Advertisement

Acute molecular biological responses during spontaneous anterior cruciate ligament healing in a rat model

  • Yuri Morishita
  • Naohiko KanemuraEmail author
  • Takanori Kokubun
  • Kenji Murata
  • Kiyomi Takayanagi
Original Article
  • 2 Downloads

Abstract

Background

Anterior cruciate ligament (ACL) injury is one of the most common injuries of the knee joint and is becoming more prevalent. While ACL reconstruction is considered the “gold standard” of treatment, some studies have demonstrated natural spontaneous healing of the ACL in humans, rabbits, and rats. At this time, the mechanism of ACL healing is poorly understood.

Aims

The purpose of this study was to determine the process of ACL healing by examining the molecular and histological changes in the acute phases, using an ACL-Transection model and a spontaneous ACL healing model.

Methods

Sixty adult male Wistar rats were randomly assigned to two groups: the ACL transection (ACLT) group and the controlled abnormal movement (CAM) group. Thirty rats were randomly assigned to three groups (day 1, day 3, and day 5). Then, all rats underwent an ACL transection procedure. The CAM group rats underwent controlled abnormal extra-articular tibial translation. Samples were harvested from rats and used for histological and biochemical analyses.

Results

Both, the ACLT and the CAM groups exhibited ruptured ACLs. However, in the CAM group, the ends of the proximal remnants were not retracted. Expressions of MMP-3 and PDGF-α increased, and expression of TGF-β1 decreased in the CAM group on day 5 (p < 0.01); PDGF-β expression in the CAM group increased significantly at each time point (p < 0.01).

Conclusion

Our results suggested that controlling abnormal movements changed intra-articular responses positively during the acute phase both histologically and biochemically.

Keywords

Anterior cruciate ligament Anterior cruciate ligament injury Wound healing Rehabilitation Acute-phase reaction 

Abbreviations

ACL

Anterior cruciate ligament

ACLT

Anterior cruciate ligament transection

CAM

Controlled abnormal movement

MCL

Medial collateral ligament

PTOA

Post-traumatic osteoarthritis

Notes

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest directly relevant to the contents of this article.

Human and animal rights

This study is an animal experimental study. All experiments were approved by the University Animal Experiment Ethics Committee (authorization number 26-5). In addition, in the actual experiments, the authors undertook to minimize the number of animals and stress on the animals.

Informed consent

Informed consent is not applicable for this type of study.

