Center of Biomedical Research Excellence (COBRE) for Skeletal Health and Repair

Assessment of Chondroprotection in ACL Injuries

Principal Investigator: Gregory Jay, MD, PhD

Abstract

Injury is a well established risk factor in the pathogenesis of osteoarthritis (OA). Several large longitudinal population studies support this observation based upon patient history and retrospective data collection instruments. However, efforts to identify patients at risk of progression have been limited. Gregory Jay, MD, PhD posits that patients with acute knee injuries and resultant inflammation are at risk for early wear and damage to articular cartilage due to loss of lubricating ability. These patients present to emergency departments and manifest an acute traumatic synovitis (TS) secondary to acute structural defects such as acute anterior cruciate ligament (ACL) injuries following trauma.

These patients are young and feature:
  1. Collagen type II fragment release consistent with early cartilage destruction,  
  2. Digestion of lubricin (PRG4) and lack lubricating ability, and
  3. Do not have any history of degenerative joint disease.

We argue that inflammation results in the destruction of lubricin, accompanied by the fibrillation of cartilage and chronic symptoms which underpin the population-based observation of early OA attributable to joint injury. Interventions intended to address some of the earliest causative factors of OA could be emergency department (ED) or primary care based. There may also be a critical time window immediately after a joint injury when limiting the extent of this process could be a primary therapeutic endpoint.

Aims

  • Specific Aim 1: To investigate the early effects of an ACL injury on lubricating mechanisms mediated by lubricin in a mammalian joint.
    • Hypothesis: An ACL injury induced in rat knee joints results in changes to lubricin metabolism leading to an elevation of the coefficient of friction (µ) of the joint. This results in permanent damage to articulating surfaces or failure of the joint to return to a low m of 0.001.
  • Specific Aim 2: Blocking the effects of TNF-a through the administration of a TNF-a inhibitor partially restores the lubricating ability of diarthrodial joints following ACL injury.
    • Hypothesis: TNF-a play a significant role in mediating changes in lubricin metabolism following ACL injury. Blocking the effects of TNF-a preserves joint lubrication and limits joint wear.
  • Specific Aim 3: Synovial fluid aspirates from patients with acute ACL injuries will be analyzed for IL-1 and TNF-a.
    • Hypothesis: An inverse relationship exists between lubricin concentration and catabolic cytokines in clinical aspirates which can be characterized as a mild inflammatory state.

