Rajaram Gopalakrishnan, BDS, PhD

Professor, Department of Diagnostic and Biological Sciences

Rajaram Gopalakrishnan

Contact Info

gopal007@umn.edu

Office Phone 612-624-0918

Fax 612-626-3076

Office Address:
16-108b Moos Tower
515 Delaware St. SE
Minneapolis, MN 55455

Mailing Address:
School of Dentistry
Room 15-229 MoosT
1291A
515 Delaware St SE
Minneapolis, MN 55455

Residency, Ohio State University (Oral and Maxillofacial Pathology), 1995

Fellowship, University of Michigan (Organogenesis), 2001

PhD, Ohio State University (Pathology), 1999

BDS, University of Madras, 1991

Post Doctoral, University of Michigan (Bone Biology), 2002

Summary

Dr. Raj Gopalakrishnan is   Professor and director of the Division of Oral and Maxillofacial Pathology, Department of Developmental and Surgical Sciences, School of Dentistry, University of Minnesota. He is also a member of the Oral Biology Graduate program at the School of Dentistry.

Dr. Gopalakrishnan received his Bachelor of Dental Surgery (B.D.S.) degree from University of Madras, Chennai, India in 1991 and completed a residency in Oral and Maxillofacial Pathology from The Ohio State University College of Dentistry in 1995. He subsequently obtained a Ph.D. in Pathology from The Ohio State University in 1999, and joined the laboratory of Dr. Renny Franceschi at the University of Michigan as a post doctoral fellow.

In 2002, he became an assistant professor at the University of Minnesota.

Expertise

Metabolic bone loss associated with antiretroviral therapy

Awards & Recognition

  • Century Club Professor of the Year, 2011
  • Seventh International Conference on the Chemistry and Biology of Mineralized Tissue, 2001
  • Fellowship, University of Michigan Center for Organogenesis Post doctoral fellowship, 2001
  • AADR Block Travel Grant, 2001
  • AADR/Warner Lambert Hatton Award, 2001
  • IADR/Unilever Hatton Award, 2001
  • New Investigator Award
  • Phi Kappa Phi Honor Society, 1998

Research

Research Summary/Interests

Dr. Gopalakrishnan’s overall research focuses on the mechanisms regulating bone remodeling. Major experimental approaches include use of global and bone-specific knockout and overexpressing transgenic mice, histological analyses of bone, static and dynamic histomorphometry, and signaling and transcriptional studies using basic molecular and cell biological techniques.

Role of BMP and Twsg-1 in osteoclastogenesis

Dr. Gopalakrishnan's research demonstrates that mice deficient in twisted gastrulation (Twsg1), an extracellular binding protein of BMP, show osteopenia due to enhanced osteoclastogenesis mediated through increased BMP signaling. Follow up publications have shown that BMP2 can directly activate osteoclasts and Twsg1 can inhibit osteoclast differentiation. Current studies focus on the function of non-canonical and canonical BMP pathways during osteoclastogenesis and regulation of these pathways in various stages of osteoclast formation. The long-term goal of Dr. Gopalakrishnan's research is to understand the regulation of osteoclast formation to enable better diagnostic and therapeutic interventions into the bone remodeling process.

PrKD signaling and osteoclasts differentiation

In collaboration with Dr. Eric Jensen and Dr. Kim Mansky, Dr. Gopalakrishnan's lab studies the effect of the protein kinase D (PrKD) pathway in osteoclastogenesis, showing PrKD activity is critical for osteoclast fusion through increased expression of DC-STAMP, a key osteoclast fusion gene. Recent publications showed that PrKD2 is the main PrKD isoform expressed in osteoclastic cells, and RNAi against PrKD2 or treatment with the PrKD inhibitor CID755673 reduced expression of DC-STAMP leading to decreased osteoclast fusion. Current studies are focused on understanding the mechanisms by which PKD2 regulates osteoclast fusion.

Functional significance of HDAC7 in osteoclast formation

Dr. Gopalakrishnan’s lab, in a co-investigation with Dr. Jensen and Dr. Mansky, recently identified histone deacytelase 7 (HDAC7) as a novel regulator of osteoclast formation. In vitro data showed that suppression of HDAC7 enhanced differentiation of osteoclasts from bone marrow macrophage cultures, while overexpression of HDAC7 inhibited osteoclast formation. Osteoclasts from HDAC7 null mice are larger in size, display increased resorption activity, and show increased expression of MITF/PU.1 target genes including DC-STAMP, OSCAR, cathepsin K and v-ATPase V0 subunit d2. Current studies focus on the interaction between HDAC7 and MITF/PU.1 transcription factors and the mechanism(s) for HDAC7 regulation of osteoclast formation.

