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Thomas Jefferson University - Vickram Srinivas, Ph.D.
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Expertise and Research Interests
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Growth of the craniofacial complex, the skull and the mandibular condyle is dependent on the activities of chondrocytes contained within the endochondral growth plate. Maturation of cells in the growth plate is accompanied by stage specific changes in energy generation. Recent studies show that metabolic control is mediated by Hypoxia Inducible Factors (HIFs), transcription factors that responds to changes in the local oxygen tension. The discovery that HIF activity is controlled by a group of oxygen sensitive prolyl hydroxylases (PHDs) provides a new insight into the regulation of chondrocyte function. Based on these observations, we have hypothesized that in the growth plate, PHD controlled activation of HIF transcriptional activity is required for chondrocyte maturation, terminal differentiation and the induction of apoptosis. Current investigations of this laboratory are aimed at testing this novel hypothesis that brings together current ideas concerning chondrocyte metabolism, the impact of the local environment, the development of the terminal differentiated state and the mechanism of cell death.
Despite decades of study, the mechanism by which the epiphyseal growth plate regulates long bone growth remains poorly understood. While it is recognized that there are a number of specific phases which characterize the maturing chondrocyte, the mechanism by which each of these stages are coordinated has escaped systematic study. Because of this paucity of information, we are still unable to answer basic clinical questions: how is growth activity in bone and between bones coordinated; why is bone growth discontinuous (stasis versus saltation); is there an advantage to discontinuous growth; does discontinuous growth favor bone repair; what is the mechanism by which chondrocytes survive epiphyseal slippage and then regain their growth potential? Our recent observation that autophagy exists a previously unrecognized step in the maturation pathway, holds promise of providing new insights into phase co-ordination that is especially relevant to the growth process. Thus, we have hypothesized that autophagy governs the timing of maturation, the extent of hypertrophy and the induction of chondrocyte apoptosis, as well as promoting the proliferation of new cells into the maturation cascade. We are also testing the hypothesis that the regulation of the autophagic process is monitored by the activities of three environmental sensors: the oxygen sensor HIF, the energy sensor AMPK, and growth factor and nutritional sensor mTOR.
Another area of investigation involves the role of the above mentioned factors and activities in the onset and pathogenesis of osteoarthritis. Osteoarthritis (OA) is the most common musculoskeletal disease affecting more than 25% of older individuals. Like other chronic conditions, the etiology of OA is multifactorial, and several local and systemic risk factors have been identified. Of these, cytokines are recognized as critical pathogenic agents. While studies of the effects of these agents have been carefully documented, they do not take into account the recent new observation: chondrocytes in articular cartilage exhibit a basal level of autophagy This basal autophagic state is regulated by three environmental sensors: the oxygen sensor HIF, the energy sensor AMP kinase (AMPK), and the growth factor and nutritional sensor mTOR. We hypothesize that IL-1b and TNF-a mediate the progression of basal autophagy to induced autophagy, a condition which results in type II apoptosis. Aside from depleting the cartilage of cells, induced autophagy would be expected to inhibit maintenance of the normal structure of the extracellular matrix, thereby exacerbating progression of the disease state. Thus, another objective of the laboratory is to explore the role, and mechanism of control, of the autophagic process in OA chondrocytes.
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Keywords
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HIF-1; HIF-2; hypoxia; PHDs(Prolyl Hydroxylase); autophagy; Osteoarthritis; growth plate; chondrocytes; cartilage; mTOR; AMPK
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Publications
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- 1) Salceda S, Beck I, Srinivas V, Caro J: Complex role of protein phosphorylation in gene activation by hypoxia,: Kidney International, 51,556-559, (1997)
- 2) Camenisch G, Tini M, Kvietikova I, Srinivas V, Caro J, Wenger R, Gassmann M: General applicability of chicken egg yolk antibodies: the performance of IgY immunoglobulins raised against the hypoxia-inducible factor 1a.: FASEB J: 13:81-88,(1999)
- 3) Srinivas V, Zhang L, Zhu X, Caro J: Characterization of an Oxygen/Redox-dependent degradation domain of Hypoxia-Inducible Factor-a(HIF-a) proteins: Biochem Biophys Res Communications: 260:557-561, (1999).
