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Nerve growth factor inhibition with tanezumab influences weight-bearing and subsequent cartilage damage in the rat medial meniscal tear model
  1. Timothy P LaBranche1,2,
  2. Alison M Bendele3,
  3. Brian C Omura3,
  4. Kathryn E Gropp4,
  5. Susan I Hurst4,
  6. Cedo M Bagi4,
  7. Thomas R Cummings4,
  8. Lonnie E Grantham II5,
  9. David L Shelton6,
  10. Mark A Zorbas7
  1. 1Pfizer Inc, Cambridge, Massachusetts, USA
  2. 2Blueprint Medicines, Cambridge, Massachusetts, USA
  3. 3Bolder BioPATH, Inc., Boulder, Colorado, USA
  4. 4Pfizer Inc, Groton, Connecticut, USA
  5. 5Arbor Analytics, LLC, Ann Arbor, Michigan, USA
  6. 6Pfizer Inc, South San Francisco, California, USA
  7. 7Pfizer Inc, San Diego, California, USA
  1. Correspondence to Dr Timothy P LaBranche, Blueprint Medicines, 38 Sidney Street, Suite 200, Cambridge, MA 02139, USA; tlabranche{at}blueprintmedicines.com

Abstract

Objective To investigate whether the effects of nerve growth factor (NGF) inhibition with tanezumab on rats with medial meniscal tear (MMT) effectively model rapidly progressive osteoarthritis (RPOA) observed in clinical trials.

Methods Male Lewis rats underwent MMT surgery and were treated weekly with tanezumab (0.1, 1 or 10 mg/kg), isotype control or vehicle for 7, 14 or 28 days. Gait deficiency was measured to assess weight-bearing on the operated limb. Joint damage was assessed via histopathology. A second arm, delayed onset of treatment (starting 3–8 weeks after MMT surgery) was used to control for analgesia early in the disease process. A third arm, mid-tibial amputation, evaluated the dependency of the model on weight-bearing.

Results Gait deficiency in untreated rats was present 3–7 days after MMT surgery, with a return to normal weight-bearing by days 14–28. Prophylactic treatment with tanezumab prevented gait deficiency and resulted in more severe cartilage damage. When onset of treatment with tanezumab was delayed to 3–8 weeks after MMT surgery, there was no increase in cartilage damage. Mid-tibial amputation completely prevented cartilage damage in untreated MMT rats.

Conclusions These data suggest that analgesia due to NGF inhibition during the acute injury phase is responsible for increased voluntary weight-bearing and subsequent cartilage damage in the rat MMT model. This model failed to replicate the hypotrophic bone response observed in tanezumab-treated patients with RPOA.

  • Knee Osteoarthritis
  • Osteoarthritis
  • Arthritis

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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Footnotes

  • Handling editor Tore K Kvien

  • Mr Omura died on 10 July 2015.

  • Contributors TPL, KEG, TRC, DLS and MAZ designed the study. BCO, AMB, SIH and CMB generated data for the study. LEG performed the statistical analyses. All authors were involved in data interpretation and writing and reviewing the manuscript.

  • Funding This study was funded by Pfizer, Inc. and Eli Lilly & Co.

  • Competing interests KEG, SIH, CMB, TRC and MAZ are employees of Pfizer and own stock and/or stock options in Pfizer. TPL and DLS were employees of Pfizer at the time of these studies and own stock and/or stock options in Pfizer. LEG is a contracted resource of and owns stock in Pfizer.

  • Ethics approval Oversight by local institutional animal care and use committees.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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