Epidemiology, risk factors and pathogenesis of BRONJ

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a significant and serious oral complication of long-term intravenous bisphosphonate (BP). Through a case-control study, Dr. Gopalakrishnan’s research showed that BRONJ cases had significantly more missing teeth, higher average clinical attachment loss (CAL), and higher percentage of sites with CAL ? 3mm than controls. In a related project using salivary proteomics, Dr. Gopalakrishnan and his collaborators identified 200 proteins differentially expressed in BRONJ patients. A majority of these proteins are predicted to have a role in drug metabolism, immunological and dermatological disease. Current and future studies are focused on clarifying the roles of these proteins in BRONJ.

Publications

Selected Publications from 2005 - Present.

  • Tasca A, Stemig M, Broege A, Huang B, Davydova J, Zwijsen A, Umans L, Jensen ED, Gopalakrishnan R, Mansky KC. Smad1/5 and smad4 expression are important for osteoclast differentiation. J Cell Biochem. 2015 Jul;116(7):1350-60. doi: 10.1002/jcb.25092. PubMed PMID: 25711193; PubMed Central PMCID: PMC4431909.
  • Huntley R, Davydova J, Petryk A, Billington CJ Jr, Jensen ED, Mansky KC, Gopalakrishnan R. The Function of Twisted Gastrulation in Regulating Osteoclast Differentiation is Dependent on BMP Binding. J Cell Biochem. 2015 Mar 24. doi: 10.1002/jcb.25174. [Epub ahead of print] PubMed PMID: 25808976.
  • Thumbigere-Math V, Michalowicz B, de Jong E, Griffin T, Basi D, Hughes P, Tsai M, Swenson K, Rockwell L,Gopalakrishnan R. Salivary proteomics in bisphosphonate-related osteonecrosis of the jaw. Oral Dis. 2013 Oct 31. doi: 10.1111/odi.12204. [Epub ahead of print] PubMed PMID: 24286378; PubMed Central. PMCID: PMC4007366.
  • Broege A, Pham L, Jensen ED, Emery A, Huang TH, Stemig M, Beppu H, Petryk A, O'Connor M, Mansky K,Gopalakrishnan R. Bone morphogenetic proteins signal via SMAD and mitogen-activated protein (MAP) kinase pathways at distinct times during osteoclastogenesis. J Biol Chem. 2013 Dec 27;288(52):37230-40. doi: 10.1074/jbc.M113.496950. Epub 2013 Nov 14. PubMed PMID: 24235143; PubMed Central PMCID: PMC3873576.
  • Thumbigere-Math V, Michalowicz BS, Hodges JS, Tsai ML, Swenson KK, Rockwell L, Gopalakrishnan R. Periodontal disease as a risk factor for bisphosphonate-related osteonecrosis of the jaw. J Periodontol. 2014 Feb;85(2):226-33. doi: 10.1902/jop.2013.130017. Epub 2013 Jun 20. PubMed PMID: 23786404; PubMed Central PMCID: PMC3972496.
  • Mansky KC, Jensen ED, Davidova J, Yamamoto M, Gopalakrishnan R. Protein kinase D promotes in vitro osteoclast differentiation and fusion. J Biol Chem. 2013 Apr 5;288(14):9826-34. doi: 10.1074/jbc.M112.444133. Epub 2013 Feb 21. PubMed PMID: 23430742; PubMed Central PMCID: PMC3617283.
  • Billington CJ Jr, Fiebig JE, Forsman CL, Pham L, Burbach N, Sun M, Jaskoll T, Mansky K, Gopalakrishnan R, O'Connor MB, Mueller TD, Petryk A. Glycosylation of Twisted Gastrulation is Required for BMP Binding and Activity during Craniofacial Development. Front Physiol. 2011 Sep 12;2:59. doi: 10.3389/fphys.2011.00059. eCollection 2011. PubMed PMID: 21941513; PubMed Central PMCID: PMC3170884.
  • Basi DL, Hughes PJ, Thumbigere-Math V, Sabino M, Mariash A, Lunos SA, Jensen E, Gopalakrishnan R. Matrix metalloproteinase-9 expression in alveolar extraction sockets of Zoledronic acid-treated rats. J Oral Maxillofac Surg. 2011 Nov;69(11):2698-707. doi: 10.1016/j.joms.2011.02.065. Epub 2011 Jul 12. PubMed PMID: 21752506.
  • Billington CJ Jr, Ng B, Forsman C, Schmidt B, Bagchi A, Symer DE, Schotta G, Gopalakrishnan R, Sarver AL, Petryk A. The molecular and cellular basis of variable craniofacial phenotypes and their genetic rescue in Twisted gastrulation mutant mice. Dev Biol. 2011 Jul 1;355(1):21-31. doi: 10.1016/j.ydbio.2011.04.026. Epub 2011 Apr 28. PubMed PMID: 21549111; PubMed Central PMCID: PMC3105466.
