, Volume 19, Issue 6, pp 355–362 | Cite as

Novel Biological Approaches to the Intra-Articular Treatment of Osteoarthritis

Novel Therapeutic Strategies


Osteoarthritis is common, incurable and difficult to treat. Because osteoarthritis is symptomatic only in a limited number of weight-bearing joints and lacks obvious extra-articular manifestations, it is well suited to local therapy administered by intra-articular injection. Several biologically based, local therapies of this type are either in clinical use or in development. Intra-articular injections of hyaluronic acid are widely used, but are highly controversial because their mode of action is unclear and clinical trials have provided contradictory results. The conclusions of meta-analyses are also discordant. An alternative therapy, based on the intra-articular injection of autologous conditioned serum, is used in Europe. This product, known as Orthokine®, is generated by incubating venous blood with etched glass beads. In this way, peripheral blood leukocytes produce elevated amounts of the interleukin-1 receptor antagonist and other anti-inflammatory mediators that are recovered in the serum. Considerable symptomatic relief has been reported in clinical trials of this product. Alternatively, instead of injecting a heterogeneous, incompletely characterized mixture of native molecules into the joint, it is possible to inject recombinant growth factors and cytokine antagonists. None of these are in routine clinical use, but promising preliminary human trials have been performed with insulin-like growth factor-1 and the interleukin-1 receptor antagonist. It is possible that sustained intra-articular production of such factors could be achieved by gene transfer. Although gene therapy for osteoarthritis is not yet a clinical reality, the first human trial should begin next year.



The author is on the Scientific Advisory Board of TissueGene Inc. and Orthogen, A.G.

Funding was received from TissueGene, Inc., Orthogen, A.G. and Osiris Therapeutics, Inc.


