SOLUBLE RECOMBINANT NEUTRAL ENDOPEPTIDASE (CD10) AS A POTENTIAL ANTIINFLAMMATORY AGENT

Several endogenous peptides, including bradykinin and sustance P, have potent inflammatory effects in the joint. Levels of these peptides ar e regulated by plasma and cell-associated peptide degrading enzymes. O ne of these peptidases, neutral endopeptidase-24.11 (NEP-24.11), is ex pressed constitutively and in high density on human synovial cells and is presumed to play a critical role in local regulation of peptide le vels in the joint. We examined the role of endogenous NEP-24.11 in reg ulating bradykinin-mediated effects in an articular model, and investi gated the ability of soluble, recombinant human NEP-24.11 to augment t he effects of the endogenous enzyme. Our studies demonstrate that endo genous synovial NEP-24.11 does not significantly modulate inflammatory peptide effects on cells when competing with colocalizing peptide rec eptors expressed in high density. Administration of excess, soluble re combinant NEP-24.11 can overcome this problem, however. Furthermore, t he activity of the recombinant enzyme was not compromised in the prese nce of oxidants or inflammatory joint fluids. Recombinant NEP-24.11 ho lds promise as a novel therapeutic strategy for the treatment of infla mmatory arthritis.