title: The role of microRNAs in the pathogenesis of MMPi-induced skin fibrodysplasia.
abstract: BACKGROUND
  Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes involved in extracellular matrix (ECM) homeostasis. MMPs have been an attractive pharmacological target for a number of indications. However, development has been hampered by the propensity of compounds targeting these enzymes to cause connective-tissue pathologies. The broad-spectrum MMP-inhibitor (MMPi) AZM551248 has been shown to induce such effects in the dog. Histopathological changes were consistent with fibrodysplasia (FD), characterised by fibroblast proliferation and the deposition of collagen in the subcutaneous tissues. We conducted a time-course study administering 20mg/kg/day AZM551248 between 4 and 17 days. Cervical subcutaneous tissue and plasma were sampled during the time-course. miRNA expression profiles in subcutaneous skin specimens following the administration of AZM551248 were determined by high-throughput-sequencing.
  
  
  RESULTS
  An increasing number of miRNAs were differentially expressed compared with vehicle treated control animals as the study progressed. Several of these were members of the miR-200 family and were significantly attenuated in response to MMPi. As the severity of FD increased at the later time-points, other miRNAs associated with TGFβ synthesis and regulation of the acute inflammatory response were modulated. Evidence indicative of epithelial to mesenchymal transition was present at all study time points. Receiver operator curve (ROC) analysis revealed that miR-21 expression in the cervical subcutaneous tissue was a sensitive and specific biomarker of FD incidence.
  
  
  CONCLUSIONS
  Our data reveal significant perturbations in canine skin miRNA expression in response to MMPi administration. Furthermore, we have identified dysregulated miRNAs that are associated with processes relevant to the key histopathological events of MMPi-induced FD.
authors.affiliation: Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Harwell Campus, Oxfordshire, UK. daniel.tonge@hpa.org.uk
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Tonge
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Tugwood
authors.forename: Janet
authors.initials: J
authors.lastname: Kelsall
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Gant
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D024061:Collagen Type III / Q000097:blood; D003240:Connective Tissue Diseases / Q000097:blood / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D004285:Dogs; D020869:Gene Expression Profiling; D061965:Matrix Metalloproteinase Inhibitors / Q000009:adverse effects*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D010879:Piperazines / Q000009:adverse effects*; D012449:Safety; D012867:Skin / Q000473:pathology*; D040521:Subcutaneous Tissue / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
chemical_list: C547126:AZM551248; D015415:Biomarkers; D024061:Collagen Type III; D061965:Matrix Metalloproteinase Inhibitors; D035683:MicroRNAs; D010879:Piperazines; D020782:Matrix Metalloproteinases