M Guma1, E Sanchez-Lopez2, A Lodi3, R Garcia-Carbonell2, S Tiziani3, M Karin2, J C Lacal4, G S Firestein1. 1. Division of Rheumatology, Allergy and Immunology, UC San Diego School of Medicine, La Jolla, California, USA. 2. Laboratory of Gene Regulation and Signal Transduction, UC San Diego School of Medicine, La Jolla, California, USA Departments of Pharmacology, UC San Diego School of Medicine, La Jolla, California, USA Pathology, UC San Diego School of Medicine, La Jolla, California, USA. 3. Department of Nutritional Sciences & Dell Pediatric Research Institute, University of Texas at Austin, Austin, Texas, USA. 4. Division of Translational Oncology, Health Research Institute and University Hospital "Fundación Jiménez Díaz", Madrid, Spain.
Abstract
OBJECTIVES: Little is known about targeting the metabolome in non-cancer conditions. Choline kinase (ChoKα), an essential enzyme for phosphatidylcholine biosynthesis, is required for cell proliferation and has been implicated in cancer invasiveness. Aggressive behaviour of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) led us to evaluate whether this metabolic pathway could play a role in RA FLS function and joint damage. METHODS: Choline metabolic profile of FLS cells was determined by (1)H magnetic resonance spectroscopy ((1)HMRS) under conditions of ChoKα inhibition. FLS function was evaluated using the ChoKα inhibitor MN58b (IC₅₀=4.2 μM). For arthritis experiments, mice were injected with K/BxN sera. MN58b (3 mg/kg) was injected daily intraperitoneal beginning on day 0 or day 4 after serum administration. RESULTS: The enzyme is expressed in synovial tissue and in cultured RA FLS. Tumour necrosis factor (TNF) and platelet-derived growth factor (PDGF) stimulation increased ChoKα expression and levels of phosphocholine in FLS measured by Western Blot (WB) and metabolomic studies of choline-containing compounds in cultured RA FLS extracts respectively, suggesting activation of this pathway in RA synovial environment. A ChoKα inhibitor also suppressed the behaviour of cultured FLS, including cell migration and resistance to apoptosis, which might contribute to cartilage destruction in RA. In a passive K/BxN arthritis model, pharmacologic ChoKα inhibition significantly decreased arthritis in pretreatment protocols as well as in established disease. CONCLUSIONS: These data suggest that ChoKα inhibition could be an effective strategy in inflammatory arthritis. It also suggests that targeting the metabolome can be a new treatment strategy in non-cancer conditions. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
OBJECTIVES: Little is known about targeting the metabolome in non-cancer conditions. Choline kinase (ChoKα), an essential enzyme for phosphatidylcholine biosynthesis, is required for cell proliferation and has been implicated in cancer invasiveness. Aggressive behaviour of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) led us to evaluate whether this metabolic pathway could play a role in RA FLS function and joint damage. METHODS:Choline metabolic profile of FLS cells was determined by (1)H magnetic resonance spectroscopy ((1)HMRS) under conditions of ChoKα inhibition. FLS function was evaluated using the ChoKα inhibitor MN58b (IC₅₀=4.2 μM). For arthritis experiments, mice were injected with K/BxN sera. MN58b (3 mg/kg) was injected daily intraperitoneal beginning on day 0 or day 4 after serum administration. RESULTS: The enzyme is expressed in synovial