Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Kinins and substance P have been implicated in the pathogenesis of inflammatory arthritis by virtue of their abilities to induce vasodilation, edema, and pain. The relative biological potencies of these peptides in vivo would depend at least in part upon their rates of catabolism in the joint. We hypothesized that human synovial lining cells may regulate intraarticular levels of kinins and neuropeptides via degradation by cell surface-associated peptidases. We exposed intact human synovial fibroblasts to kinins and substance P, in the presence or absence of specific peptidase inhibitors, and measured the amount of intact substrate remaining and degradation product(s) generated over time. Aminopeptidase M (AmM; EC 3.4.11.2), neutral endopeptidase-24.11 (NEP-24.11; EC 3.4.24.11), and dipeptidyl(amino)peptidase IV (DAP IV; EC 3.4.14.5) were identified on the cell surface of synovial cells. Bradykinin degradation was due entirely to NEP-24.11 (1.39 +/- 0.29 nmol/min per well). Lysylbradykinin was also degraded by NEP-24.11 (0.80 +/- 0.19 nmol/min per well); however, in the presence of phosphoramidon, AmM-mediated conversion to bradykinin (3.74 +/- 0.46 nmol/min per well) could be demonstrated. The combined actions of NEP-24.11 (0.93 +/- 0.15 nmol/min per well) and DAP IV (0.84 +/- 0.18 nmol/min per well) were responsible for the degradation of substance P. AmM (2.44 +/- 0.33 nmol/min per well) and NEP-24.11 (1.30 +/- 0.45 nmol/min per well) were responsible for the degradation of the opioid peptide, [Leu5]enkephalin. The identity of each of the three peptidases was confirmed via synthetic substrate hydrolysis, inhibition profile, and immunological identification. The profiles of peptidase enzymes identified in cells derived from rheumatoid and osteoarthritic joints were identical. These data demonstrate the human synovial fibroblast to be a rich source of three specific peptidases and suggest that it may play a prominent role in regulating peptide levels in the joint.
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PMID:Cultured human synovial fibroblasts rapidly metabolize kinins and neuropeptides. 138 26

Substance P (SP) is one of the endogenous tachykinin peptides implicated in neurogenic inflammation and may be critically involved in diseases as diverse as asthma, arthritis and inflammatory bowel disease. The current study was initiated to identify a rich source of SP receptor that would be amenable for studying the regulatory mechanism of the receptor. By using a radioligand receptor binding technique, sheep ileal smooth muscle membranes showed a much higher density of [3H]SP specific binding than other non-neural rat or sheep tissues and organs surveyed. Of the protease inhibitors tested, only phosphoramidon, a specific and potent enkephalinase inhibitor, prevented the degradation of [3H]SP and enhanced [3H]SP binding to the membrane. [3H]SP binding to the specific binding sites in the membranes was time-dependent and reached a steady state after 60 min at 22 degrees C in 25 mM Tris.NH3 (pH 7.4). Calcium and magnesium ions enhanced [3H]SP specific binding. Saturation binding studies showed that the dissociation constant (KD) and the density of maximum binding sites for [3H]SP specific binding were 0.54 nM and 83 fmol/mg of protein, respectively. The specificity of the [3H]SP labeled sites was SP greater than (4-11) SP greater than eledoisin greater than spantide greater than neurokinin-A greater than D-Pro2D-Phe7D-Trp9-SP. Neurokinin-B and senktide showed no inhibition of [3H]SP binding.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Identification and characterization of the substance P receptor in sheep intestinal smooth muscle membranes. 169 67

