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Jae-Hyuck Shim PhD

TitleAssociate Professor
InstitutionUniversity of Massachusetts Medical School
DepartmentMedicine
AddressUniversity of Massachusetts Medical School
364 Plantation Street, LRB280
Worcester MA 01605
Phone508-856-6245
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    Other Positions
    InstitutionUMMS - School of Medicine
    DepartmentMedicine
    DivisionRheumatology

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentImmunology and Microbiology Program


    Collapse Biography 
    Collapse education and training
    Yonsei University, Seoul, , Korea, Republic ofBSBiotechnology
    Yonsei University, Seoul, , Korea, Republic ofMSBiotechnology
    Yale University School of Medicine, New Haven, CT, United StatesPHD

    Collapse Overview 
    Collapse overview


    Bone mass reflects the coupled balance of activity of osteoblasts to synthesize and osteoclasts to degrade bone matrix.  Coupling of the activity between these two lineages is required for balance in bone remodeling, and dysregulation of this process is a major mechanism in the pathogenesis of many of human skeletal disorders, such as osteoporosis, rheumatoid arthritis, and Paget's disease of bone. Therefore, understanding the molecular mechanisms that regulate these activities is a key to developing improved therapeutics to treat human skeletal disorders.  



     



    To this end, we have taken two experimental approaches to identify the molecular pathways that control osteoclast and osteoblast activity. One is to identify new proteins that control osteoblast and osteoclast commitment and activation in skeletal biology using unbiased high-throughput screens. Mechanistic study of identified proteins has been performed in vitro system and in vivo transgenic and/or knockout mouse models. From our high-throughput screens, we have recently identified two mitogen-activated protein kinase kinase kinases (MAP3Ks) as positive regulators of osteoblast differentiation. We are further deciphering the function and mechanism by which these proteins control osteoblast activity in vitro and in vivo systems.



     



    Alternatively, using the premise that tissues emerging from similar points during vertebrate evolution may share common intracellular signaling networks to guide their activity, we have sought to leverage our extensive knowledge obtained from the immune system to understand the mechanism in which bone cells are regulated. This approach has identified several key mediators of immune system function to be essential for the regulation of skeletal system.  For example, Schnurri-3 (SHN3), a member of the ZAS family of zinc finger proteins has been discovered as a key regulator of T lymphocyte activation and adult bone formation. Mice lacking Shn3 display an osteosclerotic phenotype with profoundly increased bone mass due to augmented osteoblast activity.  We have also discovered that 3-Phosphoinositide-dependent kinase 1 (PDK1)TGFβ-activating kinase 1 (TAK1), and mixed-lineage kinase 3 (MLK3), the MAP3K2 MEKK2 key regulators of many processes including T and B lymphocyte signaling, are critical for bone development and maintenance. Mice lacking PDK1, TAK1, or MLK3 in osteoblasts display severe skeletal defects, similar to human skeletal disorders, such as Rubenstein-Taybi Syndrome (RTS)cleidocranial dysplasia (CCD) or faciogenital dysplasia (FGDY), respectively.



     



    Spatiotemporal coupling of the activity of osteoblasts and osteoclasts is required for balance in bone remodeling. However, this coupling activity, while critical in the normal individual, limits the effectiveness of current therapies to treat osteoporosis. Additionally, dysregulation of this coupling process causes human skeletal disorders such as osteoporosis and Paget’s Disease of Bone (PDB). PDB is the second most common skeletal disorder after osteoporosis, and is characterized by local areas of highly exaggerated bone remodeling. To date, the molecular pathobiology of both PDB development and the exaggerated coupling between osteoclast and osteoblast activities is unclear. Recently, we have discovered that charged multivesicular body (MVB) protein 5 (CHMP5) is a novel dampener of NF-κB signaling and osteoclast/osteoblast coupling in osteoclasts. CHMP5 inhibits NF-κB signaling by stabilizing the inhibitor of NF-κBa (IκBa), suppressing its ubiquitin-mediated proteasomal degradation via the deubiquitinating enzyme USP15.  Accordingly, CHMP5 deletion renders osteoclasts hypersensitive to RANKL stimulation, resulting in increased NF-κB activation and osteoclast differentiation. Mice lacking CHMP5 in osteoclasts (Chmp5-CTSK mice) display increased bone resorption by osteoclasts coupled with exuberant bone formation by osteoblasts, resembling an early-onset, progressive, polyostotic form of human PDB. Moreover, CHMP5 acts as a suppressor of osteoclast/osteoblast coupling both in vivo and in vitro, as CHMP5 deficient osteoclasts secrete high levels of several osteogenic factors. Thus, both in vivo and in vitro studies indicate that precise regulation of CHMP5 function is crucial for control of bone turnover rates.   