- 4) Srinivas V, Leshchinsky I, Sang N, King, MP, Minchenko A, Caro J: Oxygen sensing and HIF-1 activation does not require an active mitochondrial respiratory chain electron-transfer pathway: J Biol Chem 276:21995-21998,( 2001).
- 5) Minchenko A, Leshchinsky I, Opentanova I, Sang N, Srinivas V, Armstead V, Caro J: Hypoxia-inducible factor-1 (HIF-1) mediated expression of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKBF3) gene: its possible role in the Warburg effect: J Biol Chem: 277:6183-6187,(2001)
- 6) Sang N, Fang, J, Srinivas V, Leschchinsky I, Caro, J: Carboxyl terminal transactivation activity of HIF-1± is governed by a VHL-independent, hydroxylation-regulated, association with p300/CBP: Mol Cell Biol: 22:2984-2992,(2002)
- 7) Sang N, Leshchinsky I, Srinivas V, Caro J: Analysis of the Non-Hypoxic MAP kinase dependent pathway for the activation of HIF-1a: Cross-talk between hydroxylation dependent and independent interactions: J Biol Chem: 278;14013-14019,(2002)
- 8) Shawn P. Terkhorn, Jolene Bohensky, Masaru Ohashi, Irving M. Shapiro, Robin Jacquet*, Eiki Koyama, William Landis*, Christopher S. Adams and Vickram Srinivas: GROWTH PLATE TERMINAL DIFFERENTIATION IS REGULATED BY OXEMIC STATUS AND THE HIF-PHD AXIS ;, Proceedings of the 8th international Conference on Minerelized Tissue, Banff: pp 54-56 (2005)
- 9) Irving M. Shapiro, Christopher S. Adams, Theresa Freeman, Vickram Srinivas: Fate of the hypertrophic chondrocyte: Microenvironmental perspectives on apoptosis and survival in the epiphyseal growth plate: Embryo Today, 75: 330-339 (2005)
- 10) Vickram Srinivas and Irving M. Shapiro: Chondrocytes Embedded in the Epiphyseal Growth Plates of Long Bones Undergo Autophagy Prior to the Induction of Osteogenesis: Autophagy, 2: 215-216 (2006)
- 11) Szymczyk KH, Freeman TA, Adams CS, Srinivas V and Steinbeck M. Active caspase-3 is required for osteoclast differentiation. : J Cell Physiol. 209:836-44.(2006)
- 12) Terkhorn SP, Bohensky J, Shapiro IM, Koyama E. Srinivas V.: Expression of HIF prolyl hydroxylase isozymes in growth plate chondrocytes: Relationship between maturation and apoptotic sensitivity J. Cell. Physiol. Jan;210 (1):257-65.(2007)
- 13) Shapiro IM, Srinivas V : Metabolic consideration of epiphyseal growth: Survival responses in a taxing environment. Bone. 40; 561-567.(2007)
- 14) Bohensky J, Shapiro IM, Leshinsky S, Terkhorn SP, Adams CS, Srinivas V.: HIF-1 Regulation of Chondrocyte Apoptosis: Induction of the Autophagic Pathway. Autophagy. 3(3) 207-214(2007)
- 15) Jolene Bohensky, Irving M. Shapiro, Serge Leshinsky, Hitoshi Watanabe and Vickram Srinivas: PIM-2 is an independent regulator of chondrocyte survival and autophagy in the epiphyseal growth plate J Cell Physiol. 213: 246-251(2007)
- 16) Shapiro, IM,, Snyder, B., Freeman, T., Watanabe, H., Bohensky, J., Fertala, J and Srinivas, V.: Chondrocyte maturation is characterized by an interplay between Uncoupler Protein-3 (UCP-3) and the hypoxic environment of the growth plate: Proceeedings of the International Mineralized Tissue Society, Chile pp 51-57(2007)
