title: Inhibition of 5-LOX, COX-1, and COX-2 increases tendon healing and reduces muscle fibrosis and lipid accumulation after rotator cuff repair.
abstract: BACKGROUND
  The repair and restoration of function after chronic rotator cuff tears are often complicated by muscle atrophy, fibrosis, and fatty degeneration of the diseased muscle. The inflammatory response has been implicated in the development of fatty degeneration after cuff injuries. Licofelone is a novel anti-inflammatory drug that inhibits 5-lipoxygenase (5-LOX), as well as cyclooxygenase (COX)-1 and COX-2 enzymes, which play important roles in inducing inflammation after injuries. While previous studies have demonstrated that nonsteroidal anti-inflammatory drugs and selective inhibitors of COX-2 (coxibs) may prevent the proper healing of muscles and tendons, studies about bone and cartilage have demonstrated that drugs that inhibit 5-LOX concurrently with COX-1 and COX-2 may enhance tissue regeneration.
  
  
  OBJECTIVE
  After the repair of a chronic rotator cuff tear in rats, licofelone would increase the load to failure of repaired tendons and increase the force production of muscle fibers.
  
  
  METHODS
  Controlled laboratory study.
  
  
  METHODS
  Rats underwent supraspinatus release followed by repair 28 days later. After repair, rats began a treatment regimen of either licofelone or a vehicle for 14 days, at which time animals were euthanized. Supraspinatus muscles and tendons were then subjected to contractile, mechanical, histological, and biochemical analyses.
  
  
  RESULTS
  Compared with controls, licofelone-treated rats had a grossly apparent decrease in inflammation and increased fibrocartilage formation at the enthesis, along with a 62% increase in the maximum load to failure and a 51% increase in peak stress to failure. Licofelone resulted in a marked reduction in fibrosis and lipid content in supraspinatus muscles as well as reduced expression of several genes involved in fatty infiltration. Despite the decline in fibrosis and fat accumulation, muscle fiber specific force production was reduced by 23%.
  
  
  CONCLUSIONS
  The postoperative treatment of cuff repair with licofelone may reduce fatty degeneration and enhance the development of a stable bone-tendon interface, although decreases in muscle fiber specific force production were observed, and force production in fact declined.
  
  
  CONCLUSIONS
  This study demonstrates that the inhibition of 5-LOX, COX-1, and COX-2 modulates the healing process of repaired rotator cuff tendons. Although further studies are necessary, the treatment of patients with licofelone after cuff repair may improve the development of a stable enthesis and enhance postoperative outcomes.
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Nikhil R
authors.initials: NR
authors.lastname: Oak
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Gumucio
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Flood
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Anjali L
authors.initials: AL
authors.lastname: Saripalli
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Max E
authors.initials: ME
authors.lastname: Davis
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Harning
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Evan B
authors.initials: EB
authors.lastname: Lynch
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Roche
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Asheesh
authors.initials: A
authors.lastname: Bedi
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA cmendias@umich.edu.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Mendias
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D001696:Biomechanical Phenomena; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051445:Fibrocartilage / Q000473:pathology; D005355:Fibrosis; D006909:Hydroxyproline / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D000070778:Perilipin-1; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017006:Rotator Cuff / Q000473:pathology / Q000601:surgery*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; C545865:Atg5 protein, rat; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; C512829:Becn1 protein, rat; D002352:Carrier Proteins; C579544:Cidec protein, rat; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D047495:PPAR gamma; D000070778:Perilipin-1; D010750:Phosphoproteins; D011506:Proteins; D011758:Pyrroles; D012333:RNA, Messenger; D033921:Vesicular Transport Proteins; C551268:lipid storage droplet protein 5, mouse; D016753:Interleukin-10; C494883:Dgat1 protein, rat; D051048:Diacylglycerol O-Acyltransferase; C506641:Acat1 protein, mouse; D000101:Acetyl-CoA C-Acetyltransferase; C577013:Atg16L1 protein, rat; C088092:licofelone; D006909:Hydroxyproline
keywords: fatty degeneration; licofelone; myosteatosis; rotator cuff