Blood-Induced Joint Damage: The Devastating Effects of Acute Joint Bleeds versus Micro-Bleeds

Monique E R van Meegeren, Goris Roosendaal, Nathalie W D Jansen, Floris P J G Lafeber, Simon C Mastbergen, Monique E R van Meegeren, Goris Roosendaal, Nathalie W D Jansen, Floris P J G Lafeber, Simon C Mastbergen

Abstract

Objective: Four days of blood exposure leads to irreversible cartilage damage in vitro. In contrast, intermittent intra-articular blood injections twice a week during 4 weeks (mimicking micro-bleeds) in a canine model resulted in transient damage only. In this study, it was evaluated whether acute joint bleeds are more harmful than micro-bleeds in a canine model of knee arthropathy.

Design: Seven dogs received 4 sequential daily intra-articular blood injections twice in 2 weeks (mimicking 2 acute 4-day joint bleeds). Seven other dogs received the same blood load but in a total of 8 injections intermittently over the 4-week period with at least 1 day in between (mimicking micro-bleeds over the same timespan). Contralateral knees served as controls. Ten weeks after the last injection cartilage matrix turnover and synovial inflammation were evaluated.

Results: Only after the acute joint bleeds the release of newly formed and total (resident) cartilage matrix glycosaminoglycans were increased (P = 0.04 and P = 0.01, respectively). Furthermore, in animals with the acute joint bleeds cartilage glycosaminoglycan content was decreased (P = 0.01) and not in animals with micro-bleeds. Mild synovial inflammation was observed in both groups (both P < 0.0001) but was not different between groups.

Conclusions: In contrast to micro-bleeds, 2 acute joint bleeds lead to prolonged cartilage damage independent of the level of synovial inflammation. This model suggests that micro-bleeds are less devastating than acute joint bleeds with respect to joint damage, which might be of relevance to treatment of joint bleeds in clinical practice.

Keywords: acute joint bleed; cartilage; hemarthrosis; joint damage; micro-bleeds.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Schedule of blood injections for acute and micro-bleeds. To mimic 2 successive clinically evident joint bleeds in 4 weeks, left knees of Beagles were injected with autologous blood for 4 subsequent days twice in 4 weeks. To mimic subclinical micro-bleeds over a same time period with a same overall blood load, animals were injected in their left knee twice a week during 4 weeks with at least 1 day in between the injections. As a control, right knees were either injected according to the same injection scheme with an equal volume of saline (acute bleeds) or not injected (micro-bleeds).
Figure 2.
Figure 2.
Parameters of cartilage damage on acute and micro-bleeds. Proteoglycan synthesis rate (A), newly formed proteoglycan release (B), total proteoglycan release (C), and proteoglycan content (D) were measured 10 weeks after the last acute joint bleed (n = 7) or after the last micro-bleed (n = 7). All these parameters are also expressed as change compared to control leg (right panel of each graph) with bars representing means ± standard error of the mean. Contr = control; exp = experimental, that is, blood-injected; acute = acute joint bleeds (white bar); micro = micro-bleeds (gray bar). P values are given in case they are less than 0.05, otherwise differences were not statistically significant.
Figure 3.
Figure 3.
Macroscopic changes of the synovial tissue as a result of acute and micro-bleeds. Beagle left knee joints were injected according to the acute bleeds protocol (A and B; n = 7) or the micro-bleeds protocol (C and D; n = 7). Representative pictures of control (A and C) and experimental (blood-injected) synovial tissue (B and D) 10 weeks after the last injection are shown. Acute joint bleeds and micro-bleeds caused synovial inflammation according to the modified OARSI score (scale 0-5) (E). Macroscopy was scored by 3 blinded observers and averaged. Contr = control; exp = experimental, that is, blood-injected; OARSI = OsteoArthritis Research Society International.