- 17) Shapiro, IM, Adams, CS, Srinivas, V, and Freeman, TA.: Chondrocyte hypertrophy and apoptosis at the cartilage-bone interface. In: Bone and Osteoarthritis (Topics in Bone Biology Vol 4)(F. Bronner and M.C. Farach-Carson, eds.). pp 109-129.(2008)
- 18) Daniel J. Klionsky, Hagai Abeliovich, Patricia Agostinis, Devendra K. Agrawal, Gjumrakch Aliev, David S. Askew, Misuzu Baba, Eric H. Baehrecke, Ben A. Bahr, Andrea Ballabio, Bruce A. Bamber, Diane C. Bassham, Ettore Bergamini, Xiaoning Bi, Martine Biard-Piechaczyk, Janice S. Blum, Dale E. Bredesen, Jeffrey L. Brodsky, John H. Brumell, Ulf T. Brunk, Wilfried Bursch, Nadine Camougrand, Eduardo Cebollero, Francesco Cecconi, Yingyu Chen, Lih-Shen Chin, Augustine Choi, Charleen T. Chu, Jongkyeong Chung, Robert S.B. Clark, Peter G.H. Clarke, Steven G. Clarke, Corinne Clave, John L. Cleveland, Patrice Codogno, María I. Colombo, Ana Coto-Montes, James M. Cregg, Ana Maria Cuervo, Jayanta Debnath, Patrick B. Dennis, Phillip A. Dennis, Francesca Demarchi, Vojo Deretic, Rodney J. Devenish, Federica Di Sano, J. Fred Dice, Clark W. Distelhorst, Savithramma Dinesh-Kumar, N. Tony Eissa, Marian DiFiglia, Mojgan Djavaheri-Mergny, Frank C. Dorsey, Wulf Dröge, Michel Dron, William A. Dunn, Jr., Michael Duszenko, Zvulun Elazar, Audrey Esclatine, Eeva-Liisa Eskelinen, László Fésüs, Kim D. Finley, José M. Fuentes, Juan Fueyo, Kozo Fujisaki, Brigitte Galliot, Fen-Biao Gao, David A. Gewirtz, Spencer B. Gibson, Antje Gohla, Alfred L. Goldberg, Ramon Gonzalez, Cristina González-Estévez, Sharon Gorski, Roberta A. Gottlieb, Dieter Häussinger, You-Wen He, Kim Heidenreich, Joseph A. Hill, Maria Høyer-Hansen, Xun Hu, Wei-Pang Huang, Akiko Iwasaki, Marja Jäättelä, William T. Jackson, Xuejun Jiang, Shengkan Jin, Terje Johansen, Jae U. Jung, Motoni Kadowaki, Chanhee Kang, Ameeta Kelekar, David H. Kessel, Jan A.K.W. Kiel, Hong Pyo Kim, Adi Kimchi, Timothy J. Kinsella, Kirill Kiselyov, Katsuhiko Kitamoto, Erwin Knecht, Masaaki Komatsu, Eiki kominami, Seiji Kondo, Attila L. Kovács, Guido Kroemer, Chia-Yi Kuan, Rakesh Kumar, Mondira Kundu, Jacques Landry, Marianne Laporte, Weidong Le, Huan-Yao Lei, Beth Levine, Andrew Lieberman, Kah-Leong Lim, Fu-Cheng Lin, Willisa Liou, Leroy F. Liu, Gabriel Lopez-Berestein, Carlos López-Otín, Bo Lu, Kay F. Macleod, Walter Malorni, Wim Martinet, Ken Matsuoka, Josef Mautner, Alfred J. Meijer, Alicia Meléndez, Paul Michels, Giovanni Miotto, Wilhelm P. Mistiaen, Noboru Mizushima, Baharia Mograbi, Michael N. Moore, Paula I. Moreira, Yuji Moriyasu, Tomasz Motyl, Christian Münz, Leon O. Murphy, Naweed I. Naqvi, Thomas P. Neufeld, Ichizo Nishino, Ralph A. Nixon, Takeshi Noda, Bernd Nürnberg, Michinaga Ogawa, Nancy L. Oleinick, Laura J. Olsen, Bulent Ozpolat, Shoshana Paglin, Glen E. Palmer, Issidora S. Papassideri, Miles Parkes, David H. Perlmutter, George Perry, Mauro Piacentini, Ronit Pinkas-Kramarski, Mark