Skip to main content

Advertisement

SpringerLink
Log in

Effect of Nabumetone, Diclofenac, Ibuprofen and an Anti-Inflammatory Corticosteroid, Dexamethasone, on Cartilage Metabolism in a Biochemically-Induced Model of Osteoarthritis

  • Pharmacodynamics
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Summary

The metabolism of articular cartilage, and the effects of 3 nonsteroidal antiinflammatory drugs (nabumetone, diclofenac and ibuprofen) and an antiinflammatory steroid (dexamethasone) were studied using a biochemically-induced model of osteoarthritis in the rat. Intra-articular injections of iodoacetate produced a transient inflammation and induced marked degenerative changes to the articular cartilage of the treated joint. All drug treatments reduced the iodoacetate-induced changes in damage score, tissue wet weight, cartilage metabolism and cartilage morphology. Dexamethasone also suppressed cartilage metabolism in the control joints. Levels of plasma haptoglobin were elevated in the dexamethasone-, ibuprofen- and diclofenac-treated but not in the nabumetonetreated animals. From these results in the rat, nabumetone appears to effectively reduce disease parameters in a model of osteoarthritis while not impairing normal cartilage metabolism.

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. Wilhelmi G, Maier R, editors. Experimental studies on the effects of drugs on cartilage. In: Articular cartilage and osteoarthrosis. Bern: Hans Huber, 1983: 42–64

  2. Kalbhen DA. Biochemically induced osteoarthritis in the chicken and rat. In: Munthe E, Bjelle A, editors. Effects of drugs on osteoarthritis. Bern, Stuttgart, Vienna: Hans Huber, 1984: 48–68

    Google Scholar 

  3. Brandt KD. Animal models: insight into osteoarthritis (OA) provided by the cruciate-deficient dog. Br J Rheumatol 1991; 30 Suppl. 1: 5–9

    PubMed  Google Scholar 

  4. Greb WH, von Schrader HW, Cerlek S, et al. Endoscopic studies of nabumetone in patients with rheumatoid arthritis. Am J Med 1987; 83 Suppl. 4B: 19–24

    Article  PubMed  CAS  Google Scholar 

  5. Lemmel EM, Stroehmann I. Experience with nabumetone in the treatment of rheumatic conditions: results of an application study in 18,047 patients. Fortschr Med 1988; 106: 63–8

    Google Scholar 

  6. Roth SH. New understanding of NSAID gastropathy. Scand J Rheumatol 1989; 78 Suppl.: 24–9

    Article  CAS  Google Scholar 

  7. DeVries BJ, van den Berg WB, Vitters E, et al. Quantitation of glycosaminoglycan metabolism in anatomically intact articular cartilage of the mouse patella: in vitro and in vivo studies with 35SO-sulphate, 3H-gucosamine and 3H-acetate. Rheumatol Int 1986; 6: 273–81

    Article  CAS  Google Scholar 

  8. Farndale RW, Sayers CA, Barrett AJ. A direct spectrophotometric microassay for sulphated glycosaminoglycans in cartilage cultures. Conn Tissue Res 1982; 9: 247–8

    Article  CAS  Google Scholar 

  9. Gilbertsen RB. Rat haptoglobin: method of quantitation and response to antiarthritic therapy in collagen arthritis. Immunopharmacology 1986; 11: 69–77

    Article  PubMed  CAS  Google Scholar 

  10. Melarange R, Gentry C, Durie M, et al. Gastrointestinal irritancy, antiinflammatory activity, and prostanoid inhibition in the rat. Differentiation effects between nabumetone and etodolac. Dig Dis Sci 1994; 39: 601–8

    Article  PubMed  CAS  Google Scholar 

  11. Trotter GW, Yovich JV, Mcllwraith CW, et al. Effects of intramuscular polysulphated glycosaminoglycan on chemical and physical defects in equine articular cartilage. Can J Vet Res 1989; 53: 224–30

    PubMed  CAS  Google Scholar 

  12. Williams JA, Thonar J-MA. Early osteophyte formation after chemically induced articular cartilage injury. Am J Sports Med 1989; 17(1): 7–15

    Article  PubMed  CAS  Google Scholar 

  13. Van der Kran PM, Vitters EL, van de Putte LBA, et al. Development of osteoarthritic lesions in mice by ‘metabolic’ and ‘mechanical’ alteration in the knee joint. Am J Pathol 1989; 135: 1001–14

