Skip to main content
SpringerLink
Log in

Neutral endopeptidase (3.4.24.11) in plasma and synovial fluid of patients with rheumatoid arthritis. A marker of disease activity or a regulator of pain and inflammation?

  • Originals
  • Published:
Rheumatology International Aims and scope Submit manuscript

Summary

In recent years the role of the peripheral nervous system has been focused on the pathogenesis of rheumatoid arthritis (RA). In particular, substance P (SP), released by the sensory terminals, has been demonstrated to be involved in cartilage breakdown [13]. The aim of our work was to study the levels of SP and its peptidases, neutral endopeptidase (3.4.24.11) (NEP) and angiotensin-converting enzyme (ACE), in the synovial fluid and plasma of 30 patients with RA and 14 patients with osteoarthritis (OA). ACE and NEP were determined with a fluorimetric assay and SP with a radioimmunoassay (RIA) method. ACE levels were normal in the plasma of patients with RA and OA (6.1±1.9 and 6.7±1.4 pmol/ml/min, respectively); we found no differences in the values, of ACE between RA and OA synovial fluid (5.7±4.2 and 5.5±4.1 pmol/ml/min, respectively). NEP levels were significantly increased in plasma (139.3±36 pmol/ml/min) and synovial fluid (133.8±32 pmol/ml/min in synovial fluid) and healthy controls (89.7±14 pmol/ml/min in plasma). In synovial fluid, SP was significantly higher in RA patients (43.1±16.6 pg/ ml) than in OA patients (12±13.1 pg/ml), while plasma levels did not show any difference (RA: 14.4±10.2; OA: 13.6±10.6; healthy subjects: 11.3±3.9 pg/ml). The only relationship detected in controls and in OA was among plasma NEP and ESR (P<0.05) and synovial fluid NEP (P<0.001). Our data confirmed that SP could have a role in the pathogenesis of RA synovial inflammation through a control on neurogenic inflammation (SP degradation), vascular tone control (endothelin degradation) and on nociception (enkephalin degradation).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Erdos EG, Skidgel RA (1987) The angiotensin I converting enzyme. Lab Invest 56:345–348

    Google Scholar 

  2. Gafford JT, Skidgel RA, Erdos EG, Hersh LB (1983) Human kidney enkephalinase, a neutral metalloendopeptidase that cleaves active peptides. Biochemistry 22:3265–3271

    Google Scholar 

  3. Noveral JP, Mueller SN, Levine EM (1987) Release of angiotensin I converting enzyme by endothelial cells in vitro. J Cell Physiol 131:1–5

    Google Scholar 

  4. Yang H, Erdos EG, Levin Y (1970) A dipeptidyl carboxypeptidase that converts angiotensin I and inactivates bradykinin. Biochim Biophys Acta 214:374–376

    Google Scholar 

  5. Skidgel RA, Engelbrecht S, Johnson A, Erdos EG (1984) Hydrolysis of substance P and neurotensin by converting enzyme and neutral endopeptidase. Peptides 5:769–776

    Google Scholar 

  6. Erdos EG, Skidgel RA (1988) Human neutral endopeptidase 24.11 (enkephalinase): function, distribution and release. Adv Exp Med Biol 240:13–21

    Google Scholar 

  7. Matsas R, Kenny A, Turner AS (1984) The metabolism of neuropeptides. The hydrolysis of peptides, including enkephalins, tachykinins and their analogies by endopeptidase 24.11. Biochem J 223:433–440

    Google Scholar 

  8. Visayaraghavan J, Scicli AG, Carrettero OA, Slaughter C, Moomaw C, Hersh LB (1990) The hydrolysis of endothelins by neutral endopeptidase 24.11 (enkephalinase). JBC 65:14150–14155

    Google Scholar 

  9. Levine JD, Collier DH, Basbaum AI, Moskowitz MA, Helms CA (1985) Hypothesis: the nervous system may contribute to the pathophysiology of rheumatoid arthritis. J Rheumatol 12:406–411

