title: Statins enhance rotator cuff healing by stimulating the COX2/PGE2/EP4 pathway: an in vivo and in vitro study.
abstract: BACKGROUND
  Statins are lipid-lowering drugs with many beneficial pleiotropic effects. Cyclooxygenase (COX2) selective inhibitors that are commonly prescribed in orthopaedic patients may effect healing. Evidence indicates that statins stimulate COX2 activity.
  
  
  OBJECTIVE
  Atorvastatin (ATV) administration will enhance tendon healing by stimulating the acute inflammatory phase via increasing the production of prostaglandin E2 (PGE2).
  
  
  METHODS
  Controlled laboratory study.
  
  
  METHODS
  After experimental rotator cuff (RC) tearing and suturing, 48 Wistar rats were randomly allocated into 4 groups: (1) ATV (20 mg/kg), (2) celecoxib (CEL; COX2 inhibitor) (10 mg/kg), (3) ATV + CEL (20 mg/kg + 10 mg/kg), and (4) saline alone. Animals were sacrificed 3 weeks after RC tears and repair, and tendon integrity was tested biomechanically in tension. To further evaluate the underlying mechanism of action, human and rat primary tenocytes were obtained from the supraspinatus tendon. Cultures were treated with a therapeutic dosage of 5 commonly used statins: CEL, ATV + CEL, PGE2, and a selective antagonist of PGE2 receptor 4 (EP4). Cell proliferation (thymidine incorporation), migration (wound healing assay), and adhesion (iCELLigence) were evaluated. The expression of all PGE2 receptors (EPs) was determined by quantitative reverse transcription polymerase chain reaction.
  
  
  RESULTS
  Tension testing of healed tendons demonstrated significantly higher maximal loading and stiffness in the ATV group as compared with the saline (+30% and +20%, respectively; P < .001) and CEL groups (+33% and +50%, respectively; P < .005). Celecoxib alone did not affect tendon healing (P = .88). In line with these in vivo results, tenocytes treated with statins demonstrated significantly higher proliferation rates; CEL abrogated this effect, and PGE2 treatment stimulated tenocyte proliferation even in the presence of CEL. Also, ATV stimulated the migration (wound healing) and adhesion of tenocytes. Among all PGE2 receptors, tenocytes mainly express EP4, and an EP4 selective antagonist blocked the effect of ATV.
  
  
  CONCLUSIONS
  Results indicate that ATV enhances tendon healing by stimulating tenocyte proliferation, migration, and adhesion via increased COX2 activity and autocrine/paracrine PGE2 signaling. Findings also demonstrate that this effect is mediated by EP4 signaling.
  
  
  CONCLUSIONS
  Although chronic inflammation contributes to the development of tendinopathy, study results advocate for a positive role of PGE2 in tendon healing during the acute inflammatory phase that follows tendon surgical repair. It is therefore suggested that ATV should be further investigated as a possible modality to improve tendon healing.
authors.affiliation: Shoulder Unit, Orthopedic Surgery Division, Tel Aviv Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Bone Research Laboratory, Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Oleg
authors.initials: O
authors.lastname: Dolkart
authors.affiliation: Bone Research Laboratory, Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Liron
authors.affiliation: Shoulder Unit, Orthopedic Surgery Division, Tel Aviv Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ofir
authors.initials: O
authors.lastname: Chechik
authors.affiliation: Shoulder Unit, Orthopedic Surgery Division, Tel Aviv Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Dalia
authors.initials: D
authors.lastname: Somjen
authors.affiliation: Biomechanics Laboratory, School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Brosh
authors.affiliation: Shoulder Unit, Orthopedic Surgery Division, Tel Aviv Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel dremaman@gmail.com.
authors.forename: Eran
authors.initials: E
authors.lastname: Maman
authors.affiliation: Bone Research Laboratory, Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Yankel
authors.initials: Y
authors.lastname: Gabet
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D001696:Biomechanical Phenomena; D000068579:Celecoxib; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D023421:Models, Animal; D011720:Pyrazoles / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D011897:Random Allocation; D017208:Rats, Wistar; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D017006:Rotator Cuff / Q000601:surgery*; D013449:Sulfonamides / Q000494:pharmacology; D013710:Tendons / Q000166:cytology; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011720:Pyrazoles; D011758:Pyrroles; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013449:Sulfonamides; D000069059:Atorvastatin; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D000068579:Celecoxib; D015232:Dinoprostone
keywords: COX2; EP4; PGE2; acute inflammatory phase; rotator cuff; statins; tendon healing