Enkephalinase (endopeptidase 24.11) is a metallopeptidase that is able to cleave not only neuropeptides and hormones but also immune mediators. The enzyme was quantified in synovial fluid obtained from 36 swollen joints. Its concentration correlated with the synovial fluid cell count, mainly the polymorphonuclear cells and lymphocytes, and with the erythrocyte sedimentation rate. No statistically significant difference in enkephalinase levels was demonstrated between the groups of patients with rheumatoid arthritis, seronegative spondylarthropathy, microcrystalline arthritis, or osteoarthritis. The presence of enkephalinase in the synovial fluid could reflect the intensity of the inflammatory process, or it could represent a physiologic regulator of inflammation and pain within the joint.
Arthritis Rheum 1991 Aug
PMID:Enkephalinase: a physiologic neuroimmunomodulator detected in the synovial fluid. 185 79

The cell-surface neutral endopeptidase 3.4.24.11 (NEP) activity of the common acute lymphoblastic leukaemia antigen (CALLA) cleaves diverse peptide mediators at specific sites and it has been postulated that it regulates immune responses. The concentration of NEP was quantified in detergent extracts of synovial tissues by the percentage hydrolysis of [3H-D-Ala]-Leu enkephalin/hr/100 mg of tissue. The synovial tissue concentration of NEP was higher in all patients with rheumatoid arthritis (n = 7; group mean +/- SD = 29.4 +/- 20.2%), and was higher with degenerative joint disease (n = 6 of 8; group mean +/- SD = 11.9 +/- 10.4%) than with traumatic arthropathy (n = 3; 1.1 +/- 0.7%). The lack of direct relationship between synovial tissue NEP concentration and leukocytic infiltration suggests that the cellular source of NEP may be synoviocytes or fibroblasts, and that NEP may have distinctive pathogenetic roles in human arthritis.
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PMID:Elevated synovial tissue concentration of the common acute lymphoblastic leukaemia antigen (CALLA)-associated neutral endopeptidase (3.4.24.11) in human chronic arthritis. 214 13

The effects of various i.v. doses (2.5, 5, 10 and 15 mg/kg) of the highly efficient inhibitor of multiple enkephalin-degrading enzymes, Kelatorphan, were evaluated on the vocalization threshold to paw pressure in normal rats and in rats with Freund's adjuvant-induced arthritis. In normal rats, Kelatorphan at doses as low as 2.5 mg/kg i.v. at which the enkephalinase inhibitor acetorphan was ineffective, produced potent antinociceptive effects, comparable to that induced by 1 mg/kg i.v. morphine. In contrast, for the higher doses used (5, 10, 15 mg/kg i.v.), the effects of Kelatorphan were not more pronounced than that of acetorphan. Unlike acetorphan, Kelatorphan was found to be much more effective in arthritic than in normal rats in raising the vocalization threshold, even at the lower concentration, 2.5 mg/kg i.v.: 244% in arthritic vs 144% in normal rats. The effects of Kelatorphan were prevented by naloxone at the dose of 0.5 mg/kg i.v. The enhanced potency of Kelatorphan is discussed in relation with the increase in peptidase-sensitive dynorphin fragments in arthritic rats.
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PMID:Potent antinociceptive effects of kelatorphan (a highly efficient inhibitor of multiple enkephalin-degrading enzymes) systemically administered in normal and arthritic rats. 279 Apr 59

A number of compounds have been shown to inhibit the degradation of enkephalins. As expected, these compounds produce naloxone reversible analgesia and potentiate the analgesia produced by enkephalins and by acupuncture. One of these, D-phenylalanine, is also anti-inflammatory. D-phenylalanine has proven to be beneficial in many human patients with chronic, intractable pain. It is proposed the enkephalinase inhibitors may be effective in a number of human "endorphin deficiency diseases" such as depression, schizophrenia, convulsive disorders and arthritis. Such compounds may alleviate other conditions associated with decreased endorphin levels such as opiate withdrawal symptoms.
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PMID:D-phenylalanine and other enkephalinase inhibitors as pharmacological agents: implications for some important therapeutic application. 612 72

