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Laboratory of Molecular Osteoarthritis Research

Our goal is to understand the altered signaling pathways that prompt joint tissue disruption in osteoarthritis (OA).

We are using comprehensive state-of-the-art approaches to assess how different joint tissues contribute to OA disease. Our models span cell-based approaches, in vivo systems and analyses of retrieved tissues from patients. We believe that the combined information obtained from these models with will improve our understanding of the underlying mechanisms that lead to disease onset and progression, and will allow us to develop targeted approaches with potential therapeutic application.

We use this information to:

  • develop and combine in vivo and in vitro approaches that allow us to comprehensively study OA as a whole joint disorder
  • utilize detailed cellular, molecular, and histological analyses designed to uncover distinct cellular and molecular signatures

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Areas of Investigation

  • The identification of specific cellular and molecular signatures in synovium and adipose tissue of patients with osteoarthritis, and the evaluation of the contribution of the abnormally produced cytokines and adipokines to disease onset and progression
  • The characterization of the contribution of altered DNA methylation to the differential gene expression observed in chondrocyte hypertrophic differentiation and its relationship with osteoarthritis development
  • Investigation of the contribution of IKKalpha/CHUK to cartilage homeostasis, and its influence in the hypertrophy-like conversion of articular chondrocytes in osteoarthritis

The goal of Dr. Otero’s research is to define the altered signaling pathways that prompt to the joint tissue disruption in osteoarthritis (OA), and to develop and utilize in vivo and in vitro systems designed to dissect complex transcriptional regulatory networks that are abnormally dysregulated in OA. Ultimately, Dr. Otero’s research aims to improve our understanding of the underlying mechanisms that lead to disease onset and progression, and to develop approaches with potential therapeutic application. To this end, his research focuses in identifying and understanding the distinct cellular and molecular signatures that contribute to OA.

Areas of Investigation

  • The identification of specific cellular and molecular signatures in synovium and adipose tissue of patients with osteoarthritis, and the evaluation of the contribution of the abnormally produced cytokines and adipokines to disease onset and progression
  • The characterization of the contribution of altered DNA methylation to the differential gene expression observed in chondrocyte hypertrophic differentiation and its relationship with osteoarthritis development
  • Investigation of the contribution of IKKalpha/CHUK to cartilage homeostasis, and its influence in the hypertrophy-like conversion of articular chondrocytes in osteoarthritis

The goal of Dr. Otero’s research is to define the altered signaling pathways that prompt to the joint tissue disruption in osteoarthritis (OA), and to develop and utilize in vivo and in vitro systems designed to dissect complex transcriptional regulatory networks that are abnormally dysregulated in OA. Ultimately, Dr. Otero’s research aims to improve our understanding of the underlying mechanisms that lead to disease onset and progression, and to develop approaches with potential therapeutic application. To this end, his research focuses in identifying and understanding the distinct cellular and molecular signatures that contribute to OA.

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Principal Investigator

Miguel Otero, PhD, Assistant Scientist and Laboratory Director

Researchers

Purva Singh, PhD, Research Associate
Samantha Lessard, BA, Research Technician
Kathryn Oi, BA, Research Technician (Precision Medicine Laboratory)
Luvana Chowdhury, BA, Clinical Research Assistant (Precision Medicine Laboratory)

HSS Collaborators

Carl Blobel, MD, PhD
Mary B. Goldring, PhD
Alessandra Pernis, MD
Ed Purdue, PhD
Scott Rodeo, MD

Image - Laboratory personnel
Laboratory Personnel
Principal Investigator:
Miguel Otero, PhD

Principal Investigator

Miguel Otero, PhD, Assistant Scientist and Laboratory Director

Researchers

Purva Singh, PhD, Research Associate
Samantha Lessard, BA, Research Technician
Kathryn Oi, BA, Research Technician (Precision Medicine Laboratory)
Luvana Chowdhury, BA, Clinical Research Assistant (Precision Medicine Laboratory)

HSS Collaborators

Carl Blobel, MD, PhD
Mary B. Goldring, PhD
Alessandra Pernis, MD
Ed Purdue, PhD
Scott Rodeo, MD

