Solan N J, Ward P E, Sanders S P, Towns M C, Bathon J M
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA.
Inflammation. 1998 Feb;22(1):107-21. doi: 10.1023/a:1022304025789.
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.
包括缓激肽和P物质在内的几种内源性肽在关节中具有强大的炎症作用。这些肽的水平由血浆和细胞相关的肽降解酶调节。其中一种肽酶，中性内肽酶-24.11（NEP-24.11），在人滑膜细胞中组成性表达且密度很高，推测其在关节内肽水平的局部调节中起关键作用。我们在一个关节模型中研究了内源性NEP-24.11在调节缓激肽介导的效应中的作用，并研究了可溶性重组人NEP-2具有增强内源性酶作用的能力。我们的研究表明，当与高密度表达的共定位肽受体竞争时，内源性滑膜NEP-24.11不会显著调节炎症肽对细胞的作用。然而，给予过量的可溶性重组NEP-24.11可以克服这个问题。此外，在存在氧化剂或炎性关节液的情况下，重组酶的活性不会受到损害。重组NEP-24.11有望成为治疗炎性关节炎的一种新的治疗策略。