The effects of various i.v. doses of morphine (0.1, 0.3 and 1 mg/kg) and of thiorphan, an inhibitor of enkephalinase (0.7, 2.5, 5, 10 and 15 mg/kg), were studied upon the vocalization threshold to foot pressure in normal rats and rats with Freund's adjuvant-induced arthritis. The vocalization threshold in arthritic rats was, before any injections, significantly lower than in normal rats (mean pressure threshold for vocalization: 115.2 g +/- 14.7 (n = 152) for arthritic rats vs 182.5 g +/- 21.3 for normal rats (n = 152). The various doses of morphine in raising the vocalization threshold were more efficient in arthritic than in normal rats (maximum vocalization threshold (% of control) following 1 mg/kg morphine = 225.70 +/- 10.21 in arthritic rats vs 140.75 +/- 6.87 in normal rats, n = 9 in each case). This effect was dose-dependent, and in every case, naloxone-reversible. Injected at doses of 5-15 mg/kg, thiorphan increased the vocalization threshold (maximum = 223.91% +/- 11.96 in arthritic rats vs 223.30% +/- 5.93 in normal rats for 15 mg/kg i.v., n = 9 for each group). This effect was not greater in arthritic than in normal rats. The dose of 2.5 mg/kg of thiorphan was insufficient. Administered at 0.7 mg/kg, thiorphan significantly decreased the vocalization threshold in the arthritic rats only. These effects of thiorphan were all naloxone-reversible using doses of naloxone which were one-hundredth of those of thiorphan.
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PMID:The analgesic effects of morphine, but not those of the enkephalinase inhibitor thiorphan, are enhanced in arthritic rats. 657 99

The possibility that neuropeptides, in particular members of the tachykinin family are involved in inflammatory joint disease is widely disputed. Both clinical and experimental observations indicate that the tachykinin substance P (SP) may be involved in the pathogenesis of arthritis. We have studied the effects of tachykinins and the metabolites of SP on chondrocyte function. We have shown that the C-terminal pentapeptide sequence; H-Phe-Phe-Gly-Leu-Met-NH2 is biologically active in bovine chondrocyte cultures. The production of SP7-11 is limited by hydrolysis of the intact peptide by neutral endopeptidase (E.C. 3.4.24.11). The regulation of this enzyme would modulate the activity of substance P on articular cartilage chondrocytes.
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PMID:A metabolite of substance P, SP7-11 is involved in the pathogenesis of inflammatory joint disease. 768 13

To clarify the properties of BL-2401 ((+/-)-3-[2-benzyl-3-(propionylthio) propionyl]amino-5-methylbenzoic acid), a novel enkephalinase inhibitor, we examined its antinociceptive and antidepressant-like activities after oral administration, along with their association with endogenous opioid systems. BL-2401 produced an antinociceptive effect after oral administration in the mouse phenylbenzoquinone writhing test (ED50: 12.4 mg/kg) and the rat acetic acid writhing test (ED50: 55.8 mg/kg), the antinociceptive effect being antagonized by naloxone hydrochloride. BL-2401 also relieved arthritis-induced hyperalgesia in rats. In the mouse hot-plate and tail pressure tests, BL-2401 showed significant but modest antinociception at higher doses (200 and 400 mg/kg). In addition, BL-2401 (100 mg/kg) produced a naloxone-reversible antidepressant-like effect in the mouse forced swimming test. As for the mechanism of the action, the active metabolite of BL-2401, BL-2240 ((+/-)-3-(2-benzyl-3-mercaptopropionyl) amino-5-methylbenzoic acid), selectively inhibited enkephalinase in vitro (IC50: 5.2 nM). Oral administration of BL-2401 to mice significantly inhibited the enkephalinase activity in the striatum and also potentiated the antinociceptive effect of (D-Ala2,Met5)-enkephalin given intracisternally. These findings indicate that BL-2401 is an orally active enkephalinase inhibitor and may produce antinociceptive and antidepressant-like effects in association with endogenous opioid systems.
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PMID:Antinociceptive and antidepressant-like profiles of BL-2401, a novel enkephalinase inhibitor, in mice and rats. 946 39

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.
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PMID:Soluble recombinant neutral endopeptidase (CD10) as a potential antiinflammatory agent. 948 54


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