Publications

  1. Teeple, E, Fleming, BC, Mechrefe, AP, Crisco, JJ, Brady, MF, Jay, GD: Frictional properties of Hartley guinea pig knees with and without proteolytic disruption of the articular surface. Osteoarth Cartilag 15:309-315, 2007
  2. Elsaid, KA, Jay, GD, Chichester, CO. Reduced expression and proteolytic susceptibility of lubricin/superficial zone protein may explain early elevation in the coefficient of friction in the joints of rats with antigen-induced arthritis. Arthritis Rheumatism 56(1):108-116, 2007.
  3. Zappone, B, Marina, R, Greene, GW, Jay, GD, Israelachvili, JN: Adsorption, lubrication and wear of lubricin on model surfaces: Polymer brush-like behavior of a glycoprotein. Biophys J 92:1693-1708, 2007.
  4. Jay, GD, Torres, R, Warman, ML, Laxer, RM, Laderer, M, Breuer, KS: The role of lubricin in the mechanical behavior of synovial fluid. PNAS 104(15):6194-6199, 2007.
  5. Rucevic, M, Fast, LD, Jay GD, Trespelacios, FM, Sucov, S, Siryaporn, E, Yow-Pin Lim. Altered levels and molecular forms of granzyme K in plasma from septic patients. Shock 29(5):488-493, 2007.
  6. Crisco, JJ, Blume, J, Teeple, E, Fleming, BC, Jay, GD. Assuming exponential decay by incorporating viscous damping improves the prediction of the coefficient of friction in pendulum tests of whole articular joints. J Eng Med 221 Part H:325-333, 2007.
  7. Suner, S, Crawford, McMurdy, J, Jay, G. Non-invasive determination of hemoglobin by digital photography of palpebral conjunctiva. J Emerg Med 33(2):105-111, 2007.
  8. Suner, S, McMurdy, J, Jay, GD, Crawford, G. Digital imaging, spectroscopy, and liquid crystals in a handheld noninvasive device to determine hemoglobin concentration. J Soc Information Display 15(6):399-407, 2007.
  9. Jay, GD, Torres, JR, Rhee, DK, Helminen, HJ, Hytinnen, MM, Cha, CJ, Elsaid, K, Kim, KS, Cui, Y, Warman, ML: The association between friction and wear in diarthrodial joints lacking lubricin. Arthritis Rheum 56(11):3662-9, 2007.
  10. Suner, S, Partridge, R, Sucov, A, Chee, K, Valente, J, Jay, G. Non-invasive screening for carbon monoxide toxicity in the emergency department is valuable. Ann Emerg Med 2007;49:718-719.
  11. Kobayashi, L, Shapiro, MJ, Gutman, DC, Jay, GD: Multiple encounter simulation scenario (MESS) for clinical skills and patient safety training of personnel working in high-acuity multi-patient medical environments. Acad Emerg Med 14(12):1141-8, 2007.
  12. Plante, T, Harris, D, Savitt, J, Akhlaghi, F, Monti, J, Jay, GD. Carboxyhemoglobin monitored by bedside continuous co-oximetry. J Trauma 63(5):1187-1190, 2007.
  13. Woltman, SJ, Jay, GD, Crawford, GP. Liquid-crystal materials find a new order in biomedical applications. Nature Materials 6:929-938, 2007.
  14. Zappone B, Greene GW, Oroudjev E, Jay, GD, Israelachvili JN: Molecular aspects of the boundary lubrication by human lubricin: Effect of disulphide bonds and enzymatic digestion.Langmuir 2008; 24(4):1495-1508.
  15. Chang DP, Abu-Lail NI, Guilak F, Jay, GD, Zauscher S: Conformational Mechanics, Adsorption, and Normal Force Interactions of Lubricin and Hyaluronic Acid on Model Surfaces. Langmuir 2008; 24(4):1183-1193.
  16. Suner, S, Partridge, R, Sucov, A, Valente, J, Chee, Kerlen, Jay, GD. Non-invasive pulse CO-oximetry for carboxyhemoglobin screening in the emergency department: Identifying occult carbon monoxide toxicity. J Emerg Med 2008.
  17. Suner S, Jay, GD. Carbon monoxide has direct toxicity on the myocardium distinct from effects of hypoxia in an ex vivo rat heart model. Acad Emerg Med 15(1):59-65, 2008.
  18. Teeple E, Elsaid KA, Fleming BC, Jay GD, Aslani K, Crisco JJ, Mechrefe AP Coefficients of friction, lubricin and cartilage damage in the anterior cruciate ligament-deficient guinea pig knee. J Orthop Res 2008; 26:231-237.
  19. Taguchi, M, Sun, YL, Zhao, C, Zobitz, ME, Jay, GD, Ann, KN, Amadio, PC. Lubricin surface modification improves extrasynovial tendon gliding in a canine model in vitro. J Bone Joint Surgery 2008; 90:128-135.
  20. Elsaid, KA, Fleming, BC, Oksendahl HL, Fadale, PD, Hulstyn, MJ, Shalvoy, R, Machan, J, Jay, GD Decreased lubricin concentrations and markers of joint inflammation in synovial fluids from patients with anterior cruciate ligament injury. Arthritis Rheum 2008; 58(6):1707-1715.
  21. Coles J, Blum J, Jay GD, Darling E, Guilak F, Zauscher S. In situ frictional measurement on murine cartilage by atomic force microscopy. J Biomech 2008; 41:541-548.
  22. Chee K, Nilson D, Partridge R, Hughes A, Suner, S, Sucov, A, Jay, GD. Finding needles in a haystack: A case series of carbon monoxide poisoning detected using new technology in the emergency department. Clin Tox 2008; 46(5):461-469.  