     



    Understanding these fundamental pathways that control the differentiation of bone lineages will be crucial for both understanding these rare skeletal dysplasias and for developing new therapeutics to treat common skeletal disorders.



    Collapse Post Docs


    Xianpeng Ge




    Jungmin Kim




    Seok Kyo Seo




    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    List All   |   Timeline
    1. Min Y, Wi SM, Kang JA, Yang T, Park CS, Park SG, Chung S, Shim JH, Chun E, Lee KY. Cereblon negatively regulates TLR4 signaling through the attenuation of ubiquitination of TRAF6. Cell Death Dis. 2016; 7(7):e2313. PMID: 27468689.
      View in: PubMed
    2. Greenblatt MB, Shin DY, Oh H, Lee KY, Zhai B, Gygi SP, Lotinun S, Baron R, Liu D, Su B, Glimcher LH, Shim JH. MEKK2 mediates an alternative ß-catenin pathway that promotes bone formation. Proc Natl Acad Sci U S A. 2016 Mar 1; 113(9):E1226-35. PMID: 26884171.
      View in: PubMed
    3. Aguado LC, Schmid S, Sachs D, Shim JV, Lim JK, tenOever BR. microRNA Function Is Limited to Cytokine Control in the Acute Response to Virus Infection. Cell Host Microbe. 2015 Dec 09; 18(6):714-22. PMID: 26651947.
      View in: PubMed
    4. Moon G, Kim J, Min Y, Wi SM, Shim JH, Chun E, Lee KY. Phosphoinositide-dependent kinase-1 inhibits TRAF6 ubiquitination by interrupting the formation of TAK1-TAB2 complex in TLR4 signaling. Cell Signal. 2015 Dec; 27(12):2524-33. PMID: 26432169.
      View in: PubMed
    5. Oh DS, Koch A, Eisig S, Kim SG, Kim YH, Kim DG, Shim JH. Distinctive Capillary Action by Micro-channels in Bone-like Templates can Enhance Recruitment of Cells for Restoration of Large Bony Defect. J Vis Exp. 2015; (103). PMID: 26380953.
      View in: PubMed
    6. Greenblatt MB, Park KH, Oh H, Kim JM, Shin DY, Lee JM, Lee JW, Singh A, Lee KY, Hu D, Xiao C, Charles JF, Penninger JM, Lotinun S, Baron R, Ghosh S, Shim JH. CHMP5 controls bone turnover rates by dampening NF-?B activity in osteoclasts. J Exp Med. 2015 Jul 27; 212(8):1283-301. PMID: 26195726.
      View in: PubMed
    7. Greenblatt MB, Kim JM, Oh H, Park KH, Choo MK, Sano Y, Tye CE, Skobe Z, Davis RJ, Park JM, Bei M, Glimcher LH, Shim JH. p38a MAPK is required for tooth morphogenesis and enamel secretion. J Biol Chem. 2015 Jan 2; 290(1):284-95. PMID: 25406311.
      View in: PubMed
    8. Wi SM, Moon G, Kim J, Kim ST, Shim JH, Chun E, Lee KY. TAK1-ECSIT-TRAF6 complex plays a key role in the TLR4 signal to activate NF-?B. J Biol Chem. 2014 Dec 19; 289(51):35205-14. PMID: 25371197.
      View in: PubMed
    9. Mi Wi S, Park J, Shim JH, Chun E, Lee KY. Ubiquitination of ECSIT is crucial for the activation of p65/p50 NF-?Bs in Toll-like receptor 4 signaling. Mol Biol Cell. 2015 Jan 1; 26(1):151-60. PMID: 25355951.
      View in: PubMed
    10. Backes S, Langlois RA, Schmid S, Varble A, Shim JV, Sachs D, tenOever BR. The Mammalian response to virus infection is independent of small RNA silencing. Cell Rep. 2014 Jul 10; 8(1):114-25. PMID: 24953656.
      View in: PubMed
    11. Kim SY, Baik KH, Baek KH, Chah KH, Kim KA, Moon G, Jung E, Kim ST, Shim JH, Greenblatt MB, Chun E, Lee KY. S6K1 negatively regulates TAK1 activity in the toll-like receptor signaling pathway. Mol Cell Biol. 2014 Feb; 34(3):510-21. PMID: 24277938.
