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Cathepsins in Rotator Cuff Tendinopathy: Identification in Human Chronic Tears and Temporal Induction in a Rat Model

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Abstract

While overuse of the supraspinatus tendon is a leading factor in rotator cuff injury, the underlying biochemical changes have not been fully elucidated. In this study, torn human rotator cuff (supraspinatus) tendon tissue was analyzed for the presence of active cathepsin proteases with multiplex cysteine cathepsin zymography. In addition, an overuse injury to supraspinatus tendons was induced through downhill running in an established rat model. Histological analysis demonstrated that structural damage occurred by 8 weeks of overuse compared to control rats in the region of tendon insertion into bone. In both 4- and 8-week overuse groups, via zymography, there was approximately a 180% increase in cathepsin L activity at the insertion region compared to the controls, while no difference was found in the midsubstance area. Additionally, an over 400% increase in cathepsin K activity was observed for the insertion region of the 4-week overused tendons. More cathepsin K and L immunostaining was observed at the insertion region of the overuse groups compared to controls. These results provide important information on a yet unexplored mechanism for tendon degeneration that may operate alone or in conjunction with other proteases to contribute to chronic tendinopathy.

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Abbreviations

MMP:

Matrix metalloproteinase

OCT:

Optimum cutting temperature

H&E:

Hematoxylin and eosin

SDS:

Sodium dodecyl sulfate

References

  1. Archambault, J. M., S. A. Jelinsky, S. P. Lake, et al. Rat supraspinatus tendon expresses cartilage markers with overuse. J. Orthop. Res. 25(5):617–624, 2007.

    Article  CAS  PubMed  Google Scholar 

  2. Attia, M., A. Scott, A. Duchesnay, et al. Alterations of overused supraspinatus tendon: a possible role of glycosaminoglycans and HARP/pleiotrophin in early tendon pathology. J. Orthop. Res. 30(1):61–71, 2011.

    Article  PubMed  Google Scholar 

  3. Attia, M., E. Huet, C. Gossard, et al. Early events of overused supraspinatus tendons involve matrix metalloproteinases and EMMPRIN/CD147 in the absence of inflammation. Am. J. Sports Med. 41(4):908–917, 2013.

    Article  PubMed  Google Scholar 

  4. Barbato, J. C., L. G. Koch, A. Darvish, et al. Spectrum of aerobic endurance running performance in eleven inbred strains of rats. J. Appl. Physiol. 85(2):530–536, 1998.

    CAS  PubMed  Google Scholar 

  5. Benjamin, M., H. Toumi, J. R. Ralphs, et al. Where tendons and ligaments meet bone: attachment sites (‘entheses’) in relation to exercise and/or mechanical load. J. Anat. 208(4):471–490, 2006.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Berglund, M. E., D. A. Hart, C. Reno, and M. Wiig. Growth factor and protease expression during different phases of healing after rabbit deep flexor tendon repair. J. Orthop. Res. 29(6):886–892, 2011.

    Article  CAS  PubMed  Google Scholar 

  7. Blevins, F. T. Rotator cuff pathology in athletes. Sports Med. 24(3):205–220, 1997.

    Article  CAS  PubMed  Google Scholar 

  8. Boileau, P., N. Brassart, D. J. Watkinson, et al. Arthroscopic repair of full-thickness tears of the supraspinatus: does the tendon really heal? J. Bone Joint Surg. Am. 87(6):1229–1240, 2005.

    Article  PubMed  Google Scholar 

  9. Bromme, D., and F. Lecaille. Cathepsin K inhibitors for osteoporosis and potential off-target effects. Expert Opin. Investig. Drugs 18(5):585–600, 2009.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Bromme, D., Z. Li, M. Barnes, and E. Mehler. Human cathepsin V functional expression, tissue distribution, electrostatic surface potential, enzymatic characterization, and chromosomal localization. Biochemistry 38(8):2377–2385, 1999.

    Article  CAS  PubMed  Google Scholar 

  11. Cook, J. L., J. A. Feller, S. F. Bonar, and K. M. Khan. Abnormal tenocyte morphology is more prevalent than collagen disruption in asymptomatic athletes’ patellar tendons. J. Orthop. Res. 22(2):334–338, 2004.

    Article  CAS  PubMed  Google Scholar 

  12. Cunnane, G., O. FitzGerald, K. M. Hummel, et al. Collagenase, cathepsin B and cathepsin L gene expression in the synovial membrane of patients with early inflammatory arthritis. Rheumatology 38(1):34–42, 1999.

    Article  CAS  PubMed  Google Scholar 

  13. Dejica, V. M., J. S. Mort, S. Laverty, et al. Cleavage of type II collagen by cathepsin K in human osteoarthritic cartilage. Am. J. Pathol. 173(1):161–169, 2008.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Deval, C., S. Mordier, C. Obled, et al. Identification of cathepsin L as a differentially expressed message associated with skeletal muscle wasting. Biochem. J. 360(Pt 1):143, 2001.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Eeckhout, Y., and G. Vaes. Further studies on the activation of procollagenase, the latent precursor of bone collagenase. Effects of lysosomal cathepsin B, plasmin and kallikrein, and spontaneous activation. Biochem. J. 166(1):21–31, 1977.

