The Bulk of Autotaxin Activity Is Dispensable for Adult Mouse Life

PLoS One. 2015 Nov 16;10(11):e0143083. doi: 10.1371/journal.pone.0143083. eCollection 2015.

Abstract

Autotaxin (ATX, Enpp2) is a secreted lysophospholipase D catalysing the production of lysophosphatidic acid, a pleiotropic growth factor-like lysophospholipid. Increased ATX expression has been detected in a number of chronic inflammatory diseases and different types of cancer, while genetic interventions have proven a role for ATX in disease pathogenesis. Therefore, ATX has emerged as a potential drug target and a large number of ATX inhibitors have been developed exhibiting promising therapeutic potential. However, the embryonic lethality of ATX null mice and the ubiquitous expression of ATX and LPA receptors in adult life question the suitability of ATX as a drug target. Here we show that inducible, ubiquitous genetic deletion of ATX in adult mice, as well as long-term potent pharmacologic inhibition, are well tolerated, alleviating potential toxicity concerns of ATX therapeutic targeting.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology*
  • Animals
  • Benzoxazoles / pharmacology
  • Enzyme Activation / drug effects
  • Integrases / metabolism
  • Mice, Inbred C57BL
  • Phosphoric Diester Hydrolases / blood
  • Phosphoric Diester Hydrolases / metabolism*
  • Piperazines / pharmacology
  • Tamoxifen / pharmacology

Substances

  • 6-(3-(piperazin-1-yl)propanoyl)benzo(d)oxazol-2(3H)-one
  • Benzoxazoles
  • Piperazines
  • Tamoxifen
  • Cre recombinase
  • Integrases
  • Phosphoric Diester Hydrolases
  • alkylglycerophosphoethanolamine phosphodiesterase

Grants and funding

The present work was funded by 1) a National SYNERGASIA 2009 Grant (Project Code 09SYN-11-679), and 2) a National ARISTIA II Grant (Project Code 3311), co-financed by the European Union (European Regional Development Fund and European Social Fund respectively) and National resources through the Operational Programs “Competitiveness and Entrepreneurship” and "Education and Lifelong Learning", respectively, of the National Strategic Reference Framework (NSRF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. A. Economides is an employee of Regeneron Pharmaceuticals Inc., which provided the R26Cre mouse and paid a salary to author A. Economides, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section.