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Potential Targets for Pharmacologic Therapies for Prevention of PTA

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Post-Traumatic Arthritis

Abstract

Joint injuries are common, especially among young adults of age 18–44 years old. They are accompanied by a cascade of events that increase the risk of post-traumatic osteoarthritis (PTOA). Therefore, understanding biological responses that predispose to PTOA should help in determining treatment modalities to delay and/or prevent the onset and progression of the disease. The vast majority of the literature pointed to chondrocyte death and apoptosis, inflammation and matrix damage/fragmentation being the earliest events that follow joint trauma. Together these events lead to the development of OA-like focal cartilage lesions that if untreated have a tendency to expand and progress to fully developed disease.

Currently, the only treatments available for joint trauma are surgical interventions. Experimental biologic approaches involve engineering of cartilage with the use of cells (stem cells or chondrocytes), juvenile or adult cartilage pieces, scaffolds and various polymeric matrices. The major challenge for all of them is regeneration of normal functional mature hyaline cartilage that can sustain the load, resist compression, and most importantly, integrate with the host tissue. If the tissue is spontaneously repaired it fails to reproduce original structure and function and thus, may be more susceptible to reinjury. Thus, there is a critical need to develop novel molecular mechanism-based therapeutic approaches to biologic chondral and/or osteochondral repair. The focus of this review is on the earliest molecular and cellular manifestations of injury that can be grouped based on the following therapeutic options for PTOA: chondroprotection, anti-inflammatory, matrix protection, and matrix remodeling/matrix synthesis.

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References

  1. Kern D, Zlatkin MB, Dalinka MK. Occupational and post-traumatic arthritis. Radiol Clin North Am. 1988;26(6):1349–58.

    CAS  PubMed  Google Scholar 

  2. Roos H, Adalberth T, Dahlberg L, Lohmander LS. Osteoarthritis of the knee after injury to the anterior cruciate ligament or meniscus: the influence of time and age. Osteoarthritis Cartilage. 1995;3(4):261–7.

    Article  CAS  PubMed  Google Scholar 

  3. Anderson DD, Chubinskaya S, Guilak F, Martin JA, Oegema TR, Olson SA, et al. Post-traumatic osteoarthritis: improved understanding and opportunities for early intervention. J Orthop Res. 2011;29(6):802–9.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Butler DL, Juncosa-Melvin N, Boivin GP, Galloway MT, Shearn JT, Gooch C, et al. Functional tissue engineering for tendon repair: a multidisciplinary strategy using mesenchymal stem cells, bioscaffolds, and mechanical stimulation. J Orthop Res. 2008;26(1):1–9.

    Article  PubMed  Google Scholar 

  5. Furman BD, Strand J, Hembree WC, Ward BD, Guilak F, Olson SA. Joint degeneration following closed intraarticular fracture in the mouse knee: a model of posttraumatic arthritis. J Orthop Res. 2007;25(5):578–92.

    Article  PubMed  Google Scholar 

  6. Pelletier JP, Jovanovic D, Fernandes JC, Manning P, Connor JR, Currie MG, et al. Reduced progression of experimental osteoarthritis in vivo by selective inhibition of inducible nitric oxide synthase. Arthritis Rheum. 1998;41(7):1275–86.

    Article  CAS  PubMed  Google Scholar 

  7. Chu CR, Beynnon BD, Dragoo JL, Fleisig GS, Hart JM, Khazzam M, et al. The feasibility of randomized controlled trials for early arthritis therapies (Earth) involving acute anterior cruciate ligament tear cohorts. Am J Sports Med. 2012;40(11):2648–52.

    Article  PubMed  Google Scholar 

  8. Chu CR, Beynnon BD, Buckwalter JA, Garrett Jr WE, Katz JN, Rodeo SA, et al. Closing the gap between bench and bedside research for early arthritis therapies (EARTH): report from the AOSSM/NIH U-13 Post-Joint Injury Osteoarthritis Conference II. Am J Sports Med. 2011;39(7):1569–78.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Henrotin YE, Bruckner P, Pujol JP. The role of reactive oxygen species in homeostasis and degradation of cartilage. Osteoarthritis Cartilage. 2003;11(10):747–55.

    Article  CAS  PubMed  Google Scholar 

  10. Martin JA, Brown T, Heiner A, Buckwalter JA. Post-traumatic osteoarthritis: the role of accelerated chondrocyte senescence. Biorheology. 2004;41(3–4):479–91.

