Clinical Orthopaedics and Related Research®

, Volume 475, Issue 7, pp 1904–1910 | Cite as

Matrix Metalloproteases 1 and 3 Promoter Gene Polymorphism Is Associated With Rotator Cuff Tear

  • Jorge H. Assunção
  • Alexandre L. Godoy-Santos
  • Maria Cristina L. G. dos Santos
  • Eduardo A. Malavolta
  • Mauro E. C. Gracitelli
  • Arnaldo A. Ferreira Neto
Clinical Research

Abstract

Background

Studies suggest that the collagen degeneration and disordered arrangement of collagen fibers in rotator cuff tears are associated with an increase in activity of matrix metalloproteases 1 and 3 (MMP-1 and MMP-3), and that MMP activity may be in part genetically mediated. The degree to which this might be clinically relevant in patients with rotator cuff tears has not been well characterized.

Questions/purposes

(1) Is genetic polymorphism of MMP-1 and MMP-3 associated with rotator cuff tears? (2) Are there haplotypes of MMP-1 and MMP-3 correlated with rotator cuff tears? (3) Compared with control subjects, do patients with rotator cuff tears have a higher proportion of relatives with the same disease?

Methods

We evaluated 64 patients with full-thickness rotator cuff tears and 64 asymptomatic control subjects. Patients younger 65 years, with nontraumatic tears, were included. The tear or integrity of the rotator cuff tear was evaluated by MRI or ultrasonography in all individuals. The patients and control subjects were paired by age. MMP-1 and MMP-3 genotypes were determined using the PCR-restriction fragment length polymorphism assays.

Results

Genetic polymorphisms in MMP-1 and MMP-3 are associated with rotator cuff tear, in which individuals with rotator cuff tears have associated genotypes 1G/2G (patients, 32 of 64 [50%], control subjects, 16 of 64 [25%]; odds ratio [OR], 4.8; 95% CI, 2.1–11.0; p < 0.001) and 2G/2G were at great risk (patients, 15 of 64 [23%], control subjects, seven of 64 [11%]; OR, 5.2; 95% CI,1.8–14.9; p < 0.001), and patients with rotator cuff tears were associated with a higher proportion of 2G allele distribution (62 of 128 [48%] versus 30 of 128 [23%]; p < 0.001). Patients with the 5A/5A genotype are at greater risk of rotator cuff tear (patients, 15 of 64 [23%]; control subjects, four of 64 [6%]; OR, 5.5; 95% CI, 1.4–20.9; p = 0.021), and there was higher 5A allele distribution in patients with rotator cuff tears (patients, 68 of 128 [53%]; control subjects, 52 of 128 [41%]; p = 0.045). Individuals with the haplotype 2G/5A were more likely to have rotator cuff tears develop (patients, 42 of 64 [66%]; control subjects, 17 of 64 [27%]; OR, 5.3; 95% CI, 2.5-11.3; p < 0.001). Patients with rotator cuff tears reported, in higher number, the existence of relatives who previously had treatment for rotator cuff tears (19 of 64 [30%] versus four of 64 [6%]; OR, 6.3; 95% CI, 2.0-19.9; p = 0.001).

Conclusions

The genetic polymorphism of MMP-1 and MMP-3 is associated with rotator cuff tear. Individuals with haplotype 2G/5A were more susceptible to rotator cuff tears in the population studied.

Clinical Relevance

Knowledge of the genetic markers related to rotator cuff tears can enable identification of susceptible individuals and increase understanding of the pathogenesis of tendon degeneration.

Notes

Acknowledgments

Alberto Peters Bambirra MD, Ceci Obara Kurimori MD, and Marcelo Bordalo-Rodrigues PhD (all from the Department of Radiology, School of Medicine, University of São Paulo, São Paulo, Brazil), performed the MRI or ultrasonography examinations.

References

  1. 1.
    Abrams GD, Luria A, Carr RA, Rhodes C, Robinson WH, Sokolove J. Association of synovial inflammation and inflammatory mediators with glenohumeral rotator cuff pathology. J Shoulder Elbow Surg. 2016;25:989–997.CrossRefPubMedGoogle Scholar
  2. 2.
    Aidar M, Line SR. A simple and cost-effective protocol for DNA isolation from buccal epithelial cells. Braz Dent J. 2007;18:148–152.CrossRefPubMedGoogle Scholar
  3. 3.
    Bedi A, Kovacevic D, Hettrich C, Gulotta LV, Ehteshami JR, Warren RF, Rodeo SA. The effect of matrix metalloproteinase inhibition on tendon-to-bone healing in a rotator cuff repair model. J Shoulder Elbow Surg. 2010;19:384–391.CrossRefPubMedGoogle Scholar
  4. 4.
    Bishop JY, Santiago-Torres JE, Rimmke N, Flanigan DC. Smoking predisposes to rotator cuff pathology and shoulder dysfunction: a systematic review. Arthroscopy. 2015;31:1598–1605.CrossRefPubMedGoogle Scholar
  5. 5.
    Bodin J, Ha C, Petit Le Manac’h A, Sérazin C, Descatha A, Leclerc A, Goldberg M, Roquelaure Y. Risk factors for incidence of rotator cuff syndrome in a large working population. Scand J Work Environ Health. 2012;38:436–446.CrossRefPubMedGoogle Scholar
  6. 6.
    Castagna A, Cesari E, Gigante A, Conti M, Garofalo R. Metalloproteases and their inhibitors are altered in both torn and intact rotator cuff tendons. Musculoskelet Surg. 2013;97(suppl 1):39–47.CrossRefPubMedGoogle Scholar
  7. 7.
    DE Giorgi S, Saracino M, Castagna A. Degenerative disease in rotator cuff tears: what are the biochemical and histological changes? Joints. 2014;2:26–28.PubMedPubMedCentralGoogle Scholar
  8. 8.
    de Jesus JO, Parker L, Frangos AJ, Nazarian LN. Accuracy of MRI, MR arthrography, and ultrasound in the diagnosis of rotator cuff tears: a meta-analysis. AJR Am J Roentgenol. 2009;192:1701–1707.CrossRefPubMedGoogle Scholar
  9. 9.
    Del Buono A, Oliva F, Longo UG, Rodeo SA, Orchard J, Denaro V, Maffulli N. Metalloproteases and rotator cuff disease. J Shoulder Elbow Surg. 2012;21:200–208.CrossRefPubMedGoogle Scholar
  10. 10.
    Fox AJ, Schär MO, Wanivenhaus F, Chen T, Attia E, Binder NB, Otero M, Gilbert SL, Nguyen JT, Chaudhury S, Warren RF, Rodeo SA. Fluoroquinolones impair tendon healing in a rat rotator cuff repair model: a preliminary study. Am J Sports Med. 2014;42:2851–2859.CrossRefPubMedGoogle Scholar
  11. 11.
    Garofalo R, Cesari E, Vinci E, Castagna A. Role of metalloproteinases in rotator cuff tear. Sports Med Arthrosc. 2011;19:207–212.CrossRefPubMedGoogle Scholar
  12. 12.
    Godoy-Santos A, Cunha MV, Ortiz RT, Fernandes TD, Mattar R Jr, dos Santos MC. MMP-1 promoter polymorphism is associated with primary tendinopathy of the posterior tibial tendon. J Orthop Res. 2013;31:1103–1107.CrossRefPubMedGoogle Scholar
  13. 13.
    Gotoh M, Hamada K, Yamakawa H, Tomonaga A, Inoue A, Fukuda H. Significance of granulation tissue in torn supraspinatus insertions: an immunohistochemical study with antibodies against interleukin-1 beta, cathepsin D, and matrix metalloprotease-1. J Orthop Res. 1997;15:33–39.CrossRefPubMedGoogle Scholar
  14. 14.
    Gumina S, Arceri V, Carbone S, Albino P, Passaretti D, Campagna V, Fagnani C, Postacchini F. The association between arterial hypertension and rotator cuff tear: the influence on rotator cuff tear sizes. J Shoulder Elbow Surg. 2013;22:229–232.CrossRefPubMedGoogle Scholar
  15. 15.
    Gumina S, Candela V, Passaretti D, Latino G, Venditto T, Mariani L, Santilli V. The association between body fat and rotator cuff tear: the influence on rotator cuff tear sizes. J Shoulder Elbow Surg. 2014;23:1669-1674.CrossRefPubMedGoogle Scholar
  16. 16.
