminal differentiation. J Biol Chem 2005; 280:38544-38555.

Grall FT, Prall WC, Wei W, Gu X, Cho J-Y, Choy BK, Zerbini LF, Inan NS, Goldring SR, Gravallese EM, Goldring MB, Oettgen P, Libermann TA. The Ets transcription factor ESE-1 mediates induction of the COX-2 gene by LPS in monocytes. FEBS J 2005;272:1676-87.

Facchini A, Borzi RM, Marcu KB, Stefanelli C, Olivotto E, Goldring MB, Flamigni F. Polyamine depletion inhibits NF-kB binding to DNA and interleukin-8 production in human chondrocytes stimulated by tumor necrosis factor-a. J Cell Physiol 2005 Sep; 204(3):956-63.

Tan L, Peng H, Osaki M, Choy BK, Auron PE, Sandell LJ, Goldring MB. Egr-1 mediates transcriptional repression of COL2A1 promoter activity by interleukin-1b. J Biol Chem 2003;278:17688-700.

Grall F, Gu X, Tan L, Cho JY, Inan MS, Pettit AR, Thamrongsak U, Choy BK, Manning C, Akbarali Y, Zerbini L, Rudders S, Goldring SR, Gravallese EM, Oettgen P, Goldring MB, Libermann TA. Responses to the proinflammatory cytokines interleukin-1 and tumor necrosis factor a in cells derived from rheumatoid synovium and other joint tissues involve nuclear factor kB-mediated induction of the Ets transcription factor ESE-1. Arthritis Rheum 2003;48:1249-60.

Osaki M, Tan L, Choy BK, Yoshida Y, Cheah KS, Auron PE, Goldring MB. The TATA-containing core promoter of the type II collagen gene (COL2A1) is the target of interferon-g-mediated inhibition in human chondrocytes: requirement for Stat1 a, Jak1 and Jak2. Biochem J 2003;369:103-15.

Selected Chapters, Review Articles and Editorials:

Goldring MB, Tsuchimochi K, Ijiri K. Control of chondrogenesis. J Cell Biochem 2006; 97:33-44.

Goldring MB, Sandell LJ. Transcriptional control of chondrocyte gene expression. In: J Buckwalter, M Lotz, J F Stoltz, editors: OA, Inflammation and Degradation: A Continuum. IOS Press, Amsterdam, 2007; 118-142.

Otero M, Goldring MB. Cells of the synovium in rheumatoid arthritis. Chondrocytes. Arthritis Res Ther 2007; 9:220.

Goldring MB, Goldring SR: Osteoarthritis. J Cell Physiol 2007, 213:626-634

Arend WP, Goldring MB. The development of anti-cytokine therapeutics for rheumatic diseases [Review]. Arthritis Rheum 2008; 58:S102-S109.

Goldring MB, Otero M, Tsuchimochi K, Ijiri K, Li Y. Defining the roles of inflammatory and anabolic cytokines in cartilage metabolism. Ann Rheum Dis. 2008; 67(suppl III): iii75-iii82.

Goldring MB. Chapter 8G: Chondrocytes: Pathogenesis of Rheumatoid Arthritis. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, editors. Rheumatoid Arthritis. Mosby Elsevier, Philadelphia, 2008; pp 151-162.

Goldring MB, Goldring SR. Chapter 1: Biology of the normal joint. In: Firestein GS, Budd RC Harris ED, McInnes IB, Ruddy S, Sergent JS, (eds): Kelley’s Textbook of Rheumatology, 8^th edition. Saunders Elsevier, Philadelphia. 2009; pp 1-22.

Goldring MB. Chapter 3: Cartilage and Chondrocytes. In: Firestein GS, Budd RC Harris ED, Ruddy S, Sergent JS, (eds): Kelley’s Textbook of Rheumatology, 8^th edition. Saunders Elsevier, Philadelphia. 2009; pp 37-69.

Hidaka C, Goldring MB. Regulatory mechanisms of chondrogenesis and implications for understandiing articular cartilage homeostasis. Curr Rheum Rev 2008; 4:136-147.

Onyekuma I, Goldring MB, Hidaka C. Chondrogenesis, joint formation, and articular cartilage regeneration. J. Cell. Biochem. 2009; 107:383-392.

Goldring MB, Marcu KB. Cartilage homeostasis in health and rheumatic disease. Arthritis Res. Therapy 2009; 11(3):224.

For more publications, please see the PubMed listing.  