References

    1. Rodriguez-Merchán EC. Pathogenesis, early diagnosis, and prophylaxis for chronic hemophilic synovitis. Clin Orthop Relat Res. 1997;(343):6-11.
    1. Jansen NW, Roosendaal G, Lafeber FP. Understanding haemophilic arthropathy: an exploration of current open issues. Br J Haematol. 2008;143:632-40.
    1. Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357:535-44.
    1. Roosendaal G, Vianen ME, Wenting MJ, van Rinsum AC, van den Berg HM, Lafeber FP, et al. Iron deposits and catabolic properties of synovial tissue from patients with haemophilia. J Bone Joint Surg Br. 1998;80:540-5.
    1. Madhok R, York J, Sturrock RD. Haemophilic arthritis. Ann Rheum Dis. 1991;50:588-91.
    1. Roy S, Ghadially FN. Synovial membrane in experimentally-produced chronic haemarthrosis. Ann Rheum Di. 1969;28:402-14.
    1. Ovlisen K, Kristensen AT, Jensen AL, Tranholm M. IL-1 beta, IL-6, KC and MCP-1 are elevated in synovial fluid from haemophilic mice with experimentally induced haemarthrosis. Haemophilia. 2009;15:802-10.
    1. Roosendaal G, Vianen ME, van den Berg HM, Lafeber FP, Bijlsma JW. Cartilage damage as a result of hemarthrosis in a human in vitro model. J Rheumatol. 1997;24:1350-4.
    1. Hooiveld MJ, Roosendaal G, van den Berg HM, Bijlsma JW, Lafeber FP. Haemoglobin-derived iron-dependent hydroxyl radical formation in blood-induced joint damage: an in vitro study. Rheumatology (Oxford). 2003;42:784-90.
    1. Hooiveld M, Roosendaal G, Wenting M, van den Berg M, Bijlsma J, Lafeber F. Short-term exposure of cartilage to blood results in chondrocyte apoptosis. Am J Pathol. 2003;162:943-51.
    1. Niibayashi H, Shimizu K, Suzuki K, Yamamoto S, Yasuda T, Yamamuro T. Proteoglycan degradation in hemarthrosis. intraarticular, autologous blood injection in rat knees. Acta Orthop Scand. 1995;66:73-9.
    1. Safran MR, Johnston-Jones K, Kabo JM, Meals RA. The effect of experimental hemarthrosis on joint stiffness and synovial histology in a rabbit model. Clin Orthop Relat Res. 1994;(303):280-8.
    1. Hooiveld M, Roosendaal G, Vianen M, van den Berg M, Bijlsma J, Lafeber F. Blood-induced joint damage: long-term effects in vitro and in vivo. J Rheumatol. 2003;30:339-44.
    1. Roosendaal G, Vianen ME, Marx JJ, van den Berg HM, Lafeber FP, Bijlsma JW. Blood-induced joint damage: a human in vitro study. Arthritis Rheum. 1999;42:1025-32.
    1. Roosendaal G, TeKoppele JM, Vianen ME, van den Berg HM, Lafeber FP, Bijlsma JW. Blood-induced joint damage: a canine in vivo study. Arthritis Rheum. 1999;42:1033-9.
    1. Jansen NW, Roosendaal G, Wenting MJ, Bijlsma JW, Theobald M, Hazewinkel HA, et al. Very rapid clearance after a joint bleed in the canine knee cannot prevent adverse effects on cartilage and synovial tissue. Osteoarthritis Cartilage. 2009;17:433-40.
    1. Jansen NW, Roosendaal G, Bijlsma JW, Degroot J, Lafeber FP. Exposure of human cartilage tissue to low concentrations of blood for a short period of time leads to prolonged cartilage damage: an in vitro study. Arthritis Rheum. 2007;56:199-207.
    1. Frost-Christensen LN, Mastbergen SC, Vianen ME, Hartog A, DeGroot J, Voorhout G, et al. Degeneration, inflammation, regeneration, and pain/disability in dogs following destabilization or articular cartilage grooving of the stifle joint. Osteoarthritis Cartilage. 2008;16:1327-35.
    1. Cook JL, Kuroki K, Visco D, Pelletier JP, Schulz L, Lafeber FP. The OARSI histopathology initiative—recommendations for histological assessments of osteoarthritis in the dog. Osteoarthritis Cartilage. 2010;18(Suppl 3):S66-79.
