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The role of relaxin in anterior cruciate ligament injuries: a systematic review

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European Journal of Orthopaedic Surgery & Traumatology Aims and scope Submit manuscript

Abstract

Objective

Anterior cruciate ligament (ACL) tears are exceedingly common among the athletic population and are seen with higher incidence in females. Observational studies have noted peak ACL tear rates in the luteal phase of the menstrual cycle, a time in which the hormone relaxin peaks in serum concentration.

Methods

A systematic review of the literature was performed. Inclusion criteria specified all prospective and retrospective studies which included the role of relaxin in the pathogenesis of ACL tears.

Results

Six studies met inclusion criteria yielding 189 subjects from clinical studies and 51 in vitro samples. Included studies found that ACL samples exhibit selective relaxin binding. When pre-treated with estrogen prior to relaxin exposure, female ACL tissue samples exhibit increased expression of collagen degrading receptors.

Conclusion

Relaxin displays binding specificity to the female ACL and increased serum concentrations are correlated with increased ACL tear rates in female athletes. Further research is needed in this area.

Level of Evidence

V.

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References

  1. Hisaw F (1926) Experimental relaxation of the pubic ligament of the guinea pig. Proc Soc Exp Biol Med Soc Exp Biol Med 23:661–663

    Article  Google Scholar 

  2. Schwabe C, Steinetz B, Weiss G et al (1978) Relaxin. Recent Prog Horm Res 34:123–211

    CAS  PubMed  Google Scholar 

  3. Bani D (1997) Relaxin: a pleiotropic hormone. Gen Pharmacol 28:13–22

    Article  CAS  PubMed  Google Scholar 

  4. Bryant-Greenwood GD, Rutanen EM, Partanen S, Coelho TK, Yamamoto SY (1993) Sequential appearance of relaxin, prolactin and IGFBP-1 during growth and differentiation of the human endometrium. Mol Cell Endocrinol 95:23–29

    Article  CAS  PubMed  Google Scholar 

  5. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 62:1006–1012

    Article  PubMed  Google Scholar 

  6. Arnold C, Van Bell C, Rogers V, Cooney T (2002) The relationship between serum relaxin and knee joint laxity in female athletes. Orthopedics 25:669–673

    Article  PubMed  Google Scholar 

  7. Dragoo JL, Castillo TN, Braun HJ, Ridley BA, Kennedy AC, Golish SR (2011) Prospective correlation between serum relaxin concentration and anterior cruciate ligament tears among elite collegiate female athletes. Am J Sports Med 39:2175–2180

    Article  PubMed  Google Scholar 

  8. Dragoo JL, Lee RS, Benhaim P, Finerman GAM, Hame SL (2003) Relaxin receptors in the human female anterior cruciate ligament. Am J Sports Med 31:577–584

    Article  PubMed  Google Scholar 

  9. Galey S, Konieczko EM, Arnold CA, Cooney TE (2003) Immunohistological detection of relaxin binding to anterior cruciate ligaments. Orthopedics 26:1201–1204

    Article  PubMed  Google Scholar 

  10. Faryniarz DA, Bhargava M, Lajam C, Attia ET, Hannafin JA (2006) Quantitation of estrogen receptors and relaxin binding in human anterior cruciate ligament fibroblasts. In Vitro Cell Dev Biol Anim 42:176–181

    Article  CAS  PubMed  Google Scholar 

  11. Konopka JA, DeBaun MR, Chang W, Dragoo JL (2016) The intracellular effect of relaxin on female anterior cruciate ligament cells. Am J Sports Med 44:2384–2392

    Article  PubMed  Google Scholar 

  12. Renstrom PA (2013) Eight clinical conundrums relating to anterior cruciate ligament (ACL) injury in sport: recent evidence and a personal reflection. Br J Sports Med 47:367–372

    Article  PubMed  Google Scholar 

  13. Owens BD, Cameron KL, Clifton KB, Svoboda SJ, Wolf JM (2016) Association between serum relaxin and subsequent shoulder instability. Orthopedics 39:e724-728

