Skip to main content
SpringerLink
Log in

Chondrocyte Apoptosis: Implications for Osteochondral Allograft Transplantation

  • Symposium: New Approaches to Allograft Transplantation
  • Published:
Clinical Orthopaedics and Related Research

Abstract

Osteochondral allograft transplantation is a useful technique to manage larger articular cartilage injuries. One factor that may compromise the effectiveness of this procedure is chondrocyte cell death that occurs during the storage, preparation, and implantation of the osteochondral grafts. Loss of viable chondrocytes may negatively affect osteochondral edge integration and long-term function. A better understanding of the mechanisms responsible for chondrocyte loss could lead to interventions designed to decrease cell death and improve results. Recent studies indicate that apoptosis, or programmed cell death, is responsible for much of the chondrocyte death associated with osteochondral allograft transplantation. Theoretically, some of these cells can be rescued by blocking important apoptotic mediators. We review the role of apoptosis in cartilage degeneration, focusing on apoptosis associated with osteochondral transplantation. We also review the pathways thought to be responsible for regulating chondrocyte apoptosis, as well as experiments testing inhibitors of the apoptotic pathway. These data suggest that key contributors to the apoptotic process can be manipulated to enhance chondrocyte survival. This knowledge may lead to better surgical outcomes for osteochondral transplantation.

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. 2A–C

Similar content being viewed by others

References

  1. Aigner T, Hemmel M, Neureiter D, Gebhard PM, Zeiler G, Kirchner T, McKenna L. Apoptotic cell death is not a widespread phenomenon in normal aging and osteoarthritis human articular knee cartilage: a study of proliferation, programmed cell death (apoptosis), and viability of chondrocytes in normal and osteoarthritic human knee cartilage. Arthritis Rheum. 2001;44:1304–1312.

    Article  PubMed  CAS  Google Scholar 

  2. Aizawa T, Kon T, Einhorn TA, Gerstenfeld LC. Induction of apoptosis in chondrocytes by tumor necrosis factor-alpha. J Orthop Res. 2001;19:785–96.

    Article  PubMed  CAS  Google Scholar 

  3. Asada S, Fukuda K, Nishisaka F, Matsukawa M, Hamanisi C. Hydrogen peroxide induces apoptosis of chondrocytes; involvement of calcium ion and extracellular signal-regulated protein kinase. Inflamm Res. 2001;50:19–23.

    Article  PubMed  CAS  Google Scholar 

  4. Baars DC, Rundell SA, Haut RC. Treatment with the non-ionic surfactant poloxamer P188 reduces DNA fragmentation in cells from bovine chondral explants exposed to injurious unconfined compression. Biomechan Model Mechanbiol. 2006;5:133–139.

    Article  CAS  Google Scholar 

  5. Ball ST, Amiel D, Williams SK, Tontz W, Chen AC, Sah RL, Bugbee WD. The effects of storage on fresh human osteochondral allografts. Clin Orthop Relat Res. 2004;418:246–252.

    Article  PubMed  Google Scholar 

  6. Blanco FJ, Ochs RL, Schwarz H, Lotz M. Chondrocyte apoptosis induced by nitric oxide. Am J Pathol. 1995;146:75–85.

    PubMed  CAS  Google Scholar 

  7. Blanco FJ, Guitian R, Vázquez-Martul E, de Toro FJ, Galdo F. Osteoarthritis chondrocytes die by apoptosis. A possible pathway for osteoarthritis pathology. Arthritis Rheum. 1998;41:284–289.

    Article  PubMed  CAS  Google Scholar 

  8. Borazjani BH, Chen AC, Bae WC, Patil S, Sah RL, Firestein GS, Bugbee WD. Effect of impact on chondrocyte viability during insertion of human osteochondral grafts. J Bone Joint Surg Am. 2006;88:1934–1943.

    Article  PubMed  Google Scholar 

  9. Cao L, Lee V, Adams ME, Kiani C, Zhang Y, Hu W, Yang BB. Beta-integrin-collagen interaction reduces chondrocyte apoptosis. Matrix Biol. 1999;18:343–355.