    1. Lafeber FP, van Roy H, Wilbrink B, Huber-Bruning O, Bijlsma JW. Human osteoarthritic cartilage is synthetically more active but in culture less vital than normal cartilage. J Rheumatol. 1992;19:123-9.
    1. Tan AH, Mitra AK, Chang PC, Tay BK, Nag HL, Sim CS. Assessment of blood-induced cartilage damage in rabbit knees using scanning electron microscopy. J Orthop Surg (Hong Kong). 2003;12:199-204.
    1. Ravanbod R, Torkaman G, Esteki A. Biotribological and biomechanical changes after experimental haemarthrosis in the rabbit knee. Haemophilia. 2010;17:124-33.
    1. Hoaglund FT. Experimental hemarthrosis. the response of canine knees to injections of autologous blood. J Bone Joint Surg Am. 1967;49:285-98.
    1. Sancho FG. Experimental model of haemophilic arthropathy with high pressure haemarthrosis. Int Orthop. 1980;4:57-62.
    1. Myers SL, Brandt KD, O’Connor BL, Visco DM, Albrecht ME. Synovitis and osteoarthritic changes in canine articular cartilage after anterior cruciate ligament transection. Effect of surgical hemostasis. Arthritis Rheum. 1990;33:1406-15.
    1. Valentino LA, Hakobyan N, Kazarian T, Jabbar KJ, Jabbar AA. Experimental haemophilic synovitis: rationale and development of a murine model of human factor VIII deficiency. Haemophilia. 2004;10:280-7.
    1. Hakobyan N, Enockson C, Cole AA, Rick Sumner D, Valentino LA. Experimental haemophilic arthropathy in a mouse model of a massive haemarthrosis: gross, radiological and histological changes. Haemophilia. 2008;14:804-9.
    1. Ovlisen K, Kristensen AT, Tranholm M. In vivo models of haemophilia - status on current knowledge of clinical phenotypes and therapeutic interventions. Haemophilia. 2008;14:248-59.
    1. Porada CD, Sanada S, Long CR, Wood JA, Desai J, Frederick N, et al. Clinical and molecular characterization of a re-established line of sheep exhibiting hemophilia A. J Thromb Haemost. 2009;8:276-85.
    1. van Meegeren ME, Roosendaal G, Barten-van Rijbroek AD, Schutgens RE, Lafeber FP, Mastbergen SC. Coagulation aggravates blood-induced joint damage in dogs. Arthritis Rheum. 2012;64:3231-9.
    1. Frisbie DD, Cross MW, McIlwraith CW. A comparative study of articular cartilage thickness in the stifle of animal species used in human pre-clinical studies compared to articular cartilage thickness in the human knee. Vet Comp Orthop Traumatol. 2006;19:142-6.
    1. Griffith CJ, Laprade RF, Coobs BR, Olson EJ. Anatomy and biomechanics of the posterolateral aspect of the canine knee. J Orthop Res. 2007;25:1231-42.
    1. Mastbergen SC, Lafeber FP. Animal models of osteoarthritis—why choose a larger model? US Musculoskeletal Rev. 2009;4:11-4.
    1. Stockwell RA. The interrelationship of cell density and cartilage thickness in mammalian articular cartilage. J Anat. 1971;109:411-21.
    1. Muir H, Bullough P, Maroudas A. The distribution of collagen in human articular cartilage with some of its physiological implications. J Bone Joint Surg Br. 1970;52:554-63.
    1. Stanescu R, Leibovich SJ. The negative charge of articular cartilage surfaces. An electron microscopic study using cationized ferritin. J Bone Joint Surg Am. 1982;64:388-98.
    1. Bucht A, Larsson P, Weisbrot L, Thorne C, Pisa P, Smedegard G, et al. Expression of interferon-Gamma (IFN-γ), IL-10, IL-12 and transforming growth factor-beta (TGF-β) MRNA in synovial fluid cells from patients in the early and late phases of rheumatoid arthritis (RA). Clin Exp Immunol. 1996;103:357-67.
    1. Firestein GS, Berger AE, Tracey DE, Chosay JG, Chapman DL, Paine MM, et al. IL-1 receptor antagonist protein production and gene expression in rheumatoid arthritis and osteoarthritis synovium. J Immunol. 1992;149:1054-62.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever