Skip to main content
SpringerLink
Log in

Carrageenan-induced transient inflammation in a rabbit knee model: molecular changes consistent with an early osteoarthritis phenotype

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective

Inflammation following a knee injury is one of the factors associated with initiation of cartilage degeneration leading to osteoarthritis (OA). The hypothesis tested was that inflammation results in elevated expression of proteinases implicated in OA.

Methods

Mature female rabbits received a single carrageenan injection to the right hind knee and the left knee served as the control. Five animals were killed at time points of 1, 2 and 4 weeks. The synovium and cartilage from both knees were collected and analysed for specific mRNA levels.

Results

Interleukin (IL)-1β and IL-6 mRNA levels peaked at 2 weeks and returned to normal levels in tissues by 4 weeks post-carrageenan treatment. Matrix metalloproteinase (MMP)-13, MMP-1, MMP-3 and cathepsin K followed the trend set by the inflammatory cytokines. Both synovium and cartilage tissues exhibited similar patterns of molecular expression, with cartilage from the tibial plateau responding more strongly than the femoral condyles.

Conclusions

The acute inflammatory milieu controls the transient expression of many degradative proteinases in the knee. However, a single acute exposure to inflammation in the rabbit knee is insufficient to create a chronic inflammatory environment and other complementary factors, such as persistent mechanical instability and/or injury, may contribute to the establishment of OA.

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

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Benito MJ, Veale DJ, FitzGerald O, van den Berg WB, Bresnihan B. Synovial tissue inflammation in early and late osteoarthritis. Ann Rheum Dis. 2005;64:1263–7.

    Article  PubMed  CAS  Google Scholar 

  2. Myers SL, Brandt KD, Ehlich JW, Braunstein EM, Shelbourne KD, Heck DA, et al. Synovial inflammation in patients with early osteoarthritis of the knee. J Rheumatol. 1990;17:1662–9.

    PubMed  CAS  Google Scholar 

  3. Fernandes JC, Martel-Pelletier J, Pelletier JP. The role of cytokines in osteoarthritis pathophysiology. Biorheology. 2002;39(1–2):237–46.

    PubMed  CAS  Google Scholar 

  4. Goldring MB. The role of cytokines as inflammatory mediators in osteoarthritis: lessons from animal models. Connect Tissue Res. 1999;40(1):1–11.

    Article  PubMed  CAS  Google Scholar 

  5. Roos H, Lauren M, Adalberth T, et al. Knee osteoarthritis after meniscectomy: prevalence of radiographic changes after twenty-one years, compared with matched controls. Arthritis Rheum. 1998;41:687–93.

    Article  PubMed  CAS  Google Scholar 

  6. Gillquist J, Messner K. Anterior cruciate ligament reconstruction and the long-term incidence of gonarthrosis. Sports Med. 1999;27:143–56.

    Article  PubMed  CAS  Google Scholar 

  7. Smith MD, Triantafillou S, Parker A, Youssef PP, Coleman M. Synovial membrane inflammation and cytokine production in patients with early osteoarthritis. J Rheumatol. 1997;24(2):365–71.

    PubMed  CAS  Google Scholar 

  8. Marchand F, Perretti M, McMahon SB. Role of the immune system in chronic pain. Nat Rev Neurosci. 2005;6(7):521–32. (Review).

    Article  PubMed  CAS  Google Scholar 

  9. Stassen M, Hültner L, Schmitt E. Classical and alternative pathways of mast cell activation. Crit Rev Immunol. 2002;22(2):115–40.

    PubMed  CAS  Google Scholar 

  10. Goldring MB, Otero M, Tsuchimochi K, et al. Defining the roles of inflammatory and anabolic cytokines in cartilage metabolism. Ann Rheum Dis. 2008;67:iii75–82.

    Article  PubMed  CAS  Google Scholar 

  11. Mengshol JA, Vincenti MP, Coon CI, Barchowsky A, Brinckerhoff CE. Interleukin-1 induction of collagenase 3 (matrix metalloproteinase 13) gene expression in chondrocytes requires p38, c-Jun N-terminal kinase, and nuclear factor κB: differential regulation of collagenase 1 and collagenase 3. Arthritis Rheum. 2000;43:801–11.