    Article  PubMed  Google Scholar 

  14. Wolf JM, Williams AE, Delaronde S, Leger R, Clifton KB, King KB (2013) Relationship of serum relaxin to generalized and trapezial-metacarpal joint laxity. J Hand Surg Am 38:721–728

    Article  PubMed  Google Scholar 

  15. Wolf JM, Scher DL, Etchill EW et al (2014) Relationship of relaxin hormone and thumb carpometacarpal joint arthritis. Clin Orthop Relat Res 472:1130–1137

    Article  PubMed  Google Scholar 

  16. Xu T, Bai J, Xu M et al (2019) Relaxin inhibits patellar tendon healing in rats: a histological and biochemical evaluation. BMC Musculoskelet Disord 20:349

    Article  PubMed  PubMed Central  Google Scholar 

  17. Naqvi T, Duong TT, Hashem G, Shiga M, Zhang Q, Kapila S (2005) Relaxin’s induction of metalloproteinases is associated with the loss of collagen and glycosaminoglycans in synovial joint fibrocartilaginous explants. Arthritis Res Ther 7:R1-11

    Article  CAS  PubMed  Google Scholar 

  18. Nose-Ogura S, Yoshino O, Yamada-Nomoto K et al (2017) Oral contraceptive therapy reduces serum relaxin-2 in elite female athletes. J Obstet Gynaecol Res 43:530–535

    Article  CAS  PubMed  Google Scholar 

  19. Konopka JA, Hsue LJ, Dragoo JL (2019) Effect of oral contraceptives on soft tissue injury risk, soft tissue laxity, and muscle strength: a systematic review of the literature. Orthop J Sports Med 7:2325967119831061

    Article  PubMed  PubMed Central  Google Scholar 

  20. Konopka JA, Hsue L, Chang W, Thio T, Dragoo JL (2020) The effect of oral contraceptive hormones on anterior cruciate ligament strength. Am J Sports Med 48:85–92

    Article  PubMed  Google Scholar 

  21. Ko JH, Kang YM, Yang JH et al (2019) Regulation of MMP and TIMP expression in synovial fibroblasts from knee osteoarthritis with flexion contracture using adenovirus-mediated relaxin gene therapy. Knee 26:317–329

    Article  PubMed  Google Scholar 

  22. Kang YM, Choi YR, Yun CO et al (2014) Down-regulation of collagen synthesis and matrix metalloproteinase expression in myofibroblasts from Dupuytren nodule using adenovirus-mediated relaxin gene therapy. J Orthop Res 32:515–523

    Article  CAS  PubMed  Google Scholar 

  23. Kang YM, Lee HM, Moon SH, Kang H, Choi YR (2017) Relaxin modulates the expression of MMPs and TIMPs in fibroblasts of patients with carpal tunnel syndrome. Yonsei Med J 58:415–422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bathgate RAD, Kocan M, Scott DJ et al (2018) The relaxin receptor as a therapeutic target—perspectives from evolution and drug targeting. Pharmacol Ther 187:114–132

    Article  CAS  PubMed  Google Scholar 

  25. Teerlink JR, Cotter G, Davison BA et al (2013) Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet 381:29–39

    Article  CAS  PubMed  Google Scholar 

  26. Teerlink JR, Metra M, Felker GM et al (2009) Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study. Lancet 373:1429–1439

    Article  CAS  PubMed  Google Scholar 

  27. Metra M, Cotter G, Davison BA et al (2013) Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development program: correlation with outcomes. J Am Coll Cardiol 61:196–206

    Article  CAS  PubMed  Google Scholar 

  28. Kumar VA, Wilson SS, Ayaz SI, Levy PD (2015) Targeted biological therapies reach the heart: the case of serelaxin for heart failure. Drugs Today (Barc) 51:591–597

    Article  CAS  PubMed  Google Scholar 

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Funding

Authors have not received grant support or research funding and do not have any proprietary interests in the materials described in the article.