    CAS  PubMed  Google Scholar 

  11. Beecher BR, Martin JA, Pedersen DR, Heiner AD, Buckwalter JA. Antioxidants block cyclic loading induced chondrocyte death. Iowa Orthop J. 2007;27:1–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Kurz B, Lemke A, Kehn M, Domm C, Patwari P, Frank EH, et al. Influence of tissue maturation and antioxidants on the apoptotic response of articular cartilage after injurious compression. Arthritis Rheum. 2004;50(1):123–30.

    Article  CAS  PubMed  Google Scholar 

  13. Goodwin W, McCabe D, Sauter E, Reese E, Walter M, Buckwalter JA, et al. Rotenone prevents impact-induced chondrocyte death. J Orthop Res. 2010;28(8):1057–63.

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Hiran TS, Moulton PJ, Hancock JT. Detection of superoxide and NADPH oxidase in porcine articular chondrocytes. Free Radic Biol Med. 1997;23(5):736–43.

    Article  CAS  PubMed  Google Scholar 

  15. Pelletier JP, Jovanovic DV, Lascau-Coman V, Fernandes JC, Manning PT, Connor JR, et al. Selective inhibition of inducible nitric oxide synthase reduces progression of experimental osteoarthritis in vivo: possible link with the reduction in chondrocyte apoptosis and caspase 3 level. Arthritis Rheum. 2000;43(6):1290–9.

    Article  CAS  PubMed  Google Scholar 

  16. Borrelli Jr J. Chondrocyte apoptosis and posttraumatic arthrosis. J Orthop Trauma. 2006;20(10):726–31.

    Article  PubMed  Google Scholar 

  17. Chen CT, Burton-Wurster N, Borden C, Hueffer K, Bloom SE, Lust G. Chondrocyte necrosis and apoptosis in impact damaged articular cartilage. J Orthop Res. 2001;19(4):703–11.

    Article  CAS  PubMed  Google Scholar 

  18. D’Lima D, Hermida J, Hashimoto S, Colwell C, Lotz M. Caspase inhibitors reduce severity of cartilage lesions in experimental osteoarthritis. Arthritis Rheum. 2006;54(6):1814–21.

    Article  PubMed  Google Scholar 

  19. D’Lima DD, Hashimoto S, Chen PC, Colwell Jr CW, Lotz MK. Human chondrocyte apoptosis in response to mechanical injury. Osteoarthritis Cartilage. 2001;9(8):712–9.

    Article  PubMed  Google Scholar 

  20. Pascual Garrido C, Hakimiyan AA, Rappoport L, Oegema TR, Wimmer MA, Chubinskaya S. Anti-apoptotic treatments prevent cartilage degradation after acute trauma to human ankle cartilage. Osteoarthritis Cartilage. 2009;17(9):1244–51.

    Article  CAS  PubMed  Google Scholar 

  21. Duke RC, Ojcius DM, Young JD. Cell suicide in health and disease. Sci Am. 1996;275(6):80–7.

    Article  CAS  PubMed  Google Scholar 

  22. Huser CA, Davies ME. Calcium signaling leads to mitochondrial depolarization in impact-induced chondrocyte death in equine articular cartilage explants. Arthritis Rheum. 2007;56(7):2322–34.

    Article  CAS  PubMed  Google Scholar 

  23. Bajaj S, Shoemaker T, Hakimiyan AA, Rappoport L, Pascual-Garrido C, Oegema TR, et al. Protective effect of P188 in the model of acute trauma to human ankle cartilage: the mechanism of action. J Orthop Trauma. 2010;24(9):571–6.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Isaac DI, Golenberg N, Haut RC. Acute repair of chondrocytes in the rabbit tibiofemoral joint following blunt impact using P188 surfactant and a preliminary investigation of its long-term efficacy. J Orthop Res. 2010;28(4):553–8.

    PubMed  Google Scholar 

  25. Phillips DM, Haut RC. The use of a non-ionic surfactant (P188) to save chondrocytes from necrosis following impact loading of chondral explants. J Orthop Res. 2004;22(5):1135–42.

    Article  CAS  PubMed  Google Scholar 

  26. Evans CH, Ghivizzani SC, Robbins PD. Orthopedic gene therapy in 2008. Mol Ther. 2009;17(2):231–44.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Lotz MK, Kraus VB. New developments in osteoarthritis. Posttraumatic osteoarthritis: pathogenesis and pharmacological treatment options. Arthritis Res Ther. 2010;12(3):211.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Frisbie DD, Ghivizzani SC, Robbins PD, Evans CH, McIlwraith CW. Treatment of experimental equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor antagonist gene. Gene Ther. 2002;9(1):12–20.

