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Increased levels of apoptosis and p53 in partial-thickness supraspinatus tendon tears

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Knee Surgery, Sports Traumatology, Arthroscopy Aims and scope

Abstract

Purpose

The role of apoptosis in the progression of rotator cuff tendinopathy remains poorly understood. In particular, the extent of apoptosis in the partially torn supraspinatus tendon has not been well examined.

Methods

Biopsies were obtained from nine partially torn supraspinatus tendons, from the matched intact subscapularis tendons, and from 10 reference subscapularis tendons. Immunohistochemistry was used to assess the density of apoptotic cells (activated caspase-3; Asp175), proliferation (Ki67), and p53 (M7001), a key protein involved in regulating cell death. The Bonar scale was used to evaluate tendon degeneration.

Results

The density of apoptotic tendon cells and the density of cells expressing p53 were significantly increased in both the partially torn supraspinatus tendons and in the matched subscapularis tendons, compared with uninjured reference tendons. The Bonar score revealed significant tendon degeneration in the partially torn supraspinatus tendons compared with both matched and reference subscapularis tendons. Tendon cell proliferation was significantly increased in the partially torn supraspinatus tendons compared with reference subscapularis tendons.

Conclusions

Partial-thickness tears of the supraspinatus tendon demonstrated an increased density of apoptotic, p53+ tendon cells. The fact that apoptosis was accompanied by increased tendon cell proliferation suggests that apoptosis may be related to an ongoing injury-repair process. Increased tenocyte apoptosis may be a relatively early feature in rotator cuff tendinopathy and could represent a possible target for therapeutic intervention.

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References

  1. Amin AR, Abramson SB (1998) The role of nitric oxide in articular cartilage breakdown in osteoarthritis. Curr Opin Rheumatol 10:263–268

    Article  PubMed  CAS  Google Scholar 

  2. Barkhausen T, van Griensven M, Zeichen J et al (2003) Modulation of cell functions of human tendon fibroblasts by different repetitive cyclic mechanical stress patterns. Exp Toxicol Pathol 55:153–158

    Article  PubMed  Google Scholar 

  3. Benson RT, McDonnell SM, Knowles HJ et al (2010) Tendinopathy and tears of the rotator cuff are associated with hypoxia and apoptosis. J Bone Joint Surg Br 92:448–453

    Article  PubMed  CAS  Google Scholar 

  4. Blankenberg FG (2008) In vivo imaging of apoptosis. Cancer Biol Ther 7:1525–1532

    Article  PubMed  CAS  Google Scholar 

  5. Chen J, Wang A, Xu J et al (2010) In chronic lateral epicondylitis, apoptosis and autophagic cell death occur in the extensor carpi radialis brevis tendon. J Should Elbow Surg 19:355–362

    Article  Google Scholar 

  6. Chikanza I, Fernandes L (2000) Novel strategies for the treatment of osteoarthritis. Expert Opin Investig Drugs 9:1499–1510

    Article  PubMed  CAS  Google Scholar 

  7. Chuen FS, Chuk CY, Ping WY et al (2004) Immunohistochemical characterization of cells in adult human patellar tendons. J Histochem Cytochem 52:1151–1157

    Article  PubMed  CAS  Google Scholar 

  8. Cook JL, Feller JA, Bonar SF et al (2004) Abnormal tenocyte morphology is more prevalent than collagen disruption in asymptomatic athletes’ patellar tendons. J Orthop Res 22:334–338

    Article  PubMed  CAS  Google Scholar 

  9. Egerbacher M, Arnoczky SP, Caballero O et al (2008) Loss of homeostatic tension induces apoptosis in tendon cells: an in vitro study. Clin Orthop Relat Res 466:1562–1568

    Article  PubMed  Google Scholar 

  10. Ivkovic A, Marijanovic I, Hudetz D et al (2011) Regenerative medicine and tissue engineering in orthopaedic surgery. Front Biosci (Elite Ed) 3:923–944

    Google Scholar 

  11. Jellinger KA, Bancher C (1998) Neuropathology of Alzheimer’s disease: a critical update. J Neural Transm Suppl 54:77–95

    Article  PubMed  CAS  Google Scholar 

  12. Li G, White G, Connolly C et al (2002) Cell proliferation and apoptosis during fracture healing. J Bone Miner Res 17:791–799