    Harvie P, Ostlere SJ, Teh J, McNally EG, Clipsham K, Burston BJ, Pollard TC, Carr AJ. Genetic influences in the aetiology of tears of the rotator cuff: sibling risk of a full-thickness tear. J Bone Joint Surg Br. 2004;86:696–700.CrossRefPubMedGoogle Scholar
  17. 17.
    Kluger R, Burgstaller J, Vogl C, Brem G, Skultety M, Mueller S. A candidate gene approach identifies six SNPs in tenascin-C (TNC) associated with degenerative rotator cuff tears. J Orthop Res. 2016 Jun 1. [Epub ahead of print] doi:  10.1002/jor.23321
  18. 18.
    Lakemeier S, Braun J, Efe T, Foelsch C, Archontidou-Aprin E, Fuchs-Winkelmann S, Paletta JR, Schofer MD. Expression of matrix metalloproteinases 1, 3, and 9 in differing extents of tendon retraction in the torn rotator cuff. Knee Surg Sports Traumatol Arthrosc. 2011;19:1760–1765.CrossRefPubMedGoogle Scholar
  19. 19.
    Lenza M, Buchbinder R, Takwoingi Y, Johnston RV, Hanchard NC, Faloppa F. Magnetic resonance imaging, magnetic resonance arthrography and ultrasonography for assessing rotator cuff tears in people with shoulder pain for whom surgery is being considered. Cochrane Database Syst Rev. 2013;9:CD009020. doi:  10.1002/14651858.
  20. 20.
    Longo UG, Berton A, Khan WS, Maffulli N, Denaro V. Histopathology of rotator cuff tears. Sports Med Arthrosc. 2011;19:227–236.CrossRefPubMedGoogle Scholar
  21. 21.
    Lu Z, Cao Y, Wang Y, Zhang Q, Zhang X, Wang S, Li Y, Xie H, Jiao B, Zhang J. Polymorphisms in the matrix metalloproteinase-1, 3, and 9 promoters and susceptibility to adult astrocytoma in northern China. J Neurooncol. 2007;85:65–73.CrossRefPubMedGoogle Scholar
  22. 22.
    Maffulli N, Longo UG, Berton A, Loppini M, Denaro V. Biological factors in the pathogenesis of rotator cuff tears. Sports Med Arthrosc. 2011;19:194–201.CrossRefPubMedGoogle Scholar
  23. 23.
    Mitchell C, Adebajo A, Hay E, Carr A. Shoulder pain: diagnosis and management in primary care. BMJ. 2005;331:1124–1128.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Motta Gda R, Amaral MV, Rezende E, Pitta R, Vieira TC, Duarte ME, Vieira AR, Casado PL. Evidence of genetic variations associated with rotator cuff disease. J Shoulder Elbow Surg. 2014;23:227–235.CrossRefPubMedGoogle Scholar
  25. 25.
    Munhoz FB, Godoy-Santos AL, Santos MC. MMP-3 polymorphism: genetic marker in pathological processes. Mol Med Rep. 2010;3:735–740.PubMedGoogle Scholar
  26. 26.
    Oliva F, Osti L, Padulo J, Maffulli N. Epidemiology of the rotator cuff tears: a new incidence related to thyroid disease. Muscles Ligaments Tendons J. 2014;4:309–314.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Osawa T, Shinozaki T, Takagishi K. Multivariate analysis of biochemical markers in synovial fluid from the shoulder joint for diagnosis of rotator cuff tears. Rheumatol Int. 2005;25:436–441.CrossRefPubMedGoogle Scholar
  28. 28.
    Pardo A, Selman M. MMP-1: the elder of the family. Int J Biochem Cell Biol. 2005;37:283-287.CrossRefPubMedGoogle Scholar
  29. 29.
    Plate JF, Haubruck P, Walters J, Mannava S, Smith BP, Smith TL, Tuohy CJ. Rotator cuff injuries in professional and recreational athletes. J Surg Orthop Adv. 2013;22:134–142.CrossRefPubMedGoogle Scholar
  30. 30.
    Rahim M, Collins M, September A. Genes and musculoskeletal soft-tissue injuries. Med Sport Sci. 2016;61:68–91.CrossRefPubMedGoogle Scholar
  31. 31.
    Raleigh SM, van der Merwe L, Ribbans WJ, Smith RK, Schwellnus MP, Collins M. Variants within the MMP3 gene are associated with Achilles tendinopathy: possible interaction with the COL5A1 gene. Br J Sports Med. 2009;43:514–520.CrossRefPubMedGoogle Scholar
  32. 32.