    Google Scholar 

  14. Lust G, Miller DR. Biochemical changes in canine osteoarthrosis. In: Nuti G, editor. The aetiopathogenesis of osteoarthritis. Tunbridge Wells, England: Pitman Medical Publishing, 1980: 47–51

    Google Scholar 

  15. Pelletier J-P, Marlet-Pelletier J, Ghandur-Mnaymneh L, et al. Role of synovial membrane inflammation in cartilage matrix breakdown in the Pond-Nuki dog model of osteoarthritis. Arthritis Rheum 1985; 28: 554–61

    Article  PubMed  CAS  Google Scholar 

  16. Lindblod S, Medfors E. Arthroscopic and immunohistologic characterisation of knee-joint synovitis in osteoarthritis. Arthritis Rheum 1987; 30: 1081–8

    Article  Google Scholar 

  17. Bullough P. Synovial and osseous inflammation in osteoarthritis. Semin Arthritis Rheum 1981; 11 Suppl.: 146

    Article  Google Scholar 

  18. Peyron J. Inflammation in osteoarthritis: review of its clinical picture, disease progress, subsets, and its pathophysiology. Semin Arthritis Rheum 1981; 11: 115–6

    Article  Google Scholar 

  19. Maroudas A. Glycosaminoglycan turn-over in articular cartilage. Philos Trans R Soc Lond (Biol) 1975; 271(912): 293–313

    Article  CAS  Google Scholar 

  20. Malemud CJ, Papay RS, Goldberg VM. Proteoglycan composition and biosynthesis by human osteochondrophytic spurs of the femoral head. Biomaterials 1990; 11: 25–7

    PubMed  CAS  Google Scholar 

  21. Mankin HJ, Dorfman H, Lippiello L, et al. Biochemical and metabolic abnormalities in articular cartilage from osteoarthritic human hips. II. Correlation of morphology with biochemical and metabolic data. J Bone Joint Surg 1971; 53B: 523–37

    Google Scholar 

  22. Vignon E, Arlot M, Hartmann D, et al. Hypertrophic repair of articular cartilage in experimental osteoarthrosis. Ann Rheum Dis 1983; 42: 82–8

    Article  PubMed  CAS  Google Scholar 

  23. Chrisman OD, Fessel JM, Southwick WO. Experimental production of synovitis and marginal articular exosteses in the knee joint of dogs. Yale J Biol Med 1965; 37: 409–12

    PubMed  CAS  Google Scholar 

  24. Huskinsson EC. Classification of anti-rheumatic drugs. Anti-Rheum Drugs 1983; 1: 1–9

    Google Scholar 

  25. Silberberg M, Silberberg R, Hasler M. Fine structure of articular cartilage in mice receiving cortisone acetate, Arch Pathol 1966; 82: 569–82

    PubMed  CAS  Google Scholar 

  26. Silbermann M. Experimentally induced osteoarthrosis in the temporomandibular joint of the mouse. Acta Anat 1976; 96: 9–24

    Article  PubMed  CAS  Google Scholar 

  27. Kalbhen DA. Chemical model of osteoarthritis — a pharmacological evaluation. J Rheumatol 1987; 14: 130–1

    PubMed  CAS  Google Scholar 

  28. Sternberg M, Peyroux J, Engler R, et al. Orosomucoid, seromucoid and haptoglobin in serum during adjuvant arthritis in the rat. Experientia 1974; 30: 193–5

    Article  PubMed  CAS  Google Scholar 

  29. Billingham MEJ, Tucker MJ. Correlation between the rise in acute phase proteins and histological evidence of ulcération in the rat following indomethacin treatment. Br J Pharmacol 1979; 67: 450P

    PubMed  CAS  Google Scholar 

  30. Billingham MEJ, Carey F, Growcott JW, et al. Indomethacin-induced gastrointestinal lesions: protection by salicylate and relationship to plasma acute phase proteins. Br J Pharmacol 1988; 85: 272P

    Google Scholar 

  31. Carey F, Growcott JW. Mouse haptoglobin: a sensitive parameter for the measurement of NSAID and non-NSAID-induced gastrointestinal toxicity. Br J Pharmacol 1987; 90: 177P