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Recent Publications

  • Otero M, Peng H, El Hachem K, Culley KL, Wondimu EB, Quinn J, Asahara H, Tsuchimochi K, Hashimoto K, Goldring MB. ELF3 modulates type II collagen gene (COL2A1) transcription in chondrocytes by Inhibiting SOX9-CBP/p300-driven histone acetyltransferase activity. Connect Tissue Res. 2016 Jun 16. [Epub ahead of print] PubMed PMID: 27310669.
  • Conde J, Otero M, Scotece M, Abella V, López V, Pino J, Gómez R, Lago F, Goldring MB, Gualillo O. E74-like factor (ELF3) and NFκB regulate lipocalin-2 expression in chondrocytes. J Physiol. 2016 May 25. doi:10.1113/JP272240. [Epub ahead of print] PubMed PMID: 27222093.
  • Sadatsuki R, Kaneko H, Kinoshita M, Futami I, Nonaka R, Culley KL, Otero M, Hada S, Goldring MB, Yamada Y, Kaneko K, Arikawa-Hirasawa E, Ishijima M. Perlecan is required for the chondrogenic differentiation of synovial mesenchymal cells through regulation of Sox9 gene expression. J Orthop Res. 2016 May 30. doi: 10.1002/jor.23318. [Epub ahead of print] PubMed PMID: 27238423.
  • Shimada H, Otero M, Tsuchimochi K, Yamasaki S, Sakakima H, Matsuda F, Sakasegawa M, Setoguchi T, Xu L, Goldring MB, Tanimoto A, Komiya S, Ijiri K. CCAAT/enhancer binding protein β (C/EBPβ) regulates the transcription of growth arrest and DNA damage-inducible protein 45 β (GADD45β) in articular chondrocytes. Pathol Res Pract. 2016 Apr;212(4):302-9. doi: 10.1016/j.prp.2016.01.009. Epub 2016 Jan 27. PubMed PMID: 26896926.
  • Olivotto E, Otero M, Marcu KB, Goldring MB. Pathophysiology of osteoarthritis: canonical NF-κB/IKKβ-dependent and kinase-independent effects of IKKα in cartilage degradation and chondrocyte differentiation. RMD Open. 2015 Aug 15;1(Suppl 1):e000061. doi: 10.1136/rmdopen-2015-000061. eCollection 2015. Review. PubMed PMID: 26557379; PubMed Central PMCID: PMC4632142
  • 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;1226:143-73. doi: 10.1007/978-1-4939-1619-1_12. PubMed PMID: 25331049.
  • Goldring, M., Culley, K., Wondimu, E., Otero, M. Cartilage and Chondrocytes. Kelley & Firestein’s Textbook of Rheumatology, 10th Edition, Chapter 3. 2015; ISBN 978-0-3233-16965
  • Elizabeth W. Bradley, Lomeli R. Carpio, Meghan E. McGee-Lawrence, Derek F. Amanatullah, Sanjeev Kakar, Lauren E. Ta, Alexandra C. Newton, Miguel Otero, Mary B. Goldring, Jennifer J. Westendorf. Phlpp1 facilitates post-traumatic osteoarthritis and is induced by inflammation and promoter demethylation in human osteoarthritis. Osteoarthritis Cartilage 2015 Dec 31. pii: S1063-4584(15)01437-5. doi:10.1016/j.joca.2015.12.014.
  • Imagawa K, de Andrés 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 Nov;66(11):3040-51. doi: 10.1002/art.38774. PubMed PMID: 25048791; PubMed Central PMCID: PMC4211984.
  • Fox AJ, Schär MO, Wanivenhaus F, Chen T, Attia E, Binder NB, Otero M, Gilbert SL, Nguyen JT, Chaudhury S, Warren RF, Rodeo SA. Fluoroquinolones impair tendon healing in a rat rotator cuff repair model: a preliminary study. Am J Sports Med. 2014 Dec;42(12):2851-9
  • 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 Feb;32(2):224-30. doi: 10.1002/jor.22492. Epub 2013 Sep 21. PubMed PMID: 24108673; PubMed Central PMCID: PMC3978382
  • Eleonora Olivotto*, Miguel Otero*, Annalisa Astolfi, Daniela Platano, Annalisa Facchini, Stefania Pagani, Flavio Flamigni, Andrea Facchini, Mary B. Goldring, Rosa Maria Borzì and Kenneth B. Marcu. IKKα/CHUK regulates extracellular matrix remodeling independent of its kinase activity to facilitate articular chondrocyte differentiation. PLoS One. 2013 Sep 2;8(9):e73024 *Equal contribution
  • Hall KC, Hill D, Otero M, Plumb DA, Froemel D, Dragomir CL, Maretzky T, Boskey A, Crawford HC, Selleri L, Goldring MB, Blobel CP. ADAM17 Controls Endochondral Ossification by Regulating Terminal Differentiation of Chondrocytes. Mol Cell Biol. 2013 Aug;33(16):3077-90. doi: 10.1128/MCB.00291-13 11.
  • Ko Hashimoto, Miguel Otero, Kei Imagawa, María Carmen de Andrés, Jonathan M. Coico, Helmtrud I. Roach, Richard O.C. Oreffo, Kenneth B. Marcu, and Mary B. Goldring. Regulated transcription of human matrix metalloproteinase 13 (MMP13) and interleukin-1 beta (IL1B) genes in chondrocytes depends on methylation of specific proximal promoter CpG sites. J Biol Chem. 2013 Apr 5;288(14):10061-72
  • Natasha Baker, Paul Sharpe, Kirsty Culley, Miguel Otero, Damon Bevan, Peter Newham, Wendy Barker, Kristen M Clements, Caroline J Langham, Mary B Goldring and Jelena Gavrilovic. Dual regulation of metalloproteinase expression in chondrocytes by WISP3/CCN6. Arthritis Rheum. 2012 Jul;64(7):2289-996
  • Otero M, Plumb DA, Tsuchimochi K, Dragomir CL, Hashimoto K, Peng H, Olivotto E, Bevilacqua M, Tan L, Yang Z, Zhan Y, Oettgen P, Li Y, Marcu KB, Goldring MB.E74-like factor 3 (ELF3) impacts on matrix metalloproteinase 13 (MMP13) transcriptional control in articular chondrocytes under pro-inflammatory stress. J Biol Chem. 2012 Jan 27;287(5):3559-72
  • 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; 806:301-36. PubMed PMID: 220574618
  • Miguel Otero, Richard Loeser, Mary Goldring. Primer on OA, Chapter 5: Inflammation and OA. Osteoarthritis Research Society International (www.oarsi.org)