Author information

Authors and Affiliations

  1. Department of Orthopaedic Surgery, University of California-San Diego, San Diego, CA, 92037, USA

    Garrett K. Berger

  2. Department of Orthopaedic Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Zachary A. Rockov, Connor Byrne, Natasha E. Trentacosta & Michael A. Stone

Authors
  1. Garrett K. Berger
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  2. Zachary A. Rockov
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  3. Connor Byrne
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  4. Natasha E. Trentacosta
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  5. Michael A. Stone
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Correspondence to Garrett K. Berger.

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This work is exempt from IRB approval given that it is a systematic review.

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Informed consent is not required for systematic reviews, all data have already been published by other parties.

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Appendix: PubMed search strategy

Appendix: PubMed search strategy

(((("Ligaments"[Mesh] OR "Anterior Cruciate Ligament Reconstruction"[Mesh] OR "Medial Collateral Ligament, Knee"[Mesh] OR "Patellar Ligament"[Mesh] OR "Lateral Ligament, Ankle"[Mesh] OR "Posterior Cruciate Ligament"[Mesh] OR "Anterior Cruciate Ligament"[Mesh] OR "Median Arcuate Ligament Syndrome"[Mesh] OR "Posterior Cruciate Ligament Reconstruction"[Mesh] OR "Ulnar Collateral Ligament Reconstruction"[Mesh] OR "Collateral Ligament, Ulnar"[Mesh] OR "Anterior Cruciate Ligament Injuries"[Mesh] OR "Round Ligament of Femur"[Mesh] OR "Longitudinal Ligaments"[Mesh] OR "Plantar Plate"[Mesh] OR "Collateral Ligaments"[Mesh] OR "Round Ligaments"[Mesh] OR "Costocoracoid ligament congenitally short" [Supplementary Concept] OR "Ligamentum Flavum"[Mesh] OR "Ligaments, Articular"[Mesh] OR "Acromioclavicular Joint"[Mesh])) AND ("Relaxin"[Mesh] OR "Leydig insulin-like protein" [Supplementary Concept] OR "RLN3 protein, human" [Supplementary Concept] OR "RLN3 protein, rat" [Supplementary Concept] OR "RLN2 protein, human" [Supplementary Concept] OR "RLN1 protein, human" [Supplementary Concept] OR "phenylalanyl relaxin" [Supplementary Concept] OR "N(alpha)-formyltyrosyl-relaxin" [Supplementary Concept] OR "RXFP3 protein, rat" [Supplementary Concept] OR "relaxin receptors" [Supplementary Concept] OR "rln3a protein, zebrafish" [Supplementary Concept] OR "relaxin-3 protein, mouse" [Supplementary Concept]))) OR ((("Tendons"[Mesh] OR "Tendon Injuries"[Mesh] OR "Achilles Tendon"[Mesh] OR "Tenotomy"[Mesh] OR "Hamstring Tendons"[Mesh] OR "Patellar Ligament"[Mesh])) AND ("Relaxin"[Mesh] OR "Leydig insulin-like protein" [Supplementary Concept] OR "RLN3 protein, human" [Supplementary Concept] OR "RLN3 protein, rat" [Supplementary Concept] OR "RLN2 protein, human" [Supplementary Concept] OR "RLN1 protein, human" [Supplementary Concept] OR "phenylalanyl relaxin" [Supplementary Concept] OR "N(alpha)-formyltyrosyl-relaxin" [Supplementary Concept] OR "RXFP3 protein, rat" [Supplementary Concept] OR "relaxin receptors" [Supplementary Concept] OR "rln3a protein, zebrafish" [Supplementary Concept] OR "relaxin-3 protein, mouse" [Supplementary Concept])).

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Berger, G.K., Rockov, Z.A., Byrne, C. et al. The role of relaxin in anterior cruciate ligament injuries: a systematic review. Eur J Orthop Surg Traumatol 33, 3319–3326 (2023). https://doi.org/10.1007/s00590-023-03618-7

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  • DOI: https://doi.org/10.1007/s00590-023-03618-7

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