    Article  CAS  PubMed  Google Scholar 

  29. Fox BA, Stephens MM. Treatment of knee osteoarthritis with Orthokine-derived autologous conditioned serum. Expert Rev Clin Immunol. 2010;6(3):335–45.

    Article  CAS  PubMed  Google Scholar 

  30. 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 tumor necrosis factor alpha on chondroprotection in an animal model. Arthritis Rheum. 2009;60(10):2997–3006.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Forterre S, Zurbriggen A, Spreng D. Nitric oxide induces cell death in canine cruciate ligament cells by activation of tyrosine kinase and reactive oxygen species. BMC Vet Res. 2012;8:40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. More AS, Kumari RR, Gupta G, Lingaraju MC, Balaganur V, Pathak NN, et al. Effect of iNOS inhibitor S-methylisothiourea in monosodium iodoacetate-induced osteoathritic pain: implication for osteoarthritis therapy. Pharmacol Biochem Behav. 2013;103(4):764–72.

    Article  CAS  PubMed  Google Scholar 

  33. Little CB, Barai A, Burkhardt D, Smith SM, Fosang AJ, Werb Z, et al. Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum. 2009;60(12):3723–33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Johnson AR, Pavlovsky AG, Ortwine DF, Prior F, Man CF, Bornemeier DA, et al. Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 that reduces cartilage damage in vivo without joint fibroplasia side effects. J Biol Chem. 2007;282(38):27781–91.

    Article  CAS  PubMed  Google Scholar 

  35. Fortier LA, Barker JU, Strauss EJ, McCarrel TM, Cole BJ. The role of growth factors in cartilage repair. Clin Orthop Relat Res. 2011;469(10):2706–15.

    Article  PubMed Central  PubMed  Google Scholar 

  36. Chubinskaya S, Hurtig M, Rueger DC. OP-1/BMP-7 in cartilage repair. Int Orthop. 2007;31(6):773–81.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Badlani N, Inoue A, Healey R, Coutts R, Amiel D. The protective effect of OP-1 on articular cartilage in the development of osteoarthritis. Osteoarthritis Cartilage. 2008;16(5):600–6.

    Article  CAS  PubMed  Google Scholar 

  38. Hayashi M, Muneta T, Ju YJ, Mochizuki T, Sekiya I. Weekly intra-articular injections of bone morphogenetic protein-7 inhibits osteoarthritis progression. Arthritis Res Ther. 2008;10(5):R118.

    Article  PubMed Central  PubMed  Google Scholar 

  39. Chubinskaya S, Otten L, Soeder S, Borgia JA, Aigner T, Rueger DC, et al. Regulation of chondrocyte gene expression by osteogenic protein-1. Arthritis Res Ther. 2011;13(2):R55.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Im HJ, Pacione C, Chubinskaya S, Van Wijnen AJ, Sun Y, Loeser RF. Inhibitory effects of insulin-like growth factor-1 and osteogenic protein-1 on fibronectin fragment- and interleukin-1beta-stimulated matrix metalloproteinase-13 expression in human chondrocytes. J Biol Chem. 2003;278(28):25386–94.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Hurtig M, Chubinskaya S, Dickey J, Rueger D. BMP-7 protects against progression of cartilage degeneration after impact injury. J Orthop Res. 2009;27(5):602–11.

    Article  CAS  PubMed  Google Scholar 

  42. Hunter DJ, Pike MC, Jonas BL, Kissin E, Krop J, McAlindon T. Phase 1 safety and tolerability study of BMP-7 in symptomatic knee osteoarthritis. BMC Musculoskelet Disord. 2010;11:232.

    Article  PubMed Central  PubMed  Google Scholar 

  43. Ellman MB, An HS, Muddasani P, Im HJ. Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis. Gene. 2008;420(1):82–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Moore EE, Bendele AM, Thompson DL, Littau A, Waggie KS, Reardon B, et al. Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis. Osteoarthritis Cartilage. 2005;13(7):623–31.

    Article  CAS  PubMed  Google Scholar 

  45. Ellsworth JL, Berry J, Bukowski T, Claus J, Feldhaus A, Holderman S, et al. Fibroblast growth factor-18 is a trophic factor for mature chondrocytes and their progenitors. Osteoarthritis Cartilage. 2002;10(4):308–20.

    Article  CAS  PubMed  Google Scholar 

  46. Moran CJ, Barry FP, Maher SA, Shannon FJ, Rodeo SA. Advancing regenerative surgery in orthopaedic sports medicine: the critical role of the surgeon. Am J Sports Med. 2012;40(4):934–44.

