Soluble recombinant neutral endopeptidase (CD10) as a potential antiinflammatory agent.
Several endogenous peptides, including bradykinin and substance P, have potent inflammatory effects in the joint. Levels of these peptides are regulated by plasma and cell-associated peptide degrading enzymes. One of these peptidases, neutral endopeptidase-24.11 (NEP-24.11), is expressed constitutively and in high density on human synovial cells and is presumed to play a critical role in local regulation of peptide levels in the joint. We examined the role of endogenous NEP-24.11 in regulating bradykinin-mediated effects in an articular model, and investigated the ability of soluble, recombinant human NEP-24.11 to augment the effects of the endogenous enzyme. Our studies demonstrate that endogenous synovial NEP-24.11 does not significantly modulate inflammatory peptide effects on cells when competing with colocalizing peptide receptors expressed in high density. Administration of excess, soluble recombinant NEP-24.11 can overcome this problem, however. Furthermore, the activity of the recombinant enzyme was not compromised in the presence of oxidants or inflammatory joint fluids. Recombinant NEP-24.11 holds promise as a novel therapeutic strategy for the treatment of inflammatory arthritis.
Solan
N J
NJ
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA.
Ward
P E
PE
Sanders
S P
SP
Towns
M C
MC
Bathon
J M
JM
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000378:metabolism; D001920:Bradykinin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005347:Fibroblasts; D006801:Humans; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D010003:Osteoarthritis / Q000201:enzymology* / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D011458:Prostaglandins E / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D013582:Synovial Fluid / Q000201:enzymology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016877:Oxidants; D011458:Prostaglandins E; D011994:Recombinant Proteins; D013481:Superoxides; D015260:Neprilysin; D001920:Bradykinin; D002118:Calcium