title: Nerve growth factor inhibition with tanezumab influences weight-bearing and subsequent cartilage damage in the rat medial meniscal tear model.
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.
authors.affiliation: Pfizer Inc, Cambridge, Massachusetts, USA.|Blueprint Medicines, Cambridge, Massachusetts, USA.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: LaBranche
authors.affiliation: Bolder BioPATH, Inc., Boulder, Colorado, USA.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Bendele
authors.affiliation: Bolder BioPATH, Inc., Boulder, Colorado, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Omura
authors.affiliation: Pfizer Inc, Groton, Connecticut, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Gropp
authors.affiliation: Pfizer Inc, Groton, Connecticut, USA.
authors.forename: Susan I
authors.initials: SI
authors.lastname: Hurst
authors.affiliation: Pfizer Inc, Groton, Connecticut, USA.
authors.forename: Cedo M
authors.initials: CM
authors.lastname: Bagi
authors.affiliation: Pfizer Inc, Groton, Connecticut, USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Cummings
authors.affiliation: Arbor Analytics, LLC, Ann Arbor, Michigan, USA.
authors.forename: Lonnie E
authors.initials: LE
authors.lastname: Grantham
authors.affiliation: Pfizer Inc, South San Francisco, California, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Shelton
authors.affiliation: Pfizer Inc, San Diego, California, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Zorbas
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D001169:Arthritis, Experimental / Q000139:chemically induced; D002358:Cartilage, Articular / Q000187:drug effects / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005684:Gait; D008297:Male; D008592:Menisci, Tibial / Q000000981:diagnostic imaging / Q000473:pathology; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors*; D011859:Radiography; D011917:Rats, Inbred Lew; D000070600:Tibial Meniscus Injuries / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016474:Weight-Bearing; D055114:X-Ray Microtomography
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D020932:Nerve Growth Factor; C549319:tanezumab
keywords: Arthritis; Knee Osteoarthritis; Osteoarthritis