References

  1. 1.
    Christiansen BA, Anderson MJ, Lee CA, Williams JC, Yik JH, Haudenschild DR (2012) Musculoskeletal changes following non-invasive knee injury using a novel mouse model of post-traumatic osteoarthritis. Osteoarthr Cartil 20(7):773–782CrossRefGoogle Scholar
  2. 2.
    Lohmander LS, Ostenberg A, Englund M, Roos H (2004) High prevalence of knee osteo-arthritis, pain, and functional limitations in female soccer players 12 years after anterior cruciate ligament injury. Arthritis Rheumatol 50:3145–3152CrossRefGoogle Scholar
  3. 3.
    Øiestad BE, Engebretsen L, Storheim K, Risberg MA (2009) Knee osteoarthritis after anterior cruciate ligament injury: a systematic review. Am J Sports Med 37(7):1434–1443CrossRefGoogle Scholar
  4. 4.
    von Porat A, Roos EM, Roos H (2004) High prevalence of osteoarthritis 14 years after an anterior cruciate ligament tear in male soccer players: a study of radiographic and patient relevant outcomes. Ann Rheum Dis 63:269–273CrossRefGoogle Scholar
  5. 5.
    Bray RC, Leonard CA, Saio PT (2003) Correlation of healing capacity with vascular response in the anterior cruciate and medial collateral ligaments of the rabbit. J Orthop Res 21(6):1118–1123CrossRefGoogle Scholar
  6. 6.
    Beye JA, Hart DA, Bray RC, McDougall JJ, Salo PT (2008) Injury-induced changes in mRNA levels differ widely between anterior cruciate ligament and medial collateral ligament. Am J Sports Med 36(7):1337–1346CrossRefGoogle Scholar
  7. 7.
    Haslauer CM, Proffen BL, Johnson VM, Murray MM (2014) Expression of modulators of extracellular matrix structure after anterior cruciate ligament injury. Wound Repair Regen 22(1):103–110CrossRefGoogle Scholar
  8. 8.
    Murray MM, Martin SD, Martin TL, Spector M (2000) Histological changes in the human anterior cruciate ligament after rupture. J Bone Jt Surg Am 82-A(10):1387–1397CrossRefGoogle Scholar
  9. 9.
    Murray MM, Vavken P, Fleming BC (2013) The ACL handbook. Springer, New YorkCrossRefGoogle Scholar
  10. 10.
    Streich NA, Zimmermann D, Bode G, Schmitt H (2011) Reconstructive versus non-reconstructive treatment of anterior cruciate ligament insufficiency. A retrospective matched-pair long-term follow-up. Int Orthop 35(4):607–613CrossRefGoogle Scholar
  11. 11.
    Bigoni M, Zanchi N, Turati M (2017) Healing potential and surgical treatment of anterior cruciate ligament rupture in pediatric population. Sport Sci Health 13(3):645–646CrossRefGoogle Scholar
  12. 12.
    Bigoni M, Sacerdote P, Turati M, Franchi S, Gandolla M, Gaddi D, Moretti S, Munegato D, Augusti CA, Bresciani E, Omeljaniuk RJ, Locatelli V, Torsello A (2017) Arthroscopic anterior cruciate ligament repair for proximal anterior cruciate ligament tears in skeletally immature patients: surgical technique and preliminary results. Knee 24(1):40–48CrossRefGoogle Scholar
  13. 13.
    Costa-Paz M, Ayerza MA, Tonoira I, Astoul J, Muscolo DL (2012) Spontaneous healing in complete ACL ruptures a clinical and mri study. Clin Orthop Relat Res 470(4):979–985CrossRefGoogle Scholar
  14. 14.
    Kurosaka M, Yoshiya S, Mizuno T, Mizuno K (1998) Spontaneous healing of a tear of the anterior cruciate ligament—a report of two cases. J Bone Jt Surg Am 80(8):1200–1203CrossRefGoogle Scholar
  15. 15.
    Malanga GA, Giradi J, Nadler SF (2001) The spontaneous healing of a torn anterior cruciate ligament. Clin J Sports Med 11(2):118–120CrossRefGoogle Scholar
  16. 16.
    Ihara H, Miwa M, Takayanagi K, Nakayama A (1994) Acute torn meniscus combined with acute cruciate ligament injury—second look arthroscopy after 3-month conservative treatment. Clin Orthop Relat Res 307:146–154Google Scholar
  17. 17.
    Ihara H, Kawano T (2016) Influence of age on healing capacity of acute tears of the anterior cruciate ligament based on magnetic resonance imaging assessment. J Comput Assist Tomogr 41(2):206–211CrossRefGoogle Scholar
  18. 18.