    Article  PubMed  CAS  Google Scholar 

  10. Cao L, Yang BB. Chondrocyte apoptosis induced by aggrecan G1 domain as a result of decreased cell adhesion. Exp Cell Res. 1999;246:527–537.

    Article  PubMed  CAS  Google Scholar 

  11. Costouros JG, Dang AC, Kim HT. Inhibition of chondrocyte apoptosis in vivo following osteochondral injury. Osteoarthritis Cartilage. 2003;11:756–759.

    Article  PubMed  CAS  Google Scholar 

  12. Costouros JG, Dang AC, Kim HT. Comparison of chondrocyte apoptosis in vivo and in vitro following acute osteochondral injury. J Orthop Res. 2004;22:678–683.

    Article  PubMed  Google Scholar 

  13. Dang AC, Warren A, Kim HT. Beneficial effects of intra-articular caspase inhibition therapy following osteochondral injury. Osteoarthritis Cartilage. 2006;14:526–532.

    Article  PubMed  CAS  Google Scholar 

  14. D’Lima DD, Hashimoto S, Chen PC, Colwell CW Jr, Lotz MK. Human chondrocyte apoptosis in response to mechanical injury. Osteoarthritis Cartilage. 2001;9:712–719.

    Article  PubMed  CAS  Google Scholar 

  15. D’Lima DD, Hashimoto S, Chen PC, Lotz MK, Colwell CW Jr. In vitro and in vivo models of cartilage injury. J Bone Joint Surg Am. 2001;83(Suppl 2 Pt 1):22–24.

    PubMed  Google Scholar 

  16. D’Lima DD, Hashimoto S, Chen PC, Lotz MK, Colwell CW Jr. Prevention of chondrocyte apoptosis. J Bone Joint Surg Am. 2001;83(Suppl 2 Pt 1):25–26.

    PubMed  Google Scholar 

  17. D’Lima D, Hermida J, Hashimoto S, Colwell C, Lotz M. Caspase inhibitors reduce severity of cartilage lesions in experimental osteoarthritis. Arthritis Rheum. 2006;54:1814–1821.

    Article  PubMed  CAS  Google Scholar 

  18. Evans PJ, Miniaci A, Hurtig MB. Manual punch versus power harvesting of osteochondral grafts. Arthroscopy. 2004;20:306–310.

    Article  PubMed  Google Scholar 

  19. Frankfurt OS, Krishan A. Identification of apoptotic cells by formamide-induced DNA denaturation in condensed chromatin. J Histochem Cytochem. 2001;49:369–378.

    PubMed  CAS  Google Scholar 

  20. Green DM, Noble PC, Ahuero JS, Birdsall HH. Cellular events leading to chondrocyte death after cartilage impact injury. Arthritis Rheum. 2006;54:1509–1517.

    Article  PubMed  CAS  Google Scholar 

  21. Gross AE, Shasha N, Aubin P. Long-term followup of the use of fresh osteochondral allografts for posttraumatic knee defects. Clin Orthop Relat Res. 2005;435:79–87.

    Article  PubMed  Google Scholar 

  22. Hashimoto S, Ochs RL, Komiya S, Lotz M. Linkage of chondrocyte apoptosis and cartilage degradation in human osteoarthritis. Arthritis Rheum. 1998;41:1632–1638.

    Article  PubMed  CAS  Google Scholar 

  23. Hashimoto S, Takahashi K, Amiel D, Coutts RD, Lotz M. Chondrocyte apoptosis and nitric oxide production during experimentally induced osteoarthritis. Arthritis Rheum. 1998;417:1266–1274.

    Article  Google Scholar 

  24. Hirsch MS, Lunsford LE, Trinkaus-Randall V, Svoboda KK. Chondrocyte survival and differentiation in situ are integrin mediated. Dev Dyn. 1997;210:249–263.

    Article  PubMed  CAS  Google Scholar 

  25. Huntley JS, Bush PG, McBernie JM, Simpson AH, Hall AC. Chondrocyte death associate with femoral osteochondral harvest as performed for mosaicplasty. J Bone Joint Surg Am. 2005;87:351–360.

