Broad-spectrum matrix metalloproteinase inhibitor marimastat-induced musculoskeletal side effects in rats.
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.
Renkiewicz
Richard
R
Pfizer Global Research & Development Ann Arbor Laboratories, Pfizer, Inc, Ann Arbor, Michigan 48105, USA.
Qiu
Luping
L
Lesch
Charles
C
Sun
Xin
X
Devalaraja
Radhika
R
Cody
Theresa
T
Kaldjian
Eric
E
Welgus
Howard
H
Baragi
Vijaykumar
V
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
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C100342:marimastat