    Article  PubMed  CAS  Google Scholar 

  12. Lefebvre V, Peeters-Joris C, Vaes G. Modulation by interleukin 1 and tumor necrosis factor α of production of collagenase, tissue inhibitor of metalloproteinases and collagen types in differentiated and dedifferentiated articular chondrocytes. Biochim Biophys Acta. 1990;1052:366–78.

    Article  PubMed  CAS  Google Scholar 

  13. Reboul P, Pelletier JP, Tardif G, Cloutier JM, Martel-Pelletier J. The new collagenase, collagenase-3, is expressed and synthesized by human chondrocytes but not by synoviocytes. A role in osteoarthritis. J Clin Invest. 1996;97:2011–9.

    Article  PubMed  CAS  Google Scholar 

  14. Billinghurst RC, Dahlberg L, Ionescu M, Reiner A, Bourne R, Rorabeck C, Mitchell P, Hambor J, Diekmann O, Tschesche H, Chen J, Van War H, Poole AR. Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage. J Clin Invest. 1997;99:1534–45.

    Article  PubMed  CAS  Google Scholar 

  15. Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol. 2011;7(1):33–42.

    Article  PubMed  CAS  Google Scholar 

  16. Hayami T, Zhuo Y, Wesolowski GA, Pickarski M, Duong LT. Inhibition of cathepsin K reduces cartilage degeneration in the anterior cruciate ligament transection rabbit and murine models of osteoarthritis. Bone. 2012;50(6):1250-1259.

    Google Scholar 

  17. Pickarski M, Hayami T, Zhuo Y, le Duong T. Molecular changes in articular cartilage and subchondral bone in the rat anterior cruciate ligament transection and meniscectomized models of osteoarthritis. BMC Musculoskelet Disord. 2011;12:197.

    Article  PubMed  CAS  Google Scholar 

  18. Verma P, Dalal K. ADAMTS-4 and ADAMTS-5: key enzymes in osteoarthritis. J Cell Biochem. 2011;112(12):3507–14.

    Article  PubMed  CAS  Google Scholar 

  19. Kuroki K, Cook CR, Cook JL. Subchondral bone changes in three different canine models of osteoarthritis. Osteoarthritis Cartilage. 2011;19(9):1142–9. (Epub 2011 Jun 22).

    Article  PubMed  CAS  Google Scholar 

  20. Diaz-Torne C, Schumacher HR, Yu X, Gomez-Vaquero C, Dai L, Chen LX, Clayburne G, Einhorn E, Sachdeva RM, Singh JA, Pessler F. Absence of histologic evidence of synovitis in patients with Gulf War veterans’ illness with joint pain. Arthritis Rheum. 2007;57(7):1316–23.

    Article  PubMed  CAS  Google Scholar 

  21. Thorstensson CA, Andersson ML, Jönsson H, Saxne T, Petersson IF. Natural course of knee osteoarthritis in middle-aged subjects with knee pain: 12-year follow-up using clinical and radiographic criteria. Ann Rheum Dis. 2009;68(12):1890–3. (Epub 2008 Dec 3).

    Article  PubMed  CAS  Google Scholar 

  22. Pessler F, Chen LX, Dai L, Gomez-Vaquero C, Diaz-Torne C, Paessler ME, Scanzello C, Cakir N, Einhorn E, Schumacher HR. A histomorphometric analysis of synovial biopsies from individuals with Gulf War Veterans’ illness and joint pain compared to normal and osteoarthritis synovium. Clin Rheumatol. 2008;27(9):1127–34.

    Article  PubMed  CAS  Google Scholar 

  23. Williams FM, Spector TD. Are intra-articular injections of hylan more effective than injections of hyaluronic acid for knee osteoarthritis? Nat Clin Pract Rheumatol. 2008;4(8):400–1.

