Development of Age and Injury Induced Osteoarthritis Models for Evaluation of Therapeutics and Their Delivery Systems

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URL: http://hdl.handle.net/2047/D20416627

Abstract

Osteoarthritis (OA) is a debilitating disease of the joints, impacting over 500 million people worldwide. OA affects several load-bearing regions of the body, but specifically within the knee joint, its pathology involves deterioration of several tissues including cartilage, synovium, meniscus, ligaments and bone, ultimately leading to chronic pain, severe inflammation and joint immobility. Despite its large impact on quality of life and the discovery of several disease modifying OA drugs, no clinically approved cure exists.

Aging represents the greatest risk for OA as accumulation of advanced glycation endproducts (AGEs) increase cartilage stiffness, causing chondrocytes to exhibit senescent, inflammatory behavior. We simultaneously captured this biomechanical and biochemical response by treating cartilage explants with 100 mM ribose. Using in silico blind docking simulations, we predicted the in vitro efficacy of anti-aging therapeutics resveratrol and curcumin at suppressing AGE formation and cartilage stiffening, whilst maintaining chondrocyte health.

Another major OA cause is traumatic joint injury, following which, significant inter-tissue biological crosstalk occurs, resulting in immediate elevation of inflammatory cytokines and cartilage matrix degrading enzymes that rapidly accelerate disease onset. To represent this crosstalk in vitro, we developed co-cultures containing combinations of cartilage, synovium and meniscus tissue. In response to catabolic challenge with interleukin-1 (IL1), the synovium exhibited protective effects by lowering nitrite production. Additionally, in presence of synovium, cartilage matrix loss was further suppressed following single administration of receptor antagonist IL-1Ra. Proteomic analysis revealed IL-4, matrilin-3 and carbonic anhydrase III as proteins which may contribute to endogenous IL-1 inhibitor production, explaining the protective effects of synovium.

Finally, achieving long-term benefits of such therapeutics remains challenging due to rapid synovial joint space clearance and an inability of drugs to penetrate through the dense, negatively charged cartilage matrix following their intra-articular administration. Therefore, we synthesized cartilage-targeting and penetrating conjugates using Avidin or Cationic Peptide Carriers for delivering IL-1Ra. A single low dose of each conjugate significantly alleviated long-term IL-1-induced cartilage aggrecan and nitrite release, while rescuing cellular metabolism more effectively than free IL-1Ra. This work can potentially enable clinical translation of various drugs that have failed due to lack of cartilage targeting or systemic toxicity.

Cited Works (15)

Year	Entry
2003	Ng L, Grodzinsky AJ, Patwari P, Sandy J, Plaas A, Ortiz C. Individual cartilage aggrecan macromolecules and their constituent glycosaminoglycans visualized via atomic force microscopy. J Struct Biol. September 2003;143(3):242-257.
2009	Fox AJS, Bedi A, Rodeo SA. The basic science of articular cartilage: structure, composition, and function. Sports Health. November–December 2009;1(6):461-468.
1996	Sah RL, Trippel SB, Grodzinsky AJ. Differential effects of serum, insulin-like growth factor-I, and fibroblast growth factor-2 on the maintenance of cartilage physical properties during long-term culture. J Orthop Res. January 1996;14(1):44-52.
1961	Woessner JF Jr. The determination of hydroxyproline in tissue and protein samples containing small proportions of this imino acid. Arch Biochem Biophys. May 1961;93(2):440-447.
2014	Bajpayee AG, Wong CR, Bawendi MG, Frank EH, Grodzinsky AJ. Avidin as a model for charge driven transport into cartilage and drug delivery for treating early stage post-traumatic osteoarthritis. Biomaterials. January 2014;35(1):538-549.
2007	Lohmander LS, Englund PM, Dahl LL, Roos EM. The long-term consequence of anterior cruciate ligament and meniscus injuries: osteoarthritis. Am J Sports Med. October 2007;35(10):1756-1769.
2014	Evans CH, Kraus VB, Setton LA. Progress in intra-articular therapy. Nat Rev Rheumatol. January 2014;10(1):11-22.
1998	Johnson DL, Urban WP Jr, Caborn DNM, Vanarthos WJ, Carlson CS. Articular cartilage changes seen with magnetic resonance imaging-detected bone bruises associated with acute anterior cruciate ligament rupture. Am J Sports Med. May–June 1998;26(3):409-414.
1986	Farndale RW, Buttle DJ, Barrett AJ. Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethylmethylene blue. Biochim Biophys Acta. September 4, 1986;883(2):173-177.
1987	Felson DT, Naimark A, Anderson J, Kazis L, Castelli W, Meenan RF. The prevalence of knee osteoarthritis in the elderly: the Framingham Osteoarthritis Study. Arthritis Rheum. August 1987;30(8):914-918.
2011	Anderson DD, Chubinskaya S, Guilak F, Martin JA, Oegema TR, Olson SA, Buckwalter JA. Post-traumatic osteoarthritis: improved understanding and opportunities for early intervention. J Orthop Res. June 2011;29(6):802-809.
2011	Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier J-P, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol. January 2011;7(1):33-42.
1998	Bank RA, Bayliss MT, Lafeber FPJG, Maroudas A, Tekoppele JM. Ageing and zonal variation in post-translational modification of collagen in normal human articular cartilage: the age-related increase in non-enzymatic glycation affects biomechanical properties of cartilage. Biochem J. February 15, 1998;3301(1):345-351.
2010	Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat Rev Rheumatol. November 2010;6(11):625-635.
2006	Brown TD, Johnston RC, Saltzman CL, Marsh JL, Buckwalter JA. Posttraumatic osteoarthritis: a first estimate of incidence, prevalence, and burden of disease. J Orthop Trauma. November–December 2006;20(10):739-744.