    Google Scholar 

  10. Lotz M, Carson DA, Vaughan JH (1987) Substance P activation of rheumatoid synoviocytes: neutral pathway in pathogenesis of arthritis. Science 235:893–895

    Google Scholar 

  11. Matucci-Cerinic M, Partsch G (1992) The contribution of the peripheral nervous system and the neuropeptide network to the development of synovial inflammation. Clin Exp Rheumatol. 10:211–215

    Google Scholar 

  12. Pernow B (1985) Role of tachykinins in neurogenic inflammation. J Immunol 135:8125–8155

    Google Scholar 

  13. Levine JD, Clark R, Helms C, Moskowitz MA, Basbaum AI (1984) Intraneuronal substance P contributes to the severity of experimental arthritis. Science 226:547–552

    Google Scholar 

  14. Spillantini MG, Geppetti PA, Fanciullacci M, Michelacci S, Lecomte JM, Sicuteri F (1986) In vivo enkephalinase inhibition by acetorphan in human plasma and CSF. Eur J Pharmacol 125:147–150

    Google Scholar 

  15. Roques BP, Fournie-Zaluski MC, Soroca A, et al. (1980) The enkephalinase inhibitor, thiorphan, shares antinociceptive activity in mice. Nature 288:286–288

    Google Scholar 

  16. Spillantini MG, Sicuteri F, Salmon S, Malfroy B (1990) Characterization of endopeptidase 3.4.24.11 (enkephalinase) activity in human plasma and cerebrospinal fluid. Biochem Pharmacol 39:1353–1356

    Google Scholar 

  17. Yang HYT, Neff NH (1972) Distribution and properties of angiotensin converting enzyme of rat brain. J Neurochem 19:2443–2450

    Google Scholar 

  18. Matucci-Cerinic M, Pignone A, Lotti T, et al. (1990) Reduced angiotensin converting enzyme plasmatic activity in scleroderma. A marker of endothelial injury? J Rheumatol 17:328–330

    Google Scholar 

  19. Matucci-Cerinic M, Partsch G, Marabini S, Cagnoni M (1991) High levels of substance P in rheumatoid arthritis synovial fluid and evidence that synoviocytes are not the major source of substance P. Clin Exp Rheumatol 9:440–441

    Google Scholar 

  20. Devillier P, Weill B, Renoux M, Menkès CJ, Pradelles P (1987) Elevated levels of tachykinin-like immunoreactivity in joint fluids from patients with rheumatic inflammatory disease. N Engl J Med 314:1323

    Google Scholar 

  21. Agro A, Stanisz AM (1992) Are lymphocytes a target for substance P modulation in arthritis? Semin Arthritis Rheum 21:252–258

    Google Scholar 

  22. Menkès CJ, Renoux M, Laoussadi S, Mauborgne A, Bruxelle J, Cesselin F (1992) Substance P levels in the synovium and synovial fluid from rheumatoid arthritis and osteoarthritis. J Rheumatol (in press)

  23. Marshall KW, Chiu B, Inman R (1990) Substance P and arthritis: analysis of plasma and synovial fluid levels. Arthritis Rheum 33:87–90

    Google Scholar 

  24. Larsson J, Ekblom A, Henriksson K, Lundeberg T, Theodorrsson E (1991) Concentration of substance P, neurokinin A, calcitonin gene related peptide, neuropeptide Y, vasointestinal peptide in synovial fluid from knee joints in patients suffering from rheumatoid arthritis. Scand J Rheumatol 20:326–335

    Google Scholar 

  25. Lowe JR, Dixon JS, Guthrie JA, McWhinney P (1986) Serum and synovial fluid levels of angiotensin converting enzyme in polyarthritis. Ann Rheum Dis 45:921–924

    Google Scholar 

  26. Blann AD (1991) Von Willebrand factor antigen and angiotensin converting enzyme in synovial fluid. Scand J Rheumatol 20:213–214