  23. McMurdy, JW, Jay, GD, Suner, S and Crawford, G Noninvasive optical, electrical and acoustic methods of total hemoglobin determination. Clin Chemistry Feb 2008; 54:264-272.
  24. Shapiro, M, Gardner, R, Godwin. S, Jay, GD, Lindquist, D, Salisbury, M, Salas, E Defining team performance for simulation-based training: Methodology, metrics, and opportunities for emergency medicine. Academic Emergency Medicine 2008;15:1008 – 1097.
  25. Kobayashi, L, Patterson, M, Overly, F, Shapiro, M, Williams, K, Jay, GD Educational and research implications of portable human patient simulation in acute care medicine. Academic Emergency Medicine 2008;15:1166 – 1174.
  26. Taguchi, M, Sun, Y-L, Zhao, C, Zobitz, M, Cha, C-J, Jay, GD, An, K-N, Amadio, P: Lubricin surface modification improves tendon gliding after tendon repair in a canine model in vitro. J Orthop Res 2009; 27:257-263.
  27. McMurdy, J, Jay, GD, Suner, S, and Crawford, G: Photonics based In Vivo total hemoglobin monitoring and clinical relevance. J Biophotonics 2009; 2(5): 277-287.
  28. Drewniak, E. Jay, GD, Fleming, BC, Crisco, JJ: Comparison of two methods for calculating the frictional properties of articular cartilage using a simple pendulum and intact mouse knee joints. J Biomech 2009;(42)12:1996-9.
  29. Elsaid, KA, Machan, JT, Waller, K, Fleming, BC, Jay, GD The impact of anterior cruciate ligament injury on lubricin metabolism and the effect of inhibiting TNF-a on chondroprotection in an animal model, Arthritis Rheum, Sep 2009;60(10): 2997-3006. [PMID: 19790069] [PMCID: PMC2800051]
  30. Suner, S., Sucov, A., Valente, J., Partridge, R., B, Jay, G., SpCO Screening at Triage Continues to Identify Occult CO Toxicity. J Emer Med 10/2009, vol 37(3): 311-12
  31. Chang, D, Abu-Lail, N, Coles, J, Guilak, F, Jay, GD., Zauscher, S, Friction force microscopy of lubricin and hyaluronic acid between hydrophobic and hydrophilic surfaces. Soft Matter 2009, 5: 3438 – 3445.
  32. Taguchi, M, Zhao, C, Sun, YL, Jay, GD, An, KN, Amadio, PC, The Effect of Surface Treatment Using Hyaluronic Acid and Lubricin on the Gliding Resistance of Human Extrasynovial Tendons In Vitro. J Hand Surg AM 2009 Sept;34(7):1276-81 [PMID: 19556078] [PMCID: PMC2730995]
  33. Wei, L, Fleming, B, Sun, X, Teeple, E, Wu, W, Jay, GD, Elsaid, KE, Luo, J, Machan, J, Chen, Q, A comparison of Differential Biomarkers of Osteoarthritis with and without Post-traumatic Injury in the Hartley Guinea Pig Model. Journal of Orthopaedic Research, 27 January 2010 (28): 900-906 epub #10.1002/jor.21093 [PMID: pending]
  34. Kobayashi, L, Lindquist, D, Jenouri, I, Dushay, K, Haze, D, Sutton, E, Smith, JL, Tubbs, R, Overly, F, Foggle, J, Dunbar-Viveiros, J, Marcotte, S, Werner, D, Cooper, M, Martin, P, Tammaro, D, Jay, GD, Comparison of sudden cardiac arrest resuscitation performance data obtained from in-hospital chart review and in situ high fidelity medical simulation. Resuscitation. 2010 Jan 30, 81(4):463-471 [PMID: 20122781]
  35. Coles, J, Zhang, L, Blum, J, Warman, M, Jay, GD, Guilak, F, Zauscher, S, Loss of cartilage structure, stiffness, and frictional properties in mice lacking Prg4. Arthritis and Rheumatism 2010 (62) 6:1666- 1674 [PMID: 20191580].
  36. Jay,GD, Fleming, BC, Watkins, BA, McHugh, KA, Anderson, SC, Zhang, LX, Teeple, E, Waller, KA, Elsaid, KA Prevention of Cartilage Degeneration and Restoration of Chondroprotection by Lubricin Tribosupplementation in the Rat Following ACL Transection. Arthritis and Rheumatism2010 (62) 8:2382-2391 [PMID: pending].
  37. Nilson, D, Partridge, R, Suner, S, Jay, GD. Non-invasive Carboxyhemoglobin Monitoring: Screening Emergency Medical Services Patients for Carbon Monoxide Exposure, Journal of Prehospital and Disaster Medicine 2010 (25) 3:253-256.
  38. Zhao, C, Sun, Y-L, Kirk, R, Thoreson, A, Jay, GD, Moran, S, An, K-N, Amadio, P, Effects of a Lubricin- Containing Compound on the Results of Flexor Tendon Repairs in a Canine Model In Vivo. Journal of Bone and Joint Surgery (Am) 2010;92: 1543-1461 [PMID: pending].
  39. Teeple, E, Elsaid, KA, Fleming, BC, Jay, GD, Zhang, LX, Badger, G, Akelman, M. The Effects of Supplemental Intra-Articular Lubricin and Hyaluronic Acid on the Progression of Post-Traumatic Arthritis in the Anterior Cruciate Ligament Deficient Rat Knee. American Journal of Sports Medicine2011(39) 1:164- 172 [PMID: pending].
  40. Kohrs, R, Zhao, C, Sun, Y, Jay, GD, Zhang, L, Warman, ML, An, K, Amadio, P. Tendon Fascicle Gliding in Wild Type, Heterozygous, and Lubricin Knockout Mice. Journal of Orthopaedic Research 2011(29) 3:384-389 [PMID: 20886657].
Center of Biomedical Research Excellence (COBRE) for Skeletal Health and Repair