Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Sport Sciences for Health Aims and scope Submit manuscript

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.

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. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

ACL:

Anterior cruciate ligament

ACLT:

Anterior cruciate ligament transection

CAM:

Controlled abnormal movement

MCL:

Medial collateral ligament

PTOA:

Post-traumatic osteoarthritis

References

  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):773–782

    Article  CAS  Google Scholar 

  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 50:3145–3152

    Article  CAS  Google Scholar 

  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):1434–1443

    Article  Google Scholar 

  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 63:269–273

    Article  Google Scholar 

  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):1118–1123

    Article  Google Scholar 

  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):1337–1346

    Article  Google Scholar 

  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):103–110

    Article  Google Scholar 

  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):1387–1397

    Article  Google Scholar 

  9. Murray MM, Vavken P, Fleming BC (2013) The ACL handbook. Springer, New York

    Book  Google Scholar 

  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):607–613

    Article  Google Scholar 

  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):645–646

    Article  Google Scholar 

  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):40–48

    Article  Google Scholar 

  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):979–985

    Article  Google Scholar 

  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):1200–1203

    Article  CAS  Google Scholar 

  15. Malanga GA, Giradi J, Nadler SF (2001) The spontaneous healing of a torn anterior cruciate ligament. Clin J Sports Med 11(2):118–120

    Article  CAS  Google Scholar 

  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 307:146–154

    Google Scholar 

  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):206–211

    Article  Google Scholar 

  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):2900–2910

    Article  Google Scholar 

  19. Wang JH, Thampatty BP, Lin JS, Im HJ (2007) Mechanoregulation of gene expression in fibroblasts. Gene 391(1–2):1–15

    Article  CAS  Google Scholar 

  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):34

    Article  Google Scholar 

  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):315–322

    Article  CAS  Google Scholar 

  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):1007–1017

    Article  CAS  Google Scholar 

  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 18:19–25

    CAS  PubMed  PubMed Central  Google Scholar 

  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 19:175

    Article  Google Scholar 

  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):315–321

    Article  CAS  Google Scholar 

  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 2016:8243601

    Article  Google Scholar 

  27. Frank CB (2004) Ligament structure, physiology and function. J Musculoskelet Neuronal Interact 4(2):199–201

    CAS  PubMed  Google Scholar 

  28. Jackson DW (1993) The anterior cruciate ligament: current and future concept. Raven Press, New York

    Google Scholar 

  29. Chamberlain CS, Crowley E, Vanderby R (2009) The spatio-temporal dynamics of ligament healing. Wound Repair Regen 17(2):206–215

    Article  Google Scholar 

  30. Nagase H, Visse R, Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69(3):562–573

    Article  CAS  Google Scholar 

  31. Armstrong DG, Jude EB (2002) The role of matrix metalloproteinases in wound healing. J Am Podiatr Med Assoc 92(1):12–18

    Article  Google Scholar 

  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):495–505

    Article  Google Scholar 

  33. Chakraborti S, Mandal M, Das S, Mandal A, Chakraborti T (2003) Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem 253(1–2):269–285

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Doctoral course, Department of Health and Social Service, Graduate Course of Health and Social Service, Graduate School of Saitama Prefectural University, Koshigaya, Saitama, Japan

    Yuri Morishita

  2. Department of Physical Therapy, Faculty of Health and Social Services, Saitama Prefectural University, Koshigaya, Saitama, Japan

    Naohiko Kanemura, Takanori Kokubun, Kenji Murata & Kiyomi Takayanagi

Authors
  1. Yuri Morishita
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naohiko Kanemura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takanori Kokubun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kenji Murata
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kiyomi Takayanagi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Naohiko Kanemura.

Ethics declarations

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.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Morishita, Y., Kanemura, N., Kokubun, T. et al. Acute molecular biological responses during spontaneous anterior cruciate ligament healing in a rat model. Sport Sci Health 15, 659–666 (2019). https://doi.org/10.1007/s11332-019-00583-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11332-019-00583-9

Keywords

Search

Navigation