Research Description

Laboratory of Cartilage Biology

Proteins produced in response to excessive mechanical loading and inflammation in joints not only stimulate the production of enzymes that break down the cartilage but also impair the ability of the chondrocyte, the unique cell type in adult cartilage, to repair the damage. We have used several strategies for identifying and characterizing mediators involved in the pathogenesis of osteoarthritis (OA), including culture models of primary human and mouse chondrocytes and cell lines, mouse models, and human cartilage samples. Human cartilage is a complex tissue of matrix proteins that varies from superficial to deep layers and from loaded to unloaded zones. During OA development the normally quiescent chondrocytes with low matrix turnover undergo phenotypic modulation resulting in matrix destruction and abnormal repair. We have identified new genes, not known previously to act in cartilage, including growth arrest and DNA damage (GADD)-45b and the ETS transcription factor, ESE1/ELF3, induced in chondrocytes by bone morphogenetic protein (BMP)-2 and inflammatory cytokines, respectively. Both GADD45b and ESE1/ELF3 are induced by NF-kB and in turn, upregulate matrix metalloproteinase (MMP)-13 and suppress type II collagen gene (COL2A1) gene expression. A microarray study to compare IL-1b and BMP-2-induced genes resulted in the discovery of a novel role for GADD45b, an anti-apoptotic factor during genotoxic stress and cell cycle arrest, as a mediator of MMP-13 and Col10a1 gene expression during hypertrophic differentiation. Since GADD45b is present in quiescent chondrocytes in normal cartilage and in early OA cartilage at sites peripheral to the lesion in chondrocyte clusters and in deep zone chondrocytes, it may promote chondrocyte survival, while promoting hypertrophy during tidemark advancement. Current studies involve both in vitro analysis of signaling and transcriptional mechanisms that regulate the expression and activities of GADD45b and ESE-1 and in vivo analysis of the consequences of knockout and transgenic overexpression of these genes in mouse models, using surgical OA (good matrix with abnormal loading) and genetic models with OA-like pathology (bad matrix with normal loading) during aging. In further studies, we are examining the epigenetic regulation of MMP-13 and using proteomics and genomics approaches to map the signaling networks and microRNA targets that impact on gene expression programs during the onset and progression of OA. These studies may to lead to identification of critical targets for therapy to block cartilage damage and promote effective cartilage repair.

Postdoctoral Research Fellows:

Miguel Otero, PhD, Postdoctoral Research Fellow, joined this laboratory after completing pre-doctoral training in the laboratory of Dr. Oreste Gualillo in Spain, where he studied the interactions between adipocytokines and inflammatory mediators in arthritis. He has expertise in chondrocyte biology, development of stable cell lines,molecular analysis of gene expression by real-time PCR, promoter-reporter analysis, inhibitory RNA techniques, immunohistochemistry, and mouse models. His work focuses on the regulation of MMP-13 gene expression in vitro and in vivo. He currently holds a Postdoctoral Fellowship entitled  “ESE-1 and adipokines: A novel circuit in proinflammatory signaling” from the Arthritis Foundation, New York Chapter.

Darren A. Plumb, PhD, Postdoctoral Research Fellow, joined this laboratory after completing pre-doctoral training in the laboratory of Ray Boot-Handford at the Wellcome Trust Centre for Cell-Matrix Research, Manchester, UK. For his PhD work, he found that type XXVII collagen is expressed in normal cartilage and is important for skeletal development and used gene targeting to generate mice carrying mutant forms of type XXVII collagen for functional and phenotypic studies. He has expertise in the design of probes for in situ hybridization, production of recombinant protein to generate antiserum for immunohistochemistry and ImmunoEM, and generation of transgenic mice. His current work focuses on the generation, maintenance, and characterization of mouse models, including application of surgical OA to Elf3/Ese1 and Gadd45b knockout mice.

Ko Hashimoto, MD, PhD, Postdoctoral Research Fellow, is a trained Orthopaedic Surgeon originally from Tohoku University, Japan. He joined this laboratory after performing postdoctoral research at Bone and Joint Research Group, University of Southampton, UK, with Dr. H. I. (Trudy) Roach and continues work on a project entitled “Epigenetic regulation of MMP-13” (R21-AR054887). These studies involve investigating epigenetic mechanisms regulating the expression of MMP-13. He is currently evaluating whether MMP-13 promoter activity is determined by the interactions between DNA methylation status and transcription factor binding to cognate binding sites.

Marta Favero, MD, Postdoctoral Research Fellow, recently completed specialty training in Rheumatology at the University of Padova, Italy, with Prof. Leonardo Punzi and is working on her PhD. She is participating in a study involving molecular analyses of retrieved tissues from surgical patients with osteoarthritis, including synovium, cartilage and synovial fluid. These will involve genomics and proteomics analyses in relation to clinical databases to find biomarker associations in different subsets of the disease.

Cecilia Dragomir, M.D., Research Coordinator, received training in Ophthalmology in Romania and has considerable expertise in the analysis of human and mouse tissues by immunohistochemistry and in situ hybridization. She also helps with the care, breeding, histological characterization, and genotyping of mouse models, including the surgical mouse OA model.

Recent Postdoctoral Fellows and Visiting Scholars

Kaneyuki Tsuchimochi, MD, PhD, has completed studies on the regulation of Col10a1 gene transcription by GADD45b and has returned to the Department of Orthopaedic Surgery, Graduate School of Medicine and Dentistry, Kagoshima University, Japan.

Jinghong Chen, PhD, supported by the China Scholarship Council, performed work on toll-like receptor regulation of inflammatory pathways and transcription factors in chondrocytes. She has returned to her position as Assistant Professor at Xi'an Jiaotong University College of Medicine, Xi’an, China, where she is studying the pathogenic mechanisms of Kashin-Beck’s Disease.

Stefan Toegel, PhD, MPharmS, Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, performed a study entitled “Molecular biological study of the regulation of sialyltransferases in human chondrocytes” with support from the Austrian Science Fund.

Collaborators

Yefu Li, M.D., PhD, Harvard School of Dental Medicine, Boston, MA.
H. I. (Trudy) Roach, PhD, Bone and Joint Research Group, University of Southampton, UK.
Kenneth Marcu, PhD, Stony Brook University, Stony Brook, New York.

Summer Medical Student Interns

2007 Danielle Gluck, SUNY Upstate, Syracuse, NY
2008 *Patricio B. Roman, Dartmouth Medical School
2008 *John Harkess, University of Tennessee Health Sciences Center, Memphis
2009 Andrew Yeh, University of Hawaii
(*Recipients of Arthritis Foundation, New York Chapter, Summer Student Fellowship)