Aminopeptidase N/CD13 is highly expressed by fibroblast like synoviocytes (FLS) and may play a role in
rheumatoid arthritis (RA). CD13 was previously detected in human synovial fluid where it was significantly increased in RA compared to
osteoarthritis. In this study we found that CD13 in
biological fluids (plasma, synovial fluid, FLS culture supernatant) is present as both a soluble molecule and on extracellular vesicles, including exosomes, as assessed by differential ultracentrifugation and density gradient separation. Having determined CD13 could be released as a soluble molecule from FLS, we examined potential mechanisms by which CD13 might be shed from the FLS membrane. The use of
protease inhibitors revealed that CD13 is cleaved from the FLS surface by
metalloproteinases.
siRNA treatment of FLS revealed one of those
proteases to be MMP14. We determined that pro-inflammatory
cytokines (TNFα, IFNγ, IL-17) upregulated CD13
mRNA in FLS, which may contribute to the increased CD13 in RA synovium and synovial fluid. Inhibition of CD13 function by either inhibitors of enzymatic activity or anti-CD13
antibodies resulted in decreased growth and diminished migration of FLS. This suggests that CD13 may be involved in the pathogenic
hyperplasia of RA FLS. This data expands potential roles for CD13 in the pathogenesis of RA.