title: Broad-spectrum matrix metalloproteinase inhibitor marimastat-induced musculoskeletal side effects in rats.
abstract: OBJECTIVE
  To characterize the clinical and histopathologic changes in a rat model of broad-spectrum matrix metalloproteinase (MMP)-induced musculoskeletal syndrome (MSS), and to facilitate research into the causes and treatments of MSS in humans.
  
  
  METHODS
  Male Lewis rats weighing 150-180 gm were administered 10-30 mg of the broad-spectrum MMP inhibitor marimastat over a 2-week period via surgically implanted subcutaneous osmotic pumps. The animals were monitored and scored for the onset and severity of MSS, using clinical and histologic parameters.
  
  
  RESULTS
  Marimastat-treated rats exhibited various clinical signs, including compromised ability to rest on their hind feet, high-stepping gait, reluctance or inability to move, and hind paw swelling. Histologically, marimastat-treated rat joints were characterized by soft tissue and bone changes, such as increased epiphyseal growth plate, synovial hyperplasia, and increased cellularity in the joint capsule and extracapsular ligaments. The severity of MSS, as judged by clinical criteria (2 blinded observers using 3 clinical parameters), paw volume, and histologic score, was nearly identical. The observed changes were indistinguishable from those reported for primate models and mimic MSS in humans.
  
  
  CONCLUSIONS
  This simple and sensitive model of MSS is an attractive alternative for studying the pathology of MSS.
authors.affiliation: Pfizer Global Research & Development Ann Arbor Laboratories, Pfizer, Inc, Ann Arbor, Michigan 48105, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Renkiewicz
authors.forename: Luping
authors.initials: L
authors.lastname: Qiu
authors.forename: Charles
authors.initials: C
authors.lastname: Lesch
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
authors.forename: Radhika
authors.initials: R
authors.lastname: Devalaraja
authors.forename: Theresa
authors.initials: T
authors.lastname: Cody
authors.forename: Eric
authors.initials: E
authors.lastname: Kaldjian
authors.forename: Howard
authors.initials: H
authors.lastname: Welgus
authors.forename: Vijaykumar
authors.initials: V
authors.lastname: Baragi
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D005528:Foot / Q000473:pathology; D005684:Gait / Q000187:drug effects; D006132:Growth Plate / Q000187:drug effects / Q000473:pathology; D006614:Hindlimb / Q000187:drug effects / Q000473:pathology; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000633:toxicity*; D015918:Infusion Pumps, Implantable; D007596:Joints / Q000187:drug effects / Q000473:pathology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D009140:Musculoskeletal Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D011917:Rats, Inbred Lew; D016037:Single-Blind Method; D013583:Synovial Membrane / Q000187:drug effects / Q000473:pathology
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C100342:marimastat