title: Localization, Shedding, Regulation and Function of Aminopeptidase N/CD13 on Fibroblast like Synoviocytes.
abstract: 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.
authors.affiliation: Division of Rheumatology and Clinical Autoimmunity Center of Excellence, Department of Internal Medicine University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Morgan
authors.affiliation: Division of Rheumatology and Clinical Autoimmunity Center of Excellence, Department of Internal Medicine University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Nilofar
authors.initials: N
authors.lastname: Behbahani-Nejad
authors.affiliation: Division of Rheumatology and Clinical Autoimmunity Center of Excellence, Department of Internal Medicine University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Judith
authors.initials: J
authors.lastname: Endres
authors.affiliation: Division of Rheumatology and Clinical Autoimmunity Center of Excellence, Department of Internal Medicine University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: M Asif
authors.initials: MA
authors.lastname: Amin
authors.affiliation: Division of Rheumatology and Clinical Autoimmunity Center of Excellence, Department of Internal Medicine University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Lepore
authors.affiliation: Division of Rheumatology and Clinical Autoimmunity Center of Excellence, Department of Internal Medicine University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Yuxuan
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Orthopedic Surgery, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Urquhart
authors.affiliation: Department of Orthopedic Surgery, University of Michigan, Ann Arbor, Michigan, United States of America.|Division of Plastic Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Chung
authors.affiliation: Division of Rheumatology and Clinical Autoimmunity Center of Excellence, Department of Internal Medicine University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Fox