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Fu, S. C., B. P. Chan, W. Wang, et al. Increased expression of matrix metalloproteinase 1 (MMP1) in 11 patients with patellar tendinosis. Acta Orthop. Scand. 73(6):658–662, 2002.

    PubMed  Google Scholar 

  17. Garnero, P., O. Borel, I. Byrjalsen, et al. The collagenolytic activity of cathepsin K is unique among mammalian proteinases. J. Biol. Chem. 273(48):32347–32352, 1998.

    Article  CAS  PubMed  Google Scholar 

  18. Gimbel, J. A., J. P. Van Kleunen, S. Mehta, et al. Supraspinatus tendon organizational and mechanical properties in a chronic rotator cuff tear animal model. J. Biomech. 37(5):739–749, 2004.

    Article  PubMed  Google Scholar 

  19. Goretzki, L., M. Schmitt, K. Mann, et al. Effective activation of the proenzyme form of the urokinase-type plasminogen activator (pro-uPA) by the cysteine protease cathepsin L. FEBS Lett. 297(1–2):112–118, 1992.

    Article  CAS  PubMed  Google Scholar 

  20. Gotoh, M., K. Hamada, H. Yamakawa, et al. Significance of granulation tissue in torn supraspinatus insertions: an immunohistochemical study with antibodies against interleukin-1β, cathepsin D, and matrix metalloprotease-1. J. Orthop. Res. 15(1):33–39, 1997.

    Article  CAS  PubMed  Google Scholar 

  21. Joshi, S. K., H. T. Kim, B. T. Feeley, and X. Liu. Differential ubiquitin-proteasome and autophagy signaling following rotator cuff tears and suprascapular nerve injury. J. Orthop. Res. 32(1):138–144, 2014.

    Article  CAS  PubMed  Google Scholar 

  22. Kannus, P., and L. Jozsa. Histopathological changes preceding spontaneous rupture of a tendon. A controlled study of 891 patients. J. Bone Joint Surg. Am. 73(10):1507–1525, 1991.

    CAS  PubMed  Google Scholar 

  23. Kirschke, H., B. Wiederanders, D. Bromme, and A. Rinne. Cathepsin S from bovine spleen. Purification, distribution, intracellular localization and action on proteins. Biochem. J. 264(2):467–473, 1989.

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Kozawa, E., Y. Nishida, X. W. Cheng, et al. Osteoarthritic change is delayed in a Ctsk-knockout mouse model of osteoarthritis. Arthritis Rheum. 64(2):454–464, 2012.

    Article  CAS  PubMed  Google Scholar 

  25. Li, W. A., Z. T. Barry, J. D. Cohen, et al. Detection of femtomole quantities of mature cathepsin K with zymography. Anal. Biochem. 401(1):91–98, 2010.

    Article  CAS  PubMed  Google Scholar 

  26. Lo, I. K. Y., L. L. Marchuk, R. Hollinshead, et al. Matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase mRNA levels are specifically altered in torn rotator cuff tendons. Am. J. Sport Med. 32(5):1223–1229, 2004.

    Article  Google Scholar 

  27. Maffulli, N., U. G. Longo, F. Franceschi, et al. Movin and Bonar scores assess the same characteristics of tendon histology. Clin. Orthop. Relat. Res. 466(7):1605–1611, 2008.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Maganaris, C. N., M. V. Narici, L. C. Almekinders, and N. Maffulli. Biomechanics and pathophysiology of overuse tendon injuries: ideas on insertional tendinopathy. Sports Med. 34(14):1005–1017, 2004.

    Article  PubMed  Google Scholar 

  29. Masarachia, P. J., B. L. Pennypacker, M. Pickarski, et al. Odanacatib reduces bone turnover and increases bone mass in the lumbar spine of skeletally mature ovariectomized rhesus monkeys. J. Bone Miner. Res. 27(3):509–523, 2012.

    Article  CAS  PubMed  Google Scholar 

  30. Millar, N. L., A. Q. Wei, T. J. Molloy, et al. Heat shock protein and apoptosis in supraspinatus tendinopathy. Clin. Orthop. Relat. Res. 466(7):1569–1576, 2008.

    Article  PubMed Central  PubMed  Google Scholar 

  31. Morko, J. P., M. Soderstrom, A. M. Saamanen, et al. Up regulation of cathepsin K expression in articular chondrocytes in a transgenic mouse model for osteoarthritis. Ann. Rheum. Dis. 63(6):649–655, 2004.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Morko, J., R. Kiviranta, K. Joronen, et al. Spontaneous development of synovitis and cartilage degeneration in transgenic mice overexpressing cathepsin K. Arthritis Rheum. 52(12):3713–3717, 2005.