    Article  PubMed  Google Scholar 

  47. Akeda K, An HS, Okuma M, Attawia M, Miyamoto K, Thonar EJ, et al. Platelet-rich plasma stimulates porcine articular chondrocyte proliferation and matrix biosynthesis. Osteoarthritis Cartilage. 2006;14(12):1272–80.

    Article  CAS  PubMed  Google Scholar 

  48. Anitua E, Sanchez M, Nurden AT, Zalduendo MM, de la Fuente M, Azofra J, et al. Platelet-released growth factors enhance the secretion of hyaluronic acid and induce hepatocyte growth factor production by synovial fibroblasts from arthritic patients. Rheumatology (Oxford). 2007;46(12):1769–72.

    Article  CAS  Google Scholar 

  49. Sun Y, Feng Y, Zhang CQ, Chen SB, Cheng XG. The regenerative effect of platelet-rich plasma on healing in large osteochondral defects. Int Orthop. 2010;34(4):589–97.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Sanchez M, Fiz N, Azofra J, Usabiaga J, Aduriz Recalde E, Garcia Gutierrez A, et al. A randomized clinical trial evaluating plasma rich in growth factors (PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis. Arthroscopy. 2012;28(8):1070–8.

    Article  PubMed  Google Scholar 

  51. Gobbi A, Karnatzikos G, Mahajan V, Malchira S. Platelet-rich plasma treatment in symptomatic patients with knee osteoarthritis: preliminary results in a group of active patients. Sports Health. 2012;4(2):162–72.

    Article  PubMed Central  PubMed  Google Scholar 

  52. Mei-Dan O, Carmont MR, Laver L, Mann G, Maffulli N, Nyska M. Platelet-rich plasma or hyaluronate in the management of osteochondral lesions of the talus. Am J Sports Med. 2012;40(3):534–41.

    Article  PubMed  Google Scholar 

  53. Wang Y, Hodge AM, Wluka AE, English DR, Giles GG, O’Sullivan R, et al. Effect of antioxidants on knee cartilage and bone in healthy, middle-aged subjects: a cross-sectional study. Arthritis Res Ther. 2007;9(4):R66.

    Article  PubMed Central  PubMed  Google Scholar 

  54. Wluka AE, Stuckey S, Brand C, Cicuttini FM. Supplementary vitamin E does not affect the loss of cartilage volume in knee osteoarthritis: a 2 year double blind randomized placebo controlled study. J Rheumatol. 2002;29(12):2585–91.

    CAS  PubMed  Google Scholar 

  55. Hellio le Graverand MP, Clemmer RS, Redifer P, Brunell RM, Hayes CW, Brandt KD, et al. A 2-year randomised, double-blind, placebo-controlled, multicentre study of oral selective iNOS inhibitor, cindunistat (SD-6010), in patients with symptomatic osteoarthritis of the knee. Ann Rheum Dis. 2013;72(2):187–95.

    Article  PubMed  Google Scholar 

  56. Kraus VB, Birmingham J, Stabler TV, Feng S, Taylor DC, Moorman III CT, et al. Effects of intraarticular IL1-Ra for acute anterior cruciate ligament knee injury: a randomized controlled pilot trial (NCT00332254). Osteoarthritis Cartilage. 2012;20(4):271–8.

    Article  CAS  PubMed  Google Scholar 

  57. Yang KG, Raijmakers NJ, van Arkel ER, Caron JJ, Rijk PC, Willems WJ, et al. Autologous interleukin-1 receptor antagonist improves function and symptoms in osteoarthritis when compared to placebo in a prospective randomized controlled trial. Osteoarthritis Cartilage. 2008;16(4):498–505.

    Article  Google Scholar 

  58. Brown C, Toth A, Magnussen R. Clinical benefits of intra-articular anakinra for persistent knee effusion. J Knee Surg. 2011;24(1):61–5.

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors would like to acknowledge Dr. Arkady Margulis for tissue procurement and Dr. Lev Rappoport, Mrs. Arnavaz Hakimiyan and Carol Pacione for their technical assistance. The authors also would like to acknowledge the Gift of Hope Organ & Tissue Donor Network and donor’s families. The work was supported in part by the National Football League Foundation grant and the Ciba-Geigy Endowed Chair, Rush University Medical Center (SC).

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Correspondence to Susan Chubinskaya Ph.D. .

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Pascual-Garrido, C., Chubinskaya, S. (2015). Potential Targets for Pharmacologic Therapies for Prevention of PTA. In: Olson, MD, S., Guilak, PhD, F. (eds) Post-Traumatic Arthritis. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-7606-2_26

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  • DOI: https://doi.org/10.1007/978-1-4899-7606-2_26

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