Prescott, Tassula Proikas-Cezanne, Nina Raben, Abdelhaq Rami, Fulvio Reggiori, Bärbel Rohrer, David C. Rubinsztein, Kevin M. Ryan, Junichi Sadoshima, Hiroshi Sakagami, Yasuyoshi Sakai, Marco Sandri, Chihiro Sasakawa, Miklós Sass, Claudio Schneider, Per O. Seglen, Oleksandr Seleverstov, Jeffrey Settleman, John J. Shacka, Irving M. Shapiro, Andrei A. Sibirny, Elaine C.M. Silva-Zacarin, Hans-Uwe Simon, Cristiano Simone, Anne Simonsen, Mark A. Smith, Katharina Spanel-Borowski, Vickram Srinivas, Meredith Steeves, Harald Stenmark, Per E. Stromhaug, Carlos S. Subauste, Seiichiro Sugimoto, David Sulzer, Toshihiko Suzuki, Michele S. Swanson, Ira Tabas, Fumihiko Takeshita, Nicholas J. Talbot, Zsolt Tallóczy, Keiji Tanaka, Kozo Tanaka, Isei Tanida, Graham S. Taylor, J. Paul Taylor, Alexei Terman, Gianluca Tettamanti, Craig B. Thompson, Michael Thumm, Aviva M. Tolkovsky, Sharon A. Tooze, Ray Truant, Lesya V. Tumanovska, Yasuo Uchiyama, Takashi Ueno, Néstor L. Uzcátegui, Ida J. van der Klei, Eva C. Vaquero, Tibor Vellai, Michael W. Vogel, Hong-Gang Wang, Paul Webster, Zhijun Xi, Gutian Xiao, Joachim Yahalom, Jin-Ming Yang, George S. Yap, Xiao-Ming Yin, Tamotsu Yoshimori, Zhenyu Yue, Michisuke Yuzaki, Olga Zabirnyk, Xiaoxiang Zheng, Xiongwei Zhu and Russell L. Deter: Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes Autophagy. 4; 151-175 (2008)
- 19) Hitoshi Watanabe, Jolene Bohensky, Theresa Freeman, Vickram Srinivas and Irving M Shapiro: Hypoxic induction of UCP3 in the growth plate: UCP3 suppresses chondrocyte autophagy: J Cell Physiol. 216; 419-425 (2008)
- 20) Adam Zahm, Michael Bucaro, Vickram Srinivas, Irving M. Shapiro, Christopher S. Adams: Oxygen tension regulates preosteocyte maturation and mineralization: Bone 43; 25-31(2008)
- 21) Vickram Srinivas, Jolene Bohensky, Irving M Shapiro: Autophagy: A New Phase in the Maturation of Growth Plate Chondrocytes Is Regulated by HIF, mTOR and AMP Kinase: Cells Tissues Organs. 189; 88-92 (2009)
- 22) Vickram Srinivas, Jolene Bohensky, Adam M. Zahm and Irving M. Shapiro: Autophagy in mineralizing tissues: Microenvironmental perspectives. Cell Cycle. 8; 391-393 (2009)
- 23) Jolene Bohensky, Shawn P Terkhorn, Theresa A Freeman, Christopher S Adams, Joseph A Garcia, Irving M Shapiro and Vickram Srinivas: Regulation of Autophagy in Cartilage: HIF-2 Suppresses Chondrocyte Autophagy: Arthritis & Rheumatism. 60: 1406-1415 (2009)
- 24) ) Raihana Zaka , Arnold S Dion , Anna Kusnierz , Jolene Bohensky , Vickram Srinivas , Theresa Freeman , Charlene J Williams: Oxygen Tension Regulates the Expression of ANK (progressive ankylosis) in a Hif-1-Dependent Manner in Growth Plate Chondrocytes: Journal of Bone and Mineral Research, 10.1359/jbmr.090512 (2009)
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Individual Expertise profile of
Vickram Srinivas, Ph.D., Copyright © Vickram Srinivas, Ph.D..
Last Updated
by Vickram Srinivas, Ph.D. : Thursday, May 7, 2009 9:57:28 AM
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