      View in: PubMed
    12. Park KH, Park B, Yoon DS, Kwon SH, Shin DM, Lee JW, Lee HG, Shim JH, Park JH, Lee JM. Zinc inhibits osteoclast differentiation by suppression of Ca2+-Calcineurin-NFATc1 signaling pathway. Cell Commun Signal. 2013; 11:74. PMID: 24088289.
      View in: PubMed
    13. Yong Kim S, Jeong S, Chah KH, Jung E, Baek KH, Kim ST, Shim JH, Chun E, Lee KY. Salt-inducible kinases 1 and 3 negatively regulate Toll-like receptor 4-mediated signal. Mol Endocrinol. 2013 Nov; 27(11):1958-68. PMID: 24061540.
      View in: PubMed
    14. Greenblatt MB, Shim JH. Osteoimmunology: a brief introduction. Immune Netw. 2013 Aug; 13(4):111-5. PMID: 24009537.
      View in: PubMed
    15. Shim JH, Greenblatt MB, Zou W, Huang Z, Wein MN, Brady N, Hu D, Charron J, Brodkin HR, Petsko GA, Zaller D, Zhai B, Gygi S, Glimcher LH, Jones DC. Schnurri-3 regulates ERK downstream of WNT signaling in osteoblasts. J Clin Invest. 2013 Sep; 123(9):4010-22. PMID: 23945236.
      View in: PubMed
    16. Greenblatt MB, Shim JH, Glimcher LH. Mitogen-activated protein kinase pathways in osteoblasts. Annu Rev Cell Dev Biol. 2013; 29:63-79. PMID: 23725048.
      View in: PubMed
    17. Park TY, Kim SH, Shin YC, Lee NH, Lee RK, Shim JH, Glimcher LH, Mook-Jung I, Cheong E, Kim WK, Honda F, Morio T, Lim JS, Lee SK. Amelioration of neurodegenerative diseases by cell death-induced cytoplasmic delivery of humanin. J Control Release. 2013 Mar 28; 166(3):307-15. PMID: 23298615.
      View in: PubMed
    18. Wein MN, Jones DC, Shim JH, Aliprantis AO, Sulyanto R, Lazarevic V, Poliachik SL, Gross TS, Glimcher LH. Control of bone resorption in mice by Schnurri-3. Proc Natl Acad Sci U S A. 2012 May 22; 109(21):8173-8. PMID: 22573816.
      View in: PubMed
    19. Shim JH, Greenblatt MB, Singh A, Brady N, Hu D, Drapp R, Ogawa W, Kasuga M, Noda T, Yang SH, Lee SK, Rebel VI, Glimcher LH. Administration of BMP2/7 in utero partially reverses Rubinstein-Taybi syndrome-like skeletal defects induced by Pdk1 or Cbp mutations in mice. J Clin Invest. 2012 Jan; 122(1):91-106. PMID: 22133875.
      View in: PubMed
    20. Zou W, Greenblatt MB, Shim JH, Kant S, Zhai B, Lotinun S, Brady N, Hu DZ, Gygi SP, Baron R, Davis RJ, Jones D, Glimcher LH. MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice. J Clin Invest. 2011 Nov; 121(11):4383-92. PMID: 21965325.
      View in: PubMed
    21. Zou W, Chen X, Shim JH, Huang Z, Brady N, Hu D, Drapp R, Sigrist K, Glimcher LH, Jones D. The E3 ubiquitin ligase Wwp2 regulates craniofacial development through mono-ubiquitylation of Goosecoid. Nat Cell Biol. 2011 Jan; 13(1):59-65. PMID: 21170031.
      View in: PubMed
    22. Lazarevic V, Chen X, Shim JH, Hwang ES, Jang E, Bolm AN, Oukka M, Kuchroo VK, Glimcher LH. T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding ROR?t. Nat Immunol. 2011 Jan; 12(1):96-104. PMID: 21151104.
      View in: PubMed
    23. Shin MJ, Shim JH, Lee JY, Chae WJ, Lee HK, Morio T, Park JH, Chang EJ, Lee SK. Qualitative and quantitative differences in the intensity of Fas-mediated intracellular signals determine life and death in T cells. Int J Hematol. 2010 Sep; 92(2):262-70. PMID: 20658220.