    Article  PubMed  CAS  Google Scholar 

  26. Islam N, Haqqi TM, Jepsen KJ, Kraay M, Welter JF, Goldberg VM, Malemud CJ. Hydrostatic pressure induces apoptosis in human chondrocytes from osteoarthritic cartilage through up-regulation of tumor necrosis factor-alpha, inducible nitric oxide synthase, p53, c-myc, and bax-alpha, and suppression of bcl-2. J Cell Biochem. 2002;87:266–278.

    Article  PubMed  CAS  Google Scholar 

  27. Jamali AA, Hatcher SL, You Z. Donor cell survival in a fresh osteochondral allograft at twenty-nine years. A case report. J Bone Joint Surg Am. 2007;89:166–169.

    Article  PubMed  Google Scholar 

  28. Kim HA, Lee YJ, Seong SC, Choe KW, Song YW. Apoptotic chondrocyte death in human osteoarthritis. J Rheumatol. 2000;27:455–462.

    PubMed  CAS  Google Scholar 

  29. Kim HT, Lo M, Pillarisetty R. Chondrocyte apoptosis following intra-articular fracture in humans. Osteoarthritis Cartilage. 2002;10:747–749.

    Article  PubMed  CAS  Google Scholar 

  30. Lee MS, Trindade MC, Ikenoue T, Goodman SB, Schurman DJ, Smith RL. Regulation of nitric oxide and bcl-2 expression by shear stress in human osteoarthritic chondrocytes in vitro. J Cell Biochem. 2003;90:80–86.

    Article  PubMed  CAS  Google Scholar 

  31. Lo MY, Kim HT. Chondrocyte apoptosis induced by collagen degradation: inhibition by caspase inhibitors and IGF-1. J Orthop Res. 2004;22:140–144.

    Article  PubMed  CAS  Google Scholar 

  32. Lo MY, Kim HT. Chondrocyte apoptosis induced by hydrogen peroxide requires caspase activation but not mitochondrial pore transition. J Orthop Res. 2004;22:1120–1125.

    Article  PubMed  CAS  Google Scholar 

  33. Majno G, Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol. 1995;146:3–15.

    PubMed  CAS  Google Scholar 

  34. Mankin HJ, Gebhardt MC, Jennings LC, Springfield DS, Tomford WW. Long-term results of allograft replacement in the management of bone tumors. Clin Orthop Relat Res. 1996;324:86–97.

    Article  PubMed  Google Scholar 

  35. Matsuo M., Nishida K, Yoshida A, Murakami T, Inoue H. Expression of caspase-3 and -9 relevant to cartilage destruction and chondrocyte apoptosis in human osteoarthritic cartilage. Acta Med Okayama. 2001;55:333–340.

    PubMed  CAS  Google Scholar 

  36. Maury AC, Safir O, Heras FL, Pritzker KP, Gross AE. Twenty-five-year chondrocyte viability in fresh osteochondral allograft. A case report. J Bone Joint Surg Am. 2007;89:159–165.

    Article  PubMed  CAS  Google Scholar 

  37. McCulloch PC, Kang RW, Sobhy MH, Hayden JK, Cole BJ. Prospective evaluation of prolonged fresh osteochondral allograft transplantation of the femoral condyle: minimum 2-year follow-up. Am J Sports Med. 2007;35:411–420.

    Article  PubMed  Google Scholar 

  38. Murray MM, Zurakowski D, Vrahas MS. The death of articular chondrocytes after intra-articular fracture in humans. J Trauma. 2004;56:128–131.

    Article  PubMed  Google Scholar 

  39. Nuttall ME, Nadeau DP, Fisher PW, Wang F, Keller PM, DeWolf WE Jr, Goldring MB, Badger AM, Lee D, Levy MA, Gowen M, Lark MW. Inhibition of caspase-3-like activity prevents apoptosis while retaining functionality of human chondrocytes in vitro. J Orthop Res. 2000;18:356–363.