    Article  CAS  PubMed  Google Scholar 

  33. Oliva, F., D. Barisani, A. Grasso, and N. Maffulli. Gene expression analysis in calcific tendinopathy of the rotator cuff. Eur. Cells Mater. 21:548–557, 2011.

    CAS  Google Scholar 

  34. Park, K. Y., W. A. Li, and M. O. Platt. Patient specific proteolytic activity of monocyte-derived macrophages and osteoclasts predicted with temporal kinase activation states during differentiation. Integr. Biol. (Camb.) 4(12):1459–1469, 2012.

    Article  CAS  Google Scholar 

  35. Patterson-Kane, J. C., A. M. Wilson, E. C. Firth, et al. Exercise-related alterations in crimp morphology in the central regions of superficial digital flexor tendons from young thoroughbreds: a controlled study. Equine Vet. J. 30(1):61–64, 1998.

    Article  CAS  PubMed  Google Scholar 

  36. Riley, G. P., R. L. Harrall, C. R. Constant, et al. Tendon degeneration and chronic shoulder pain: changes in the collagen composition of the human rotator cuff tendons in rotator cuff tendinitis. Ann. Rheum. Dis. 53(6):359–366, 1994.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Scott, A., J. L. Cook, D. A. Hart, et al. Tenocyte responses to mechanical loading in vivo: a role for local insulin-like growth factor 1 signaling in early tendinosis in rats. Arthritis Rheum. 56(3):871–881, 2007.

    Article  CAS  PubMed  Google Scholar 

  38. Sharma, P., and N. Maffulli. Tendon injury and tendinopathy: healing and repair. J. Bone Joint Surg. Am. 87(1):187–202, 2005.

    Article  PubMed  Google Scholar 

  39. Sher, J. S. Anatomy, biomechanics, and pathophysiology of rotator cuff disease. In: Disorders of the Shoulder: Diagnosis and Management, edited by J. P. Iannotti, and G. R. Williams. Philadelphia: Lippincott, Williams, and Wilkins, 1999, pp. 3–29.

    Google Scholar 

  40. Silverstein, B., E. Welp, N. Nelson, and J. Kalat. Claims incidence of work-related disorders of the upper extremities: washington state, 1987 through 1995. Am. J. Public Health 88(12):1827–1833, 1998.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Soslowsky, L. J., J. E. Carpenter, C. M. DeBano, et al. Development and use of an animal model for investigations on rotator cuff disease. J. Shoulder Elb. Surg. 5(5):383–392, 1996.

    Article  CAS  Google Scholar 

  42. Soslowsky, L. J., S. Thomopoulos, S. Tun, et al. Neer award 1999 Overuse activity injures the supraspinatus tendon in an animal model: a histologic and biomechanical study. J. Shoulder Elb. Surg. 9(2):79–84, 2000.

    Article  CAS  Google Scholar 

  43. Wilder, C. L., K. Y. Park, P. M. Keegan, and M. O. Platt. Manipulating substrate and pH in zymography protocols selectively distinguishes cathepsins K, L, S, and V activity in cells and tissues. Arch. Biochem. Biophys. 516(1):52–57, 2011.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The authors thank Jennifer Lei for assistance in animal studies, Meredith Fay and Ang (Kevin) Li for help in tissue processing, and Bernard Kippelen’s laboratory at Georgia Tech for use of the circular polarized microscope. This study was supported by a National Football League Charities Medical Grant, a Regenerative Engineering and Medicine Seed Grant (REM) from Georgia Tech and Emory University through the Atlanta Clinical & Translational Science Institute (Advancing Translational Sciences of the National Institutes of Health, UL1TR000454) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number R01AR063692. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. W.H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive, Atlanta, GA, 30332, USA

    Song P. Seto, Akia N. Parks, Yongzhi Qiu, Manu O. Platt & Johnna S. Temenoff

  2. McKay Orthopaedic Research Laboratory, University of Pennsylvania, 424 Stemmler Hall, Philadelphia, PA, 19104, USA

    Louis J. Soslowsky

  3. Department of Orthopaedics, Emory University, Atlanta, GA, 30329, USA

    Spero Karas

  4. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA, 30332, USA

    Manu O. Platt & Johnna S. Temenoff

  5. W.H. Coulter Department of Biomedical Engineering, Georgia Tech/Emory University, 315 Ferst Drive, Rm 2305, Atlanta, GA, 30332, USA

    Johnna S. Temenoff

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  1. Song P. Seto
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Correspondence to Johnna S. Temenoff.

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Associate Editor Michael S. Detamore oversaw the review of this article.

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Seto, S.P., Parks, A.N., Qiu, Y. et al. Cathepsins in Rotator Cuff Tendinopathy: Identification in Human Chronic Tears and Temporal Induction in a Rat Model. Ann Biomed Eng 43, 2036–2046 (2015). https://doi.org/10.1007/s10439-014-1245-8

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  • DOI: https://doi.org/10.1007/s10439-014-1245-8

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