    Kokubun T, Kanemura N, Murata K, Moriyama H, Morita S, Jinno T, Ihara H, Takayanagi K (2016) effect of changing the joint kinematics of knees with a ruptured anterior cruciate ligament on the molecular biological responses and spontaneous healing in a rat model. Am J Sports Med 44(11):2900–2910CrossRefGoogle Scholar
  19. 19.
    Wang JH, Thampatty BP, Lin JS, Im HJ (2007) Mechanoregulation of gene expression in fibroblasts. Gene 391(1–2):1–15CrossRefGoogle Scholar
  20. 20.
    Haslauer CM, Proffen BL, Johnson VM, Hill A, Murray MM (2014) Gene expression of catabolic inflammatory cytokines peak before anabolic inflammatory cytokines after ACL injury in a preclinical model. J Inflamm (Lond) 11(1):34CrossRefGoogle Scholar
  21. 21.
    Tang Z, Yang L, Zhang J, Wang Y, Chen PC, Sung KL (2009) Coordinated expression of MMPs and TIMPs in rat knee intra-articular tissues after ACL injury. Connect Tissue Res 50(5):315–322CrossRefGoogle Scholar
  22. 22.
    Murray MM, Spindler KP, Ballard P, Welch TP, Zurakowski D, Nanney LB (2007) enhanced histologic repair in a central wound in the anterior cruciate ligament with a collagen–platelet-rich plasma scaffold. J Orthop Res 25(8):1007–1017CrossRefGoogle Scholar
  23. 23.
    Lee J, Harwood FL, Akeson WH, Amiel D (1998) growth factor expression in healing rabbit medial collateral and anterior cruciate ligaments. Iowa Orthop J 18:19–25Google Scholar
  24. 24.
    Nishikawa Y, Kokubun T, Kanemura N, Takahashi T, Matsumoto M, Maruyama H, Takayanagi K (2018) Effects of controlled abnormal joint movement on the molecular biological response in intra-articular tissues during the acute phase of anterior cruciate ligament injury in a rat model. BMC Musculoskelet Disord 19:175CrossRefGoogle Scholar
  25. 25.
    Bigoni M, Sacerdote P, Turati M, Franchi S, Gandolla M, Gaddi D, Moretti S, Munegato D, Augusti CA, Bresciani E, Omeljaniuk RJ, Locatelli V, Torsello A (2013) Acute and late changes in intraarticular cytokine levels following anterior cruciate ligament injury. J Orthop Res 31(2):315–321CrossRefGoogle Scholar
  26. 26.
    Bigoni M, TuratiM Gandolla M, Sacerdote P, Piatti M, Castelnuovo A, Franchi S, Gorla M, Munegato D, Gaddi D, Pedrocchi A, Omeljaniuk RJ, Locatelli V, Torsello A (2016) Effects of ACL reconstructive surgery on temporal variations of cytokine levels in synovial fluid. Mediat Inflamm 2016:8243601CrossRefGoogle Scholar
  27. 27.
    Frank CB (2004) Ligament structure, physiology and function. J Musculoskelet Neuronal Interact 4(2):199–201Google Scholar
  28. 28.
    Jackson DW (1993) The anterior cruciate ligament: current and future concept. Raven Press, New YorkGoogle Scholar
  29. 29.
    Chamberlain CS, Crowley E, Vanderby R (2009) The spatio-temporal dynamics of ligament healing. Wound Repair Regen 17(2):206–215CrossRefGoogle Scholar
  30. 30.
    Nagase H, Visse R, Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69(3):562–573CrossRefGoogle Scholar
  31. 31.
    Armstrong DG, Jude EB (2002) The role of matrix metalloproteinases in wound healing. J Am Podiatr Med Assoc 92(1):12–18CrossRefGoogle Scholar
  32. 32.
    Xie J, Wang C, Yin L, Xu C, Zhang Y, Sung KL (2013) Interleukin-1 beta influences on lysyl oxidases and matrix metalloproteinases profile of injured anterior cruciate ligament and medial collateral ligament fibroblasts. Int Orthop 37(3):495–505CrossRefGoogle Scholar
  33. 33.
    Chakraborti S, Mandal M, Das S, Mandal A, Chakraborti T (2003) Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem 253(1–2):269–285CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2019

Authors and Affiliations

  • Yuri Morishita
    • 1
  • Naohiko Kanemura
    • 2
    Email author
  • Takanori Kokubun
    • 2
  • Kenji Murata
    • 2
  • Kiyomi Takayanagi
    • 2
  1. 1.Doctoral course, Department of Health and Social Service, Graduate Course of Health and Social ServiceGraduate School of Saitama Prefectural UniversityKoshigayaJapan
  2. 2.Department of Physical Therapy, Faculty of Health and Social ServicesSaitama Prefectural UniversityKoshigayaJapan

Personalised recommendations