  • Thumbigere-Math V, Tu L, Huckabay S, Dudek AZ, Lunos S, Basi DL, Hughes PJ, Leach JW, Swenson KK,Gopalakrishnan R. A retrospective study evaluating frequency and risk factors of osteonecrosis of the jaw in 576 cancer patients receiving intravenous bisphosphonates. Am J Clin Oncol. 2012 Aug;35(4):386-92. doi: 10.1097/COC.0b013e3182155fcb. PubMed PMID: 22561331.
  • Pham L, Kaiser B, Romsa A, Schwarz T, Gopalakrishnan R, Jensen ED, Mansky KC. HDAC3 and HDAC7 have opposite effects on osteoclast differentiation. J Biol Chem. 2011 Apr 8;286(14):12056-65. doi: 10.1074/jbc.M110.216853. Epub 2011 Feb 15.PMID: 21324898
  • Pham L, Beyer K, Jensen ED, Rodriguez JS, Davydova J, Yamamoto M, Petryk A, Gopalakrishnan R, Mansky KC. Bone morphogenetic protein 2 signaling in osteoclasts is negatively regulated by the BMP antagonist, twisted gastrulation. J Cell Biochem. 2011 Mar;112(3):793-803. doi: 10.1002/jcb.23003. PubMed PMID: 21328453; PubMed Central PMCID: PMC3335346.
  • Jensen ED, Pham L, Billington CJ Jr, Espe K, Carlson AE, Westendorf JJ, Petryk A, Gopalakrishnan R, Mansky K. Bone morphogenic protein 2 directly enhances differentiation of murine osteoclast precursors. J Cell Biochem. 2010 Mar 1;109(4):672-82. doi: 10.1002/jcb.22462. PubMed PMID: 20039313; PubMed Central PMCID: PMC2836597.
  • Sotillo Rodriguez JE, Mansky KC, Jensen ED, Carlson AE, Schwarz T, Pham L, MacKenzie B, Prasad H, Rohrer MD, Petryk A, Gopalakrishnan R. Enhanced osteoclastogenesis causes osteopenia in twisted gastrulation-deficient mice through increased BMP signaling. J Bone Miner Res. 2009 Nov;24(11):1917-26. doi: 10.1359/jbmr.090507. PubMed PMID: 19419314; PubMed Central PMCID: PMC2765934.
  • MacKenzie B, Wolff R, Lowe N, Billington CJ Jr, Peterson A, Schmidt B, Graf D, Mina M, Gopalakrishnan R, Petryk A. Twisted gastrulation limits apoptosis in the distal region of the mandibular arch in mice. Dev Biol. 2009 Apr 1;328(1):13-23. doi: 10.1016/j.ydbio.2008.12.041. Epub 2009 Jan 20. PubMed PMID: 19389368; PubMed Central PMCID: PMC2851169.
  • Suttamanatwong S, Jensen ED, Schilling J, Franceschi RT, Carlson AE, Mansky KC, Gopalakrishnan R. Sp proteins and Runx2 mediate regulation of matrix gla protein (MGP) expression by parathyroid hormone. J Cell Biochem. 2009 May 15;107(2):284-92. doi: 10.1002/jcb.22124. PubMed PMID: 19306294; PubMed Central PMCID: PMC2747369.
  • Jensen ED, Gopalakrishnan R, Westendorf JJ. Bone morphogenic protein 2 activates protein kinase D to regulate histone deacetylase 7 localization and repression of Runx2. J Biol Chem. 2009 Jan 23;284(4):2225-34. doi: 10.1074/jbc.M800586200. Epub 2008 Nov 21. PubMed PMID: 19029091; PubMed Central PMCID: PMC2629084.
  • Suttamanatwong S, Franceschi RT, Carlson AE, Gopalakrishnan R. Regulation of matrix Gla protein by parathyroid hormone in MC3T3-E1 osteoblast-like cells involves protein kinase A and extracellular signal-regulated kinase pathways.J Cell Biochem. 2007 Oct 1;102(2):496-505. PubMed PMID: 17407158.
  • Gopalakrishnan R, Suttamanatwong S, Carlson AE, Franceschi RT. Role of matrix Gla protein in parathyroid hormone inhibition of osteoblast mineralization. Cells Tissues Organs. 2005;181(3-4):166-75. Review. PubMed PMID: 16612082.
  • Petryk A, Shimmi O, Jia X, Carlson AE, Tervonen L, Jarcho MP, O'connor MB, Gopalakrishnan R. Twisted gastrulation and chordin inhibit differentiation and mineralization in MC3T3-E1 osteoblast-like cells. Bone. 2005 Apr;36(4):617-26. PubMed PMID: 15780974.

PUBMED Link to Publications

Clinical

Board Certifications

American Board of Oral and Maxillofacial Pathology Certification in 2002