  1. 1.
    Jordan KM, Arden NK, Doherty M, et al. EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis 2003; 62(12): 1145–55PubMedCrossRefGoogle Scholar
  2. 2.
    Chadwick DJ, Goode J, editors. Osteoarthritic joint pain. Chichester (UK): Wiley, 2004CrossRefGoogle Scholar
  3. 3.
    Sandell LJ, Aigner T. Articular cartilage and changes in arthritis. An introduction: cell biology of osteoarthritis. Arthritis Res 2001; 3(2): 107–13PubMedCrossRefGoogle Scholar
  4. 4.
    Fukui N, Purple CR, Sandell LJ. Cell biology of osteoarthritis: the chondrocyte’s response to injury. Curr Rheumatol Rep 2001; 3(6): 496–505PubMedCrossRefGoogle Scholar
  5. 5.
    Iannone F, Lapadula G. The pathophysiology of osteoarthritis. Aging Clin Exp Res 2003; 15(5): 364–72PubMedGoogle Scholar
  6. 6.
    van den Berg WB. Lessons from animal models of osteoarthritis. Curr Opin Rheumatol 2001; 13(5): 452–6PubMedCrossRefGoogle Scholar
  7. 7.
    Alexander CJ. Idiopathic osteoarthritis: time to change paradigms? Skeletal Radiol 2004; 33(6): 321–4PubMedCrossRefGoogle Scholar
  8. 8.
    Scott Simonet W. Genetics of primary generalized osteoarthritis. Mol Genet Metab 2002; 77(1-2): 31–4PubMedCrossRefGoogle Scholar
  9. 9.
    Ulrich-Vinther M, Maloney MD, Schwarz EM, et al. Articular cartilage biology. J Am Acad Orthop Surg 2003; 11(6): 421–30PubMedGoogle Scholar
  10. 10.
    van den Berg WB. The role of cytokines and growth factors in cartilage destruction in osteoarthritis and rheumatoid arthritis. Z Rheumatol 1999; 58(3): 136–41PubMedCrossRefGoogle Scholar
  11. 11.
    Berenbaum F. Signaling transduction: target in osteoarthritis. Curr Opin Rheumatol 2004; 16(5): 616–22PubMedCrossRefGoogle Scholar
  12. 12.
    Kuhn K, D’Lima DD, Hashimoto S, et al. Cell death in cartilage. Osteoarthritis Cartilage 2004; 12(1): 1–16PubMedCrossRefGoogle Scholar
  13. 13.
    Aigner T, Kim HA, Roach HI. Apoptosis in osteoarthritis. Rheum Dis Clin North Am 2004; 30(3): 639–53, xiPubMedCrossRefGoogle Scholar
  14. 14.
    Hardingham T, Tew S, Murdoch A. Tissue engineering: chondrocytes and cartilage. Arthritis Res 2002; 4Suppl. 3: S63–8PubMedCrossRefGoogle Scholar
  15. 15.
    Balazs EA, Watson D, Duff IF, et al. Hyaluronic acid in synovial fluid: I. Molecular parameters of hyaluronic acid in normal and arthritis human fluids. Arthritis Rheum 1967; 10(4): 357–76PubMedCrossRefGoogle Scholar
  16. 16.
    Balazs EA. Viscoelastic properties of hyaluronic acid and biological lubrication. Univ Mich Med Cent J 1968: 255-9Google Scholar
  17. 17.
    Butler J, Rydell NW, Balazs EA. Hyaluronic acid in synovial fluid: VI. Effect of intra-articular injection of hyaluronic acid on the clinical symptoms of arthritis in track horses. Acta Vet Scand 1970; 11(2): 139–55PubMedGoogle Scholar
  18. 18.
    Peyron JG, Balazs EA. Preliminary clinical assessment of Na-hyaluronate injection into human arthritic joints. Pathol Biol (Paris) 1974; 22(8): 731–6Google Scholar
  19. 19.
    Moreland LW. Intra-articular hyaluronan (hyaluronic acid) and hylans for the treatment of osteoarthritis: mechanisms of action. Arthritis Res Ther 2003; 5(2): 54–67PubMedCrossRefGoogle Scholar
  20. 20.
    Lo GH, LaValley M, McAlindon T, et al. Intra-articular hyaluronic acid in treatment of knee osteoarthritis: a meta-analysis. JAMA 2003; 290(23): 3115–21PubMedCrossRefGoogle Scholar
  21. 21.
    Wang CT, Lin J, Chang CJ, et al. Therapeutic effects of hyaluronic acid on osteoarthritis of the knee: a meta-analysis of randomized controlled trials. J Bone Joint Surg Am 2004; 86-A(3): 538–45PubMedGoogle Scholar
  22. 22.
    Arrich J, Piribauer F, Mad P, et al. Intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee: systematic review and meta-analysis. CMAJ 2005; 172(8): 1039–43PubMedCrossRefGoogle Scholar
  23. 23.
    Bellamy N, Campbell J, Robinson V, et al. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2005; (2): CD005321PubMedGoogle Scholar
  24. 24.
    Smith MM, Ghosh P. The synthesis of hyaluronic acid by human synovial fibroblasts is influenced by the nature of the hyaluronate in the extracellular environment. Rheumatol Int 1987; 7(3): 113–22PubMedCrossRefGoogle Scholar
  25. 25.
    Arend WP, Leung DY. IgG induction of IL-1 receptor antagonist production by human monocytes. Immunol Rev 1994; 139: 71–8PubMedCrossRefGoogle Scholar
  26. 26.
    Meijer H, Reinecke J, Becker C, et al. The production of anti-inflammatory cytokines in whole blood by physico-chemical induction. Inflamm Res 2003; 52(10): 404–7PubMedCrossRefGoogle Scholar