tissue and in cultured RA FLS. Tumour necrosis factor (TNF) and platelet-derived growth factor (PDGF) stimulation increased ChoKα expression and levels of phosphocholine in FLS measured by Western Blot (WB) and metabolomic studies of choline-containing compounds in cultured RA FLS extracts respectively, suggesting activation of this pathway in RA synovial environment. A ChoKα inhibitor also suppressed the behaviour of cultured FLS, including cell migration and resistance to apoptosis, which might contribute to cartilage destruction in RA. In a passive K/BxN arthritis model, pharmacologic ChoKα inhibition significantly decreased arthritis in pretreatment protocols as well as in established disease. CONCLUSIONS: These data suggest that ChoKα inhibition could be an effective strategy in inflammatory arthritis. It also suggests that targeting the metabolome can be a new treatment strategy in non-cancer conditions. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: Agustín Rodríguez-González; Ana Ramírez de Molina; Félix Fernández; Maria Angeles Ramos; Maria del Carmen Núñez; Joaquín Campos; Juan Carlos Lacal Journal: Oncogene Date: 2003-12-04 Impact factor: 9.867
Authors: Stephanie Lefèvre; Anette Knedla; Christoph Tennie; Andreas Kampmann; Christina Wunrau; Robert Dinser; Adelheid Korb; Eva-Maria Schnäker; Ingo H Tarner; Paul D Robbins; Christopher H Evans; Henning Stürz; Jürgen Steinmeyer; Steffen Gay; Jürgen Schölmerich; Thomas Pap; Ulf Müller-Ladner; Elena Neumann Journal: Nat Med Date: 2009-11-08 Impact factor: 53.440
Authors: Nikolaos Psychogios; David D Hau; Jun Peng; An Chi Guo; Rupasri Mandal; Souhaila Bouatra; Igor Sinelnikov; Ramanarayan Krishnamurthy; Roman Eisner; Bijaya Gautam; Nelson Young; Jianguo Xia; Craig Knox; Edison Dong; Paul Huang; Zsuzsanna Hollander; Theresa L Pedersen; Steven R Smith; Fiona Bamforth; Russ Greiner; Bruce McManus; John W Newman; Theodore Goodfriend; David S Wishart Journal: PLoS One Date: 2011-02-16 Impact factor: 3.240
Authors: David S Wishart; Dan Tzur; Craig Knox; Roman Eisner; An Chi Guo; Nelson Young; Dean Cheng; Kevin Jewell; David Arndt; Summit Sawhney; Chris Fung; Lisa Nikolai; Mike Lewis; Marie-Aude Coutouly; Ian Forsythe; Peter Tang; Savita Shrivastava; Kevin Jeroncic; Paul Stothard; Godwin Amegbey; David Block; David D Hau; James Wagner; Jessica Miniaci; Melisa Clements; Mulu Gebremedhin; Natalie Guo; Ying Zhang; Gavin E Duggan; Glen D Macinnis; Alim M Weljie; Reza Dowlatabadi; Fiona Bamforth; Derrick Clive; Russ Greiner; Liang Li; Tom Marrie; Brian D Sykes; Hans J Vogel; Lori Querengesser Journal: Nucleic Acids Res Date: 2007-01 Impact factor: 16.971
Authors: Patricia G Oliveira; Ricard Garcia-Carbonell; Adam P Croft; Marta F Bustamante; Jeff M Smith; Ramon L Serrano; Elsa Sanchez-Lopez; Xiao Liu; Tatiana Kisseleva; Nissim Hay; Christopher D Buckley; Gary S Firestein; Anne N Murphy; Shigeki Miyamoto; Monica Guma Journal: Ann Rheum Dis Date: 2018-07-30 Impact factor: 19.103
Authors: Jane Falconer; Anne N Murphy; Stephen P Young; Andrew R Clark; Stefano Tiziani; Monica Guma; Christopher D Buckley Journal: Arthritis Rheumatol Date: 2018-06-04 Impact factor: 10.995
Authors: Elsa Sanchez-Lopez; Zhenyu Zhong; Alexandra Stubelius; Shannon R Sweeney; Laela M Booshehri; Laura Antonucci; Ru Liu-Bryan; Alessia Lodi; Robert Terkeltaub; Juan Carlos Lacal; Anne N Murphy; Hal M Hoffman; Stefano Tiziani; Monica Guma; Michael Karin Journal: Cell Metab Date: 2019-04-11 Impact factor: 27.287