    Google Scholar 

  32. Gross V, Andus T, Caesar I, et al. Evidence for continuous stimulation of interleukin-6 production in Crohn’s disease. Gastroenterology 1992; 102: 514–9

    PubMed  CAS  Google Scholar 

  33. Melarange R, Gentry C, Blower P, et al. Nabumetone, in contrast to etodolac, lacks gastrointestinal irritance in the rat: assessment by the inflammatory marker, haptoglobin, and blood loss. Inflammopharm 1995; 3: 259–70

    Article  CAS  Google Scholar 

  34. Graham DY, Smith JL, Dobbs SM. Gastric adaptation with aspirin administration in man. Dig Dis Sci 1983; 28: 1–6

    Article  PubMed  CAS  Google Scholar 

  35. Melarange R, Gentry C, O’Connell C, et al. Anti-inflammatory and gastrointestinal irritancy: comparative 1 month repeat oral dose studies in the rat with nabumetone, ibuprofen and diclofenac. In: Parnham MJ, Bray MA, van den Berg WB, editors. Drugs in inflammation. Basel: Birkhauser. Agents Actions 1991; Suppl. 32: 33–7

    Chapter  Google Scholar 

  36. Melarange R, Gentry C, O’Connell C, et al. The anti-inflammatory drug nabumetone lacks the gastrointestinal damaging potential of loxoprofen or naproxen. Jap J Inflamm 1991; 11: 607–14

    CAS  Google Scholar 

  37. Melarange R, Gentry C, O’Connell C, et al. Anti-inflammatory and gastrointestinal effects of nabumetone or its active metabolite, 6-methoxy-2-naphthylacetic acid (6MNA): comparative studies with indomethacin. Dig Dis Sci 1992; 37: 1847–52

    Article  PubMed  CAS  Google Scholar 

  38. Melarange R, Gentry C, Blower PR, et al. Nabumetone, an effective anti-inflammatory agent, lacks gastrointestinal irritancy in the rat when dosed orally for one month: comparison with tiaprofenic acid and etodolac. Eur J Rheumatol Inflamm 1994; 14: 14–22

    Google Scholar 

  39. Baumann H, Prowse KR, Marinkovic S, et al. Stimulation of hepatic acute phase response by cytokines and glucocorticoids. Ann NY Acad Sci 1989; 557: 280–96

    Article  PubMed  CAS  Google Scholar 

  40. Milner JC. Osteoarthritis of the hip and indomethacin. J Bone Joint Surg 1972; 54B: 752

    Google Scholar 

  41. Brandt KD, Slowman-Kovacs S. Nonsteroidal anti-inflammatory drugs in the treatment of osteoarthritis. Clin Orthop Rel Res 1986; 213: 84–91

    CAS  Google Scholar 

  42. Brandt KD. Effects of nonsteroidal anti-inflammatory drugs on chondrocyte metabolism in vitro and in vivo. Am J Med 1987; 83 Suppl.: 29–34

    Article  PubMed  CAS  Google Scholar 

  43. Burkhardt D, Ghosh P. Laboratory evaluation of anti-arthritic drugs as potential chondroprotective agents. Semin Arthritis Rheum 1987; 17 Suppl. 1: 3–34

    PubMed  CAS  Google Scholar 

  44. Doherty M. ‘Chondroprotection’ by nonsteroidal anti-inflammatory drugs. Ann Rheum Dis 1989; 48: 619–21

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Research and Development Technologies, SmithKline Beecham Pharmaceuticals, Harlow, Essex, England

    Clive Gentry, Richard Melarange, Michael Durie & Grace Moore

  2. ITR Medical and Scientific Affairs, SmithKline Beecham Pharmaceuticals, Philadelphia, Pennsylvania, USA

    Ron Spangler (Director)

Authors
  1. Clive Gentry
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard Melarange
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Durie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Grace Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ron Spangler
    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

Gentry, C., Melarange, R., Durie, M. et al. Effect of Nabumetone, Diclofenac, Ibuprofen and an Anti-Inflammatory Corticosteroid, Dexamethasone, on Cartilage Metabolism in a Biochemically-Induced Model of Osteoarthritis. Clin. Drug Invest. 11, 49–59 (1996). https://doi.org/10.2165/00044011-199611010-00006

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00044011-199611010-00006

Keywords

Search

Navigation