Matrix metalloproteinase (
MMP) inhibitors, candidate therapeutic agents for a number of diseases, are known to be associated with acute
fibrosis-type adverse effects in a number of species, including humans. The broad-spectrum
MMP inhibitor,
AZM551248, has previously been shown to cause these effects in the dog. Changes were characterized by the abnormal and extensive proliferation of fibroblasts and the deposition of
collagen particularly in the subcutaneous connective tissues (subcutis) and were termed fibrodysplasia (FD). We performed a time-course study in dogs using
AZM551248 and sampled skin, subcutis, and plasma before and during the development of FD. Detailed histopathological analysis and global gene expression profiling were performed on the subcutaneous tissues. The gene expression analysis of the subcutis indicated that extracellular matrix (ECM) remodeling was initiated asymptomatically at or before the earliest time point, day 4, and this was associated with dysregulation of expression of a number of
MMPs and
proteolytic enzymes. At later time points, the FD became progressively more extensive and severe, and this was associated with gene expression changes characteristic of tissue
fibrosis, for example those associated with
procollagen synthesis and processing. We postulate that
AZM551248 inhibition of
MMP action within the subcutis modulates the activity of several
transcription factors and this in turn upregulates expression of specific
proteases which initiate ECM remodeling. Persistent
MMP inhibition results in the progression of ECM remodeling, culminating in
collagen deposition and overt
fibrosis. Our data indicate that inhibition of
MMPs 1, 2, 3, and 9 is a key early event in AZM551248-induced FD in dog subcutis.