    Article  PubMed  Google Scholar 

  24. Tapper JE, Ronsky JL, Powers MJ, Sutherland C, Majima T, Frank CB, Shrive NG. In vivo measurement of the dynamic 3-D kinematics of the ovine stifle joint. J Biomech Eng. 2004;126(2):301–5.

    Article  PubMed  Google Scholar 

  25. Funakoshi Y, Hariu M, Tapper JE, Marchuk LL, Shrive NG, Kanaya F, Rattner JB, Hart DA, Frank CB. Periarticular ligament changes following ACL/MCL transection in an ovine stifle joint model of osteoarthritis. J Orthop Res. 2007;25(8):997–1006.

    Article  PubMed  Google Scholar 

  26. Kydd AS, Reno CR, Tsao HW, Hart DA. Early inflammatory arthritis in the rabbit: the influence of intraarticular and systemic corticosteroids on mRNA levels in connective tissues of the knee. J Rheumatol. 2007;34(1):130–9.

    PubMed  CAS  Google Scholar 

  27. Borthakur A, Bhattacharyya S, Dudeja PK, Tobacman JK. Carrageenan induces interleukin-8 production through distinct Bcl10 pathway in normal human colonic epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2007;292(3):G829–38.

    Article  PubMed  CAS  Google Scholar 

  28. Tonussi CR, Ferreira SH. Tumor necrosis factor-alpha mediates carrageenan-induced knee joint incapacitation and also trigger overt ociception in previously inflamed rat knee joints. Pain. 1999;82:81–7.

    Article  PubMed  CAS  Google Scholar 

  29. Radhakrishnan R, Moore SA, Sluka KA. Unilateral carrageenan injection into muscle or joint induces chronic bilateral hyperalgesia in rats. Pain. 2003;104(3):567–77.

    Article  PubMed  CAS  Google Scholar 

  30. Bhattacharyya S, Dudeja PK, Tobacman JK. Tumor necrosis factor alpha-induced inflammation is increased but apoptosis is inhibited by common food additive carrageenan. J Biol Chem. 2010;285(50):39511–22.

    Article  PubMed  CAS  Google Scholar 

  31. Reno C, Marchuk L, Sciore P, Frank CB, Hart DA. Rapid isolation of total RNA from small samples of hypocellular, dense connective tissues. Biotechniques. 1997;22(6):1082–6.

    PubMed  CAS  Google Scholar 

  32. Parreno J, Buckley-Herd G, de-Hemptinne I, Hart DA. Osteoblastic MG-63 cell differentiation, contraction, and mRNA expression in stress-relaxed 3D collagen I gels. Mol Cell Biochem. 2008;317(1-2):21–32.

    Article  PubMed  CAS  Google Scholar 

  33. Vinardell T, Dejica V, Poole AR, Mort JS, Richard H, Laverty S. Evidence to suggest that cathepsin K degrades articular cartilage in naturally occurring equine osteoarthritis. Osteoarthritis Cartilage. 2009;17(3):375–83.

    Article  PubMed  CAS  Google Scholar 

  34. Le Hellio Graverand MP, Eggerer J, Sciore P, Reno C, Vignon E, Otterness I, Hart DA. Matrix metalloproteinase-13 expression in rabbit knee joint connective tissues influence of maturation and response to injury. Matrix Biol. 2000;19(5):431–41.

    Article  Google Scholar 

  35. Tang Z, Yang L, Wang Y, Xue R, Zhang J, Huang W, Chen PC, Sung KL. Contributions of different intraarticular tissues to the acute phase elevation of synovial fluid MMP-2 following rat ACL rupture. J Orthop Res. 2009;27(2):243–8.

    Article  PubMed  CAS  Google Scholar 

  36. Heard BJ, Achari Y, Chung M, Shrive NG, Frank CB. Early joint tissue changes are highly correlated with a set of inflammatory and degradative synovial biomarkers after ACL autograft and its sham surgery in an ovine model. J Orthop Res. 2011;29(8):1185–92.