    Google Scholar 

  27. Veale D, Fitzgerald O (1990) Serum and synovial fluid angiotensin converting enzyme in inflammatory joint disease. Br J Rheumatol 29:[Suppl] 1:23

    Google Scholar 

  28. Appelboom T, de Martelaer V, de Prez E, Hauzeur JP, Deschodt-Lanckman M (1991) Enkephalinase: a physiologic neuroimmunomodulator detected in the synovial fluid. Arthritis Rheum 34:1048–1055

    Google Scholar 

  29. Hughes J, Smith JW, Hosterlitz HW, Fathergill LA, Morgan BA, Morris HR (1975) Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 258:577–579

    Google Scholar 

  30. Fredrickson RCA (1977) Cyclic AMP receptor in mitochondria. Life Sci 21:23–41

    Google Scholar 

  31. Way EL, Glasgow CE (1978) The endorphins: possible physiologic roles and therapeutic applications. Clin Ther 1:371–386

    Google Scholar 

  32. Sagen J, Wang H (1990) Prolonged analgesia by enkephalinase inhibition in rats with spinal cord adrenal medullary transplants. Eur J Pharmacol 179:427–433

    Google Scholar 

  33. Bjurholm A, Kreicbergs A, Brodin E, Schutzberg M (1988) Substance P and CGRP-immunoreactive nerves in bone. Peptides 9:165–171

    Google Scholar 

  34. Blalock JE (1989) A molecular basis for bidirectional communication between the immune and neuroendocrine systems. Physiol Rev 69:1–32

    Google Scholar 

  35. Partsch G, Matucci-Cerinic M (1990) Evidence that substance P is not released by capsaicin from osteoarthritis and rheumatoid arthritis synoviocytes in vitro. Ann Rheum Dis 49:653

    Google Scholar 

  36. Mapp PL, Walsh DA, Cruwys SC, Kidd BL, Blake DR (1991) Localization of neutral endopeptidase to the human synovium. Br J Rheumatol 30:121 [Suppl 2]

    Google Scholar 

  37. Sreedharan SP, Goetzl ES, Malfroy B (1990) Elevated synovial tissue concentration of the common acute lymphoblastic leukemia antigen (CALLA)-associated neutral endopeptidase (3.4.24.11) in human chronic arthritis. Immunology 71:142–144

    Google Scholar 

  38. Bathon JM, Proud D, Mizutani S, Ward PE (1992) Cultured human synovial fibroblasts rapidly metabolize kinins and neuropeptides. J Clin Invest 90:981–991

    Google Scholar 

  39. Kenny HJ, Bowes MA, Gee NS, Matsas R (1985) Endopeptidase-24.11: a cell surface enzyme for metabolizing regulatory peptides. Biochem Soc Trans 13:293–295

    Google Scholar 

  40. Iwamoto I, Kimura A, Ochiai K, Tomioka H, Yoshida S (1991) Distribution of neutral endopeptidase activity in human blood leucocytes. J Leukocyte Biol 49:116–125

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Internal Medicine, University of Cagliari, Italy

    M. Matucci-Cerinic

  2. Institute of Internal Medicine IV, University of Florence, Italy

    A. Lombardi, G. Leoncini, A. Pignone & L. Sacerdoti

  3. Medical Research Council, Molecular Neurobiology Unit, University of Cambridge, United Kingdom

    M. G. Spillantini

  4. Ludwig Boltzmann Institute for Rheumatology, Wien-Oberlaa, Austria

    G. Partsch

Authors
  1. M. Matucci-Cerinic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Lombardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. Leoncini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Pignone
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L. Sacerdoti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. G. Spillantini
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G. Partsch
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Matucci-Cerinic, M., Lombardi, A., Leoncini, G. et al. Neutral endopeptidase (3.4.24.11) in plasma and synovial fluid of patients with rheumatoid arthritis. A marker of disease activity or a regulator of pain and inflammation?. Rheumatol Int 13, 1–4 (1993). https://doi.org/10.1007/BF00290326

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00290326

Key words

Search

Navigation