    Article  PubMed  CAS  Google Scholar 

  40. Pelletier JP, Jovanovic DV, Lascau-Coman V, Fernandes JC, Manning PT, Connor JR, Currie MG, Martel-Pelletier J. 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;43:1290–1299.

    Article  PubMed  CAS  Google Scholar 

  41. Pelletier JP, Fernandes JC, Jovanovic DV, Reboul P, Martel-Pelletier J. Chondrocyte death in experimental osteoarthritis is mediated by MEK 1/2 and p38 pathways: role of cyclooxygenase-2 and inducible nitric oxide synthase. J Rheumatol. 2001;28:2509–2519.

    PubMed  CAS  Google Scholar 

  42. Robertson CM, Allen RT, Pennock AT, Bugbee WD, Amiel D. Upregulation of apoptotic and matrix-related gene expression during fresh osteochondral allograft storage. Clin Orthop Relat Res. 2006;442:260–266.

    Article  PubMed  Google Scholar 

  43. Serbest G, Horwitz J, Jost M, Barbee K. Mechanisms of cell death and neuroprotection by poloxamer 188 after mechanical trauma. FASEB J. 2006;20:308–310.

    PubMed  CAS  Google Scholar 

  44. Sharif M, Whitehouse A, Sharman P, Perry M, Adams M. Increased apoptosis in human osteoarthritic cartilage corresponds to reduced cell density and expression of caspase-3. Arthritis Rheum. 2004;50:507–515.

    Article  PubMed  CAS  Google Scholar 

  45. Stevenson S, Dannucci GA, Sharkey NA, Pool RR. The fate of articular cartilage after transplantation of fresh and cryopreserved tissue-antigen-matched and mismatched osteochondral allografts in dogs. J Bone Joint Surg Am. 1989;71:1297–1307.

    PubMed  CAS  Google Scholar 

  46. Tew SR, Kwan AP, Hann A, Thomson BM, Arcerh CW. The reactions of articular cartilage to experimental wounding: role of apoptosis. Arthritis Rheum. 2000;43:215–225.

    Article  PubMed  CAS  Google Scholar 

  47. Wasiak J, Clar C, Villanueva E. Autologous cartilage implantation for full thickness articular cartilage defects of the knee. Cochrane Database Syst Rev. 2006;3:CD005489.

    PubMed  CAS  Google Scholar 

  48. Williams RJ 3rd, Ranawat AS, Potter HG, Carter T, Warren RF. Fresh stored allografts for the treatment of osteochondral defects of the knee. J Bone Joint Surg Am. 2007;89:718–726.

    Article  PubMed  Google Scholar 

  49. Wyllie AH, Kerr JF, Currie AR. Cell death: the significance of apoptosis. Int Rev Cytol. 1980;68:251–306.

    Article  PubMed  CAS  Google Scholar 

  50. Zhang Z, McCaffery JM, Spencer RGS, Francomano CA. Growth and integration of neocartilage with native cartilage in vitor. J Orthop Res. 2005;23:433–439.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Orthopedic Surgery Section, San Francisco VA Medical Center, 4150 Clement Street (112), San Francisco, CA, 94121, USA

    Hubert T. Kim MD, PhD

  2. Stanford University School of Medicine, Stanford, CA, USA

    Margie S. Teng BS

  3. Department of Orthopedic Surgery, University of California, San Francisco, San Francisco, CA, USA

    Alexis C. Dang MD

Authors
  1. Hubert T. Kim MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Margie S. Teng BS
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexis C. Dang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hubert T. Kim MD, PhD.

Additional information

This research was performed at the San Francisco VA Medical Center.

One or more of the authors (HTK) has received funding from the Musculoskeletal Transplant Foundation, the Orthopaedic Research and Education Foundation, VA Medical Research, and the University of California, San Francisco.

Each author certifies that his or her institution has approved the animal protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.

About this article

Cite this article

Kim, H.T., Teng, M.S. & Dang, A.C. Chondrocyte Apoptosis: Implications for Osteochondral Allograft Transplantation. Clin Orthop Relat Res 466, 1819–1825 (2008). https://doi.org/10.1007/s11999-008-0304-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11999-008-0304-6

Keywords

Search

Navigation