    Article  PubMed  Google Scholar 

  37. Irie K, Uchiyama E, Iwaso H. Intraarticular inflammatory cytokines in acute anterior cruciate ligament injured knee. Knee. 2003;10(1):93–6.

    Article  PubMed  Google Scholar 

  38. Attia E, Brown H, Henshaw R, George S, Hannafin JA. Patterns of gene expression in a rabbit partial anterior cruciate ligament transection model: the potential role of mechanical forces. Am J Sports Med. 2010;38(2):348–56.

    Article  PubMed  Google Scholar 

  39. Parks WC, Wilson CL, López-Boado YS. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol. 2004;4(8):617–29. (review).

    Article  PubMed  CAS  Google Scholar 

  40. Loram LC, Fuller A, Fick LG, Cartmell T, Poole S, Mitchell D. Cytokine profiles during carrageenan-induced inflammatory hyperalgesia in rat muscle and hind paw. J Pain. 2007;8(2):127–36.

    Article  PubMed  CAS  Google Scholar 

  41. Lyyra T, Kiviranta I, Väätäinen U, Helminen HJ, Jurvelin JS. In vivo characterization of indentation stiffness of articular cartilage in the normal human knee. J Biomed Mater Res. 1999;48(4):482–7.

    Article  PubMed  CAS  Google Scholar 

  42. Rogers BA, Murphy CL, Cannon SR, Briggs TW. Topographical variation in glycosaminoglycan content in human articular cartilage. J Bone Joint Surg Br. 2006;88(12):1670–4.

    Article  PubMed  CAS  Google Scholar 

  43. Stroup GB, Lark MW, Veber DF, Bhattacharyya A, Blake S, Dare LC, Erhard KF, Hoffman SJ, James IE, Marquis RW, Ru Y, Vasko-Moser JA, Smith BR, Tomaszek T, Gowen M. Potent and selective inhibition of human cathepsin K leads to inhibition of bone resorption in vivo in a non-human primate. J Bone Miner Res. 2001;16(10):1739–46.

    Article  PubMed  CAS  Google Scholar 

  44. Salminen-Mankonen HJ, Morko J, Vuorio E. Role of cathepsin K in normal joints and in the development of arthritis. Curr Drug Targets. 2007;8(2):315–23.

    Article  PubMed  CAS  Google Scholar 

  45. Takahashi D, Iwasaki N, Kon S, Matsui Y, Majima T, Minami A, Uede T. Down-regulation of cathepsin K in synovium leads to progression of osteoarthritis in rabbits. Arthritis Rheum. 2009;60(8):2372–80.

    Article  PubMed  CAS  Google Scholar 

  46. Asagiri M, Hirai T, Kunigami T, Kamano S, Gober HJ, Okamoto K, et al. Cathepsin K-dependent toll-like receptor 9 signalling revealed in experimental arthritis. Science. 2008;319:624–7.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge the financial support provided by the Canadian Institutes for Health Research (CBF) and an Osteoarthritis Team Grant (OA-ITG) from Alberta Innovates Health Solutions (CBF and DAH). CBF is the McCaig Professor at McCaig Institute for Bone and Joint Health and DAH is the Calgary Foundation Grace-Glaum Professor in Arthritis Research.

Author information

Authors and Affiliations

  1. Faculty of Medicine, Health Sciences Centre, McCaig Institute for Bone and Joint Health, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada

    Yamini Achari, Carol R. Reno, Cyril B. Frank & David A. Hart

Authors
  1. Yamini Achari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carol R. Reno
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cyril B. Frank
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David A. Hart
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David A. Hart.

Additional information

Responsible Editor: John Di Battista.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Achari, Y., Reno, C.R., Frank, C.B. et al. Carrageenan-induced transient inflammation in a rabbit knee model: molecular changes consistent with an early osteoarthritis phenotype. Inflamm. Res. 61, 907–914 (2012). https://doi.org/10.1007/s00011-012-0483-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-012-0483-1

Keywords

Search

Navigation