      View in: PubMed
    24. Greenblatt MB, Shim JH, Zou W, Sitara D, Schweitzer M, Hu D, Lotinun S, Sano Y, Baron R, Park JM, Arthur S, Xie M, Schneider MD, Zhai B, Gygi S, Davis R, Glimcher LH. The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice. J Clin Invest. 2010 Jul; 120(7):2457-73. PMID: 20551513.
      View in: PubMed
    25. Greenblatt MB, Shim JH, Glimcher LH. TAK1 mediates BMP signaling in cartilage. Ann N Y Acad Sci. 2010 Mar; 1192:385-90. PMID: 20392264.
      View in: PubMed
    26. Shim JH, Greenblatt MB, Xie M, Schneider MD, Zou W, Zhai B, Gygi S, Glimcher LH. TAK1 is an essential regulator of BMP signalling in cartilage. EMBO J. 2009 Jul 22; 28(14):2028-41. PMID: 19536134.
      View in: PubMed
    27. Kim SY, Jo HY, Kim MH, Cha YY, Choi SW, Shim JH, Kim TJ, Lee KY. H2O2-dependent hyperoxidation of peroxiredoxin 6 (Prdx6) plays a role in cellular toxicity via up-regulation of iPLA2 activity. J Biol Chem. 2008 Nov 28; 283(48):33563-8. PMID: 18826942.
      View in: PubMed
    28. Mendoza H, Campbell DG, Burness K, Hastie J, Ronkina N, Shim JH, Arthur JS, Davis RJ, Gaestel M, Johnson GL, Ghosh S, Cohen P. Roles for TAB1 in regulating the IL-1-dependent phosphorylation of the TAB3 regulatory subunit and activity of the TAK1 complex. Biochem J. 2008 Feb 1; 409(3):711-22. PMID: 18021073.
      View in: PubMed
    29. Shim JH, Xiao C, Hayden MS, Lee KY, Trombetta ES, Pypaert M, Nara A, Yoshimori T, Wilm B, Erdjument-Bromage H, Tempst P, Hogan BL, Mellman I, Ghosh S. CHMP5 is essential for late endosome function and down-regulation of receptor signaling during mouse embryogenesis. J Cell Biol. 2006 Mar 27; 172(7):1045-56. PMID: 16567502.
      View in: PubMed
    30. Shim JH, Xiao C, Paschal AE, Bailey ST, Rao P, Hayden MS, Lee KY, Bussey C, Steckel M, Tanaka N, Yamada G, Akira S, Matsumoto K, Ghosh S. TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes Dev. 2005 Nov 15; 19(22):2668-81. PMID: 16260493.
      View in: PubMed
    31. Lee KY, D'Acquisto F, Hayden MS, Shim JH, Ghosh S. PDK1 nucleates T cell receptor-induced signaling complex for NF-kappaB activation. Science. 2005 Apr 1; 308(5718):114-8. PMID: 15802604.
      View in: PubMed
    32. May MJ, Larsen SE, Shim JH, Madge LA, Ghosh S. A novel ubiquitin-like domain in IkappaB kinase beta is required for functional activity of the kinase. J Biol Chem. 2004 Oct 29; 279(44):45528-39. PMID: 15319427.
      View in: PubMed
    33. Xiao C, Shim JH, Klüppel M, Zhang SS, Dong C, Flavell RA, Fu XY, Wrana JL, Hogan BL, Ghosh S. Ecsit is required for Bmp signaling and mesoderm formation during mouse embryogenesis. Genes Dev. 2003 Dec 1; 17(23):2933-49. PMID: 14633973.
      View in: PubMed
    34. Shim JH, Lee HK, Chang EJ, Chae WJ, Han JH, Han DJ, Morio T, Yang JJ, Bothwell A, Lee SK. Immunosuppressive effects of tautomycetin in vivo and in vitro via T cell-specific apoptosis induction. Proc Natl Acad Sci U S A. 2002 Aug 6; 99(16):10617-22. PMID: 12149481.
      View in: PubMed
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