For a complete publication list, please see PubMed

Funding Sources

  • NIH (NIA)
    R21 AG049980-01A1 “Impact of the DNA Methylome in Chondrocyte Hypertrophy in OA"
  • The Nancy Dickerson Whitehead Research Fellowship
  • Marina Kellen French Foundation
  • Ambrose Monell Foundation

Recent Publications

  • Otero M, Peng H, El Hachem K, Culley KL, Wondimu EB, Quinn J, Asahara H, Tsuchimochi K, Hashimoto K, Goldring MB. ELF3 modulates type II collagen gene (COL2A1) transcription in chondrocytes by Inhibiting SOX9-CBP/p300-driven histone acetyltransferase activity. Connect Tissue Res. 2016 Jun 16. [Epub ahead of print] PubMed PMID: 27310669.
  • Conde J, Otero M, Scotece M, Abella V, López V, Pino J, Gómez R, Lago F, Goldring MB, Gualillo O. E74-like factor (ELF3) and NFκB regulate lipocalin-2 expression in chondrocytes. J Physiol. 2016 May 25. doi:10.1113/JP272240. [Epub ahead of print] PubMed PMID: 27222093.
  • Sadatsuki R, Kaneko H, Kinoshita M, Futami I, Nonaka R, Culley KL, Otero M, Hada S, Goldring MB, Yamada Y, Kaneko K, Arikawa-Hirasawa E, Ishijima M. Perlecan is required for the chondrogenic differentiation of synovial mesenchymal cells through regulation of Sox9 gene expression. J Orthop Res. 2016 May 30. doi: 10.1002/jor.23318. [Epub ahead of print] PubMed PMID: 27238423.
  • Shimada H, Otero M, Tsuchimochi K, Yamasaki S, Sakakima H, Matsuda F, Sakasegawa M, Setoguchi T, Xu L, Goldring MB, Tanimoto A, Komiya S, Ijiri K. CCAAT/enhancer binding protein β (C/EBPβ) regulates the transcription of growth arrest and DNA damage-inducible protein 45 β (GADD45β) in articular chondrocytes. Pathol Res Pract. 2016 Apr;212(4):302-9. doi: 10.1016/j.prp.2016.01.009. Epub 2016 Jan 27. PubMed PMID: 26896926.
  • Olivotto E, Otero M, Marcu KB, Goldring MB. Pathophysiology of osteoarthritis: canonical NF-κB/IKKβ-dependent and kinase-independent effects of IKKα in cartilage degradation and chondrocyte differentiation. RMD Open. 2015 Aug 15;1(Suppl 1):e000061. doi: 10.1136/rmdopen-2015-000061. eCollection 2015. Review. PubMed PMID: 26557379; PubMed Central PMCID: PMC4632142
  • 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;1226:143-73. doi: 10.1007/978-1-4939-1619-1_12. PubMed PMID: 25331049.
  • Goldring, M., Culley, K., Wondimu, E., Otero, M. Cartilage and Chondrocytes. Kelley & Firestein’s Textbook of Rheumatology, 10th Edition, Chapter 3. 2015; ISBN 978-0-3233-16965
  • Elizabeth W. Bradley, Lomeli R. Carpio, Meghan E. McGee-Lawrence, Derek F. Amanatullah, Sanjeev Kakar, Lauren E. Ta, Alexandra C. Newton, Miguel Otero, Mary B. Goldring, Jennifer J. Westendorf. Phlpp1 facilitates post-traumatic osteoarthritis and is induced by inflammation and promoter demethylation in human osteoarthritis. Osteoarthritis Cartilage 2015 Dec 31. pii: S1063-4584(15)01437-5. doi:10.1016/j.joca.2015.12.014.
