Inhibition of 5-LOX, COX-1, and COX-2 increases tendon healing and reduces muscle fibrosis and lipid accumulation after rotator cuff repair

Am J Sports Med. 2014 Dec;42(12):2860-8. doi: 10.1177/0363546514549943. Epub 2014 Sep 22.

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.

Hypothesis: 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.

Study design: 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%.

Conclusion: 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.

Clinical relevance: 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.

Keywords: fatty degeneration; licofelone; myosteatosis; rotator cuff.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetyl-CoA C-Acetyltransferase / genetics
  • Acetyl-CoA C-Acetyltransferase / metabolism
  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy-Related Protein 5
  • Beclin-1
  • Biomechanical Phenomena
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Diacylglycerol O-Acyltransferase / genetics
  • Diacylglycerol O-Acyltransferase / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Fibrocartilage / pathology
  • Fibrosis
  • Hydroxyproline / metabolism
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lipid Metabolism / drug effects*
  • Male
  • Muscle Contraction / drug effects
  • Muscle Fibers, Fast-Twitch / drug effects
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Perilipin-1
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Proteins / genetics
  • Proteins / metabolism
  • Pyrroles / pharmacology*
  • RNA, Messenger / metabolism
  • Rats, Sprague-Dawley
  • Rotator Cuff / pathology
  • Rotator Cuff / surgery*
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism
  • Wound Healing / drug effects*
  • Wound Healing / physiology

Substances

  • Apoptosis Regulatory Proteins
  • Atg5 protein, rat
  • Autophagy-Related Protein 5
  • Beclin-1
  • Becn1 protein, rat
  • Carrier Proteins
  • Cidec protein, rat
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Muscle Proteins
  • PPAR gamma
  • Perilipin-1
  • Phosphoproteins
  • Proteins
  • Pyrroles
  • RNA, Messenger
  • Vesicular Transport Proteins
  • lipid storage droplet protein 5, mouse
  • Interleukin-10
  • Dgat1 protein, rat
  • Diacylglycerol O-Acyltransferase
  • Acat1 protein, mouse
  • Acetyl-CoA C-Acetyltransferase
  • Atg16L1 protein, rat
  • licofelone
  • Hydroxyproline