    Roy JS, Braën C, Leblond J, Desmeules F, Dionne CE, MacDermid JC, Bureau NJ, Frémont P. Diagnostic accuracy of ultrasonography, MRI and MR arthrography in the characterisation of rotator cuff disorders: a systematic review and meta-analysis. Br J Sports Med. 2015;49:1316–1328.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Rutter JL, Mitchell TI, Butticè G, Meyers J, Gusella JF, Ozelius LJ, Brinckerhoff CE. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates an Ets binding site and augments transcription. Cancer Res. 1998;58:5321–5325.PubMedGoogle Scholar
  34. 34.
    Schneider S, Roessli D, Excoffier L. Arlequin ver 2.000: a software for population genetics data analysis. Available at: http://www.cmpg.unibe.ch/software/arlequin/archive/website/software/2.000/manual/Arlequin.pdf. Accessed January 26, 2017.
  35. 35.
    September AV, Schwellnus MP, Collins M. Tendon and ligament injuries: the genetic component. Br J Sports Med. 2007;41:241–246, discussion 246.Google Scholar
  36. 36.
    Tashjian RZ, Farnham JM, Albright FS, Teerlink CC, Cannon-Albright LA. Evidence for an inherited predisposition contributing to the risk for rotator cuff disease. J Bone Joint Surg Am. 2009;91:1136–1142.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Tashjian RZ, Granger EK, Farnham JM, Cannon-Albright LA, Teerlink CC. Genome-wide association study for rotator cuff tears identifies two significant single-nucleotide polymorphisms. J Shoulder Elbow Surg. 2016;25:174–179.CrossRefPubMedGoogle Scholar
  38. 38.
    Teerlink CC, Cannon-Albright LA, Tashjian RZ. Significant association of full-thickness rotator cuff tears and estrogen-related receptor-β (ESRRB). J Shoulder Elbow Surg. 2015;24:e31–35.CrossRefPubMedGoogle Scholar
  39. 39.
    Teunis T, Lubberts B, Reilly BT, Ring D. A systematic review and pooled analysis of the prevalence of rotator cuff disease with increasing age. J Shoulder Elbow Surg. 2014;23:1913–1921.CrossRefPubMedGoogle Scholar
  40. 40.
    Voloshin I, Gelinas J, Maloney MD, O’Keefe RJ, Bigliani LU, Blaine TA. Proinflammatory cytokines and metalloproteases are expressed in the subacromial bursa in patients with rotator cuff disease. Arthroscopy. 2005;21:1076.e1–1076.e9.Google Scholar
  41. 41.
    Yadav H, Nho S, Romeo A, MacGillivray JD. Rotator cuff tears: pathology and repair. Knee Surg Sports Traumatol Arthrosc. 2009;17:409–421.CrossRefPubMedGoogle Scholar
  42. 42.
    Yamamoto A, Takagishi K, Kobayashi T, Shitara H, Osawa T. Factors involved in the presence of symptoms associated with rotator cuff tears: a comparison of asymptomatic and symptomatic rotator cuff tears in the general population. J Shoulder Elbow Surg. 2011;20:1133-1137.CrossRefPubMedGoogle Scholar
  43. 43.
    Yamamoto A, Takagishi K, Osawa T, Yanagawa T, Nakajima D, Shitara H, Kobayashi T. Prevalence and risk factors of a rotator cuff tear in the general population. J Shoulder Elbow Surg. 2010;19:116–120.CrossRefPubMedGoogle Scholar
  44. 44.
    Ye S, Eriksson P, Hamsten A, Kurkinen M, Humphries SE, Henney AM. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem. 1996;271:13055–13060.CrossRefPubMedGoogle Scholar

Copyright information

© The Association of Bone and Joint Surgeons® 2017

Authors and Affiliations

  • Jorge H. Assunção
    • 1
  • Alexandre L. Godoy-Santos
    • 1
  • Maria Cristina L. G. dos Santos
    • 2
  • Eduardo A. Malavolta
    • 1
  • Mauro E. C. Gracitelli
    • 1
  • Arnaldo A. Ferreira Neto
    • 1
  1. 1.Department of Orthopedics and Traumatology, School of MedicineUniversity of São PauloSão PauloBrazil
  2. 2.Department of Cell BiologyUniversity Federal of ParanáCuritibaBrazil

Personalised recommendations