  27. 27.
    Wright-Carpenter T, Klein P, Schaferhoff P, et al. Treatment of muscle injuries by local administration of autologous conditioned serum: a pilot study on sportsmen with muscle strains. Int J Sports Med 2004; 25(8): 588–93PubMedCrossRefGoogle Scholar
  28. 28.
    Wright-Carpenter T, Opolon P, Appell HJ, et al. Treatment of muscle injuries by local administration of autologous conditioned serum: animal experiments using a muscle contusion model. Int J Sports Med 2004; 25(8): 582–7PubMedCrossRefGoogle Scholar
  29. 29.
    van Beuningen HM, Glansbeek HL, van der Kraan PM, et al. Osteoarthritis-like changes in the murine knee joint resulting from intra-articular transforming growth factor-beta injections. Osteoarthritis Cartilage 2000; 8(1): 25–33PubMedCrossRefGoogle Scholar
  30. 30.
    Martel-Pelletier J, Di Battista JA, Lajeunesse D, et al. IGF/IGFBP axis in cartilage and bone in osteoarthritis pathogenesis. Inflamm Res 1998; 47(3): 90–100PubMedCrossRefGoogle Scholar
  31. 31.
    Studer RK, Levicoff E, Georgescu H, et al. Nitric oxide inhibits chondrocyte response to IGF-I: inhibition of IGF-IRbeta tyrosine phosphorylation. Am J Physiol Cell Physiol 2000; 279(4): C961–9PubMedGoogle Scholar
  32. 32.
    Furst DE. Anakinra: review of recombinant human interleukin-I receptor antagonist in the treatment of rheumatoid arthritis. Clin Ther 2004; 26(12): 1960–75PubMedCrossRefGoogle Scholar
  33. 33.
    Pelletier JP, Caron JP, Evans C, et al. In vivo suppression of early experimental osteoarthritis by interleukin-1 receptor antagonist using gene therapy. Arthritis Rheum 1997; 40(6): 1012–9PubMedCrossRefGoogle Scholar
  34. 34.
    Chevalier X, Giraudeau B, Conrozier T, et al. Safety study of intra-articular injection of interleukin 1 receptor antagonist in patients with painful knee osteoarthritis: a multicenter study. J Rheumatol 2005; 32(7): 1317–23PubMedGoogle Scholar
  35. 35.
    Bandara G, Robbins PD, Georgescu HI, et al. Gene transfer to synoviocytes: prospects for gene treatment of arthritis. DNA Cell Biol 1992; 11(3): 227–31PubMedCrossRefGoogle Scholar
  36. 36.
    Bandara G, Mueller GM, Galea-Lauri J, et al. Intraarticular expression of biologically active interleukin 1-receptor-antagonist protein by ex vivo gene transfer. Proc Natl Acad Sci U S A 1993; 90(22): 10764–8PubMedCrossRefGoogle Scholar
  37. 37.
    Evans CH, Ghivizzani SC, Robbins PD. Arthritis gene therapy: what next? Arthritis Rheum. In pressGoogle Scholar
  38. 38.
    Evans CH, Robbins PD, Ghivizzani SC, et al. Gene transfer to human joints: progress toward a gene therapy of arthritis. Proc Natl Acad Sci U S A 2005; 102(24): 8698–703PubMedCrossRefGoogle Scholar
  39. 39.
    Evans CH, Gouze JN, Gouze E, et al. Osteoarthritis gene therapy. Gene Ther 2004; 11(4): 379–89PubMedCrossRefGoogle Scholar
  40. 40.
    Evans CH. Gene therapies for osteoarthritis. Curr Rheumatol Rep 2004; 6(1): 31–40PubMedCrossRefGoogle Scholar
  41. 41.
    Evans CH, Ghivizzani SC, Herndon JH, et al. Gene therapy for the treatment of musculoskeletal diseases. J Am Acad Orthop Surg 2005; 13: 230–42PubMedGoogle Scholar
  42. 42.
    Zhang X, Mao Z, Yu C. Suppression of early experimental osteoarthritis by gene transfer of interleukin-1 receptor antagonist and interleukin-10. J Orthop Res 2004; 22(4): 742–50PubMedCrossRefGoogle Scholar
  43. 43.
    Frisbie DD, Ghivizzani SC, Robbins PD, et al. Treatment of experimental equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor antagonist gene. Gene Ther 2002; 9(1): 12–20PubMedCrossRefGoogle Scholar
  44. 44.
    Fernandes J, Tardif G, Martel-Pelletier J, et al. In vivo transfer of interleukin-1 receptor antagonist gene in osteoarthritic rabbit knee joints: prevention of osteoarthritis progression. Am J Pathol 1999; 154(4): 1159–69PubMedCrossRefGoogle Scholar
  45. 45.
    Luyten FP. Mesenchymal stem cells in osteoarthritis. Curr Opin Rheumatol 2004; 16(5): 599–603PubMedCrossRefGoogle Scholar
  46. 46.
    Chondrogen™clinical trial information. Baltimore (MD): Osiris Therapeutics, Inc. [online]. Available from URL: [Accessed 2005 Nov 4]
  47. 47.
    Garnero P, Delmas PD. Biomarkers in osteoarthritis. Curr Opin Rheumatol 2003; 15(5): 641–6PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  1. 1.Harvard Medical SchoolCenter for Molecular OrthopaedicsBostonUSA
  2. 2.Center for Molecular OrthopaedicsBostonUSA

Personalised recommendations