    Article  PubMed  Google Scholar 

  13. Lian O, Scott A, Engebretsen L et al (2007) Excessive apoptosis in patellar tendinopathy in athletes. Am J Sports Med 35:605–611

    Article  PubMed  Google Scholar 

  14. Lotz M, Hashimoto S, Kuhn K (1999) Mechanisms of chondrocyte apoptosis. Osteoarthr Cartil 7:389–391

    Article  PubMed  CAS  Google Scholar 

  15. Lui PP, Cheuk YC, Hung LK et al (2007) Increased apoptosis at the late stage of tendon healing. Wound Repair Regen 15:702–707

    Article  PubMed  Google Scholar 

  16. Lundgreen K, Lian OB, Engebretsen L et al (2011) Tenocyte apoptosis in the torn rotator cuff: a primary or secondary pathological event? Br J Sports Med 45:1035–1039

    Article  PubMed  Google Scholar 

  17. Maffulli N, Longo UG, Franceschi F et al (2008) Movin and Bonar scores assess the same characteristics of tendon histology. Clin Orthop Relat Res 466:1605–1611

    Article  PubMed  Google Scholar 

  18. Majewski M, Porter RM, Betz OB et al (2012) Improvement of tendon repair using muscle grafts transduced with TGF–beta1 cDNA. Eur Cell Mater 23:94–102

    PubMed  CAS  Google Scholar 

  19. Mall NA, Kim HM, Keener JD et al (2010) Symptomatic progression of asymptomatic rotator cuff tears: a prospective study of clinical and sonographic variables. J Bone Joint Surg Am 92:2623–2633

    Article  PubMed  Google Scholar 

  20. Millar NL, Hueber AJ, Reilly JH et al (2010) Inflammation is present in early human tendinopathy. Am J Sports Med 38:2085–2091

    Article  PubMed  Google Scholar 

  21. Millar NL, Reilly JH, Kerr SC et al (2012) Hypoxia: a critical regulator of early human tendinopathy. Ann Rheum Dis 71:302–310

    Article  PubMed  CAS  Google Scholar 

  22. Millar NL, Wei AQ, Molloy TJ et al (2008) Heat shock protein and apoptosis in supraspinatus tendinopathy. Clin Orthop Relat Res 466:1569–1576

    Article  PubMed  Google Scholar 

  23. Millar NL, Wei AQ, Molloy TJ et al (2009) Cytokines and apoptosis in supraspinatus tendinopathy. J Bone Joint Surg Br 91:417–424

    PubMed  CAS  Google Scholar 

  24. Osawa T, Shinozaki T, Takagishi K (2005) Multivariate analysis of biochemical markers in synovial fluid from the shoulder joint for diagnosis of rotator cuff tears. Rheumatol Int 25:436–441

    Article  PubMed  CAS  Google Scholar 

  25. Pearce CJ, Ismail M, Calder JD (2009) Is apoptosis the cause of noninsertional achilles tendinopathy? Am J Sports Med 37:2440–2444

    Article  PubMed  Google Scholar 

  26. Poulsen RC, Carr AJ, Hulley PA (2011) Protection against glucocorticoid-induced damage in human tenocytes by modulation of ERK, Akt, and forkhead signaling. Endocrinology 152:503–514

    Article  PubMed  CAS  Google Scholar 

  27. Reilly P, Macleod I, Macfarlane R et al (2006) Dead men and radiologists don’t lie: a review of cadaveric and radiological studies of rotator cuff tear prevalence. Ann R Coll Surg Engl 88:116–121

    Article  PubMed  CAS  Google Scholar 

  28. Scott A, Khan KM, Duronio V (2005) IGF-I activates PKB and prevents anoxic apoptosis in Achilles tendon cells. J Orthop Res 23:1219–1225

    Article  PubMed  CAS  Google Scholar 

  29. Scott A, Khan KM, Heer J et al (2005) High strain mechanical loading rapidly induces tendon apoptosis: an ex vivo rat tibialis anterior model. Br J Sports Med 39:e25

    Article  PubMed  CAS  Google Scholar 

  30. Shindle MK, Chen CC, Robertson C et al (2011) Full-thickness supraspinatus tears are associated with more synovial inflammation and tissue degeneration than partial-thickness tears. J Should Elbow Surg 20:917–927