  • Imagawa K, de Andrés 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 Nov;66(11):3040-51. doi: 10.1002/art.38774. PubMed PMID: 25048791; PubMed Central PMCID: PMC4211984.
  • Fox AJ, Schär MO, Wanivenhaus F, Chen T, Attia E, Binder NB, Otero M, Gilbert SL, Nguyen JT, Chaudhury S, Warren RF, Rodeo SA. Fluoroquinolones impair tendon healing in a rat rotator cuff repair model: a preliminary study. Am J Sports Med. 2014 Dec;42(12):2851-9
  • 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 Feb;32(2):224-30. doi: 10.1002/jor.22492. Epub 2013 Sep 21. PubMed PMID: 24108673; PubMed Central PMCID: PMC3978382
  • Eleonora Olivotto*, Miguel Otero*, Annalisa Astolfi, Daniela Platano, Annalisa Facchini, Stefania Pagani, Flavio Flamigni, Andrea Facchini, Mary B. Goldring, Rosa Maria Borzì and Kenneth B. Marcu. IKKα/CHUK regulates extracellular matrix remodeling independent of its kinase activity to facilitate articular chondrocyte differentiation. PLoS One. 2013 Sep 2;8(9):e73024 *Equal contribution
  • Hall KC, Hill D, Otero M, Plumb DA, Froemel D, Dragomir CL, Maretzky T, Boskey A, Crawford HC, Selleri L, Goldring MB, Blobel CP. ADAM17 Controls Endochondral Ossification by Regulating Terminal Differentiation of Chondrocytes. Mol Cell Biol. 2013 Aug;33(16):3077-90. doi: 10.1128/MCB.00291-13 11.
  • Ko Hashimoto, Miguel Otero, Kei Imagawa, María Carmen de Andrés, Jonathan M. Coico, Helmtrud I. Roach, Richard O.C. Oreffo, Kenneth B. Marcu, and Mary B. Goldring. Regulated transcription of human matrix metalloproteinase 13 (MMP13) and interleukin-1 beta (IL1B) genes in chondrocytes depends on methylation of specific proximal promoter CpG sites. J Biol Chem. 2013 Apr 5;288(14):10061-72
  • Natasha Baker, Paul Sharpe, Kirsty Culley, Miguel Otero, Damon Bevan, Peter Newham, Wendy Barker, Kristen M Clements, Caroline J Langham, Mary B Goldring and Jelena Gavrilovic. Dual regulation of metalloproteinase expression in chondrocytes by WISP3/CCN6. Arthritis Rheum. 2012 Jul;64(7):2289-996
  • Otero M, Plumb DA, Tsuchimochi K, Dragomir CL, Hashimoto K, Peng H, Olivotto E, Bevilacqua M, Tan L, Yang Z, Zhan Y, Oettgen P, Li Y, Marcu KB, Goldring MB.E74-like factor 3 (ELF3) impacts on matrix metalloproteinase 13 (MMP13) transcriptional control in articular chondrocytes under pro-inflammatory stress. J Biol Chem. 2012 Jan 27;287(5):3559-72
  • 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; 806:301-36. PubMed PMID: 220574618
  • Miguel Otero, Richard Loeser, Mary Goldring. Primer on OA, Chapter 5: Inflammation and OA. Osteoarthritis Research Society International (www.oarsi.org)

For a complete publication list, please see PubMed

Funding Sources

  • NIH (NIA)
    R21 AG049980-01A1 “Impact of the DNA Methylome in Chondrocyte Hypertrophy in OA"
  • The Nancy Dickerson Whitehead Research Fellowship
  • Marina Kellen French Foundation
  • Ambrose Monell Foundation