Characterization of fibrodysplasia in the dog following inhibition of metalloproteinases.
Musculoskeletal side effects are a widely reported consequence of administration of particular matrix metalloproteinase inhibitors (MMPi) in clinical trials. We describe here histopathological findings during dog studies with a fairly selective MMPi AZM551248, that are consistent with these human clinical changes. They were characterized by a dose-and time-dependent formative connective tissue alteration we have termed "fibrodysplasia." The most sensitive site was the subcuticular connective tissue, although musculoskeletal tissues were also extensively involved. In the subcutis, changes occurred initially around pre-existing blood vessels, but then more diffusely. There was proliferation of cells showing myofibroblast differentiation identified by elevated levels of alpha-smooth muscle actin, fibronectin, and transforming growth factor beta, and the deposition of collagen type III with a lesser quantity of collagen type I. On longer-term administration at lower doses, there was evidence of active fibrodysplasia arising and resolving during the dosing period, resulting in the multifocal deposition of mature collagen. Although there was organ specificity, essentially identical changes occurred at multiple connective tissue sites. We conclude that MMPi-induced fibrodysplasia in animals and, by inference, musculoskeletal side effects in humans are potentially diffuse connective tissue disorders.
AstraZeneca Pharmaceuticals - Safety Assessment, Mereside, Alderley Park, Macclesfield, United Kingdom. russell.westwood@astrazeneca.com
Russell
R
Westwood
Robert C
RC
Scott
Rebecca L
RL
Somers
Michelle
M
Coulson
Rose A
RA
Maciewicz
D000818:Animals; D003238:Connective Tissue / Q000187:drug effects / Q000473:pathology*; D004285:Dogs; D005355:Fibrosis; D045726:Metalloproteases / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000633:toxicity*; D011480:Protease Inhibitors / Q000633:toxicity*; D013710:Tendons / Q000187:drug effects / Q000473:pathology; D018675:Toxicity Tests
C547126:AZM551248; D010879:Piperazines; D011480:Protease Inhibitors; D045726:Metalloproteases