    Article  Google Scholar 

  31. Tuoheti Y, Itoi E, Pradhan RL et al (2005) Apoptosis in the supraspinatus tendon with stage II subacromial impingement. J Should Elbow Surg 14:535–541

    Article  Google Scholar 

  32. Unglaub F, Thomas SB, Kroeber MW et al (2009) Apoptotic pathways in degenerative disk lesions in the wrist. Arthroscopy 25:1380–1386

    Article  PubMed  Google Scholar 

  33. Visser LC, Arnoczky SP, Caballero O et al (2010) Platelet-rich fibrin constructs elute higher concentrations of transforming growth factor-beta1 and increase tendon cell proliferation over time when compared to blood clots: a comparative in vitro analysis. Vet Surg 39:811–817

    Article  PubMed  Google Scholar 

  34. Visser LC, Arnoczky SP, Caballero O et al (2011) Evaluation of the use of an autologous platelet-rich fibrin membrane to enhance tendon healing in dogs. Am J Vet Res 72:699–705

    Article  PubMed  Google Scholar 

  35. Wu B, Chen J, Rosa TD et al (2011) Cellular response and extracellular matrix breakdown in rotator cuff tendon rupture. Arch Orthop Trauma Surg 131:405–411

    Article  PubMed  Google Scholar 

  36. Wu YF, Chen CH, Cao Y et al (2010) Molecular events of cellular apoptosis and proliferation in the early tendon healing period. J Hand Surg Am 35:2–10

    Article  PubMed  CAS  Google Scholar 

  37. Wu YF, Zhou YL, Mao WF et al (2012) Cellular apoptosis and proliferation in the middle and late intrasynovial tendon healing periods. J Hand Surg Am 37:209–216

    Article  PubMed  Google Scholar 

  38. Xu Y, Bonar F, Murrell GA (2011) Neoinnervation in rotator cuff tendinopathy. Sports Med Arthrosc 19:354–359

    Article  PubMed  Google Scholar 

  39. Yamaguchi K, Tetro AM, Blam O et al (2001) Natural history of asymptomatic rotator cuff tears: a longitudinal analysis of asymptomatic tears detected sonographically. J Should Elbow Surg 10:199–203

    Article  CAS  Google Scholar 

  40. Yamanaka K, Matsumoto T (1994) The joint side tear of the rotator cuff. A followup study by arthrography. Clin Orthop Relat Res 304:68–73

    Google Scholar 

  41. Yuan J, Murrell GA, Wei AQ et al (2002) Apoptosis in rotator cuff tendonopathy. J Orthop Res 20:1372–1379

    Article  PubMed  Google Scholar 

  42. Yuan J, Wang MX, Murrell GA (2003) Cell death and tendinopathy. Clin Sports Med 22:693–701

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Mrs Ingeborg Løstegaard Goverud and Gloria Fong for excellent technical service. The research was funded by a Research at Work grant from the WorksafeBC research secretariat and a grant from the South-Eastern Regional Health Authority in Norway through the Osteoarthritis Research Group.

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Authors and Affiliations

  1. Department of Orthopaedics, Lovisenberg Deaconal Hospital, Oslo Sports Trauma Research Center , Lovisenberggata 17, 0456, Oslo, Norway

    Kirsten Lundgreen

  2. Kristiansund Hospital, Kristiansund, Norway

    Øystein Lian

  3. Department of Physical Therapy, University of British Columbia, Vancouver, BC, Canada

    Alex Scott

  4. Department of Orthopaedics, Oslo University Hospital, Oslo Sports Trauma Research Center, Oslo, Norway

    Lars Engebretsen

Authors
  1. Kirsten Lundgreen
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  2. Øystein Lian
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  3. Alex Scott
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  4. Lars Engebretsen
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Correspondence to Kirsten Lundgreen.

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Lundgreen, K., Lian, Ø., Scott, A. et al. Increased levels of apoptosis and p53 in partial-thickness supraspinatus tendon tears. Knee Surg Sports Traumatol Arthrosc 21, 1636–1641 (2013). https://doi.org/10.1007/s00167-012-2226-9

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  • DOI: https://doi.org/10.1007/s00167-012-2226-9

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