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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. 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.

SUBMITTER: Oak NR

PROVIDER: S-EPMC4246014 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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

Oak Nikhil R NR Gumucio Jonathan P JP Flood Michael D MD Saripalli Anjali L AL Davis Max E ME Harning Julie A JA Lynch Evan B EB Roche Stuart M SM Bedi Asheesh A Mendias Christopher L CL

The American journal of sports medicine 20140922 12

<h4>Background</h4>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. ...[more]

PMID: 25245131

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Project description:BackgroundMore than 450,000 rotator cuff repairs are performed annually, yet healing of tendon to bone often fails. This failure is rooted in the fibrovascular healing response, which does not regenerate the native attachment site. Better healing outcomes may be achieved by targeting inflammation during the early period after repair. Rather than broad inhibition of inflammation, which may impair healing, the current study utilized a molecularly targeted approach to suppress IKKβ, shutting down only the inflammatory arm of the nuclear factor κB (NF-κB) signaling pathway.PurposeTo evaluate the therapeutic potential of IKKβ inhibition in a clinically relevant model of rat rotator cuff repair.Study designControlled laboratory study.MethodsAfter validating the efficacy of the IKKβ inhibitor in vitro, it was administered orally once a day for 7 days after surgery in a rat rotator cuff repair model. The effect of treatment on reducing inflammation and improving repair quality was evaluated after 3 days and 2, 4, and 8 weeks of healing, using gene expression, biomechanics, bone morphometry, and histology.ResultsInhibition of IKKβ attenuated cytokine and chemokine production in vitro, demonstrating the potential for this inhibitor to reduce inflammation in vivo. Oral treatment with IKKβ inhibitor reduced NF-κB target gene expression by up to 80% compared with a nontreated group at day 3, with a subset of these genes suppressed through 14 days. Furthermore, the IKKβ inhibitor led to enhanced tenogenesis and extracellular matrix production, as demonstrated by gene expression and histological analyses. At 4 weeks, inhibitor treatment led to increased toughness, no effects on failure load and strength, and decreases in stiffness and modulus when compared with vehicle control. At 8 weeks, IKKβ inhibitor treatment led to increased toughness, failure load, and strength compared with control animals. IKKβ inhibitor treatment prevented the bone loss near the tendon attachment that occurred in repairs in control.ConclusionPharmacological inhibition of IKKβ successfully suppressed excessive inflammation and enhanced tendon-to-bone healing after rotator cuff repair in a rat model.Clinical relevanceThe NF-κB pathway is a promising target for enhancing outcomes after rotator cuff repair.

Project description:ObjectiveThe purpose of this study was to investigate the effect of hyaluronic acid (HA) in the tendon-bone healing process after rotator cuff repair in a rabbit model.MethodsIn vitro, rat bone marrow stromal cells (rBMSCs) were cultured in media for cartilage-related and inflammation-related gene expression levels examination at 1.0 mg/mL of HA. In vivo, 48 New Zealand white rabbits underwent rotator cuff repair surgery, and they were randomly divided into three groups: (1) control group (n = 16), (2) microfracture (MF) group accepting MF treatment (n = 16) and (3) MF/HA group accepting MF with HA treatment (n = 16). Four rabbits from each group were sacrificed at 6 and 12 weeks postoperatively for histological evaluation and biomechanical testing.ResultsIn vitro experiments reveal that HA significantly decreased inflammation-related mRNA expression (IL-1, TNF?) compared with the control group. At 6 weeks after surgery, there was no significant difference of load-to-failure between groups. At 12 weeks after surgery, the mean failure load of the MF/HA group was significantly higher than that of the control group (100.5 ± 10.1 N vs. 68.0 ± 6.2 N; p = 0.0115). The mean failure load of the MF group appeared higher than that of the control group, whereas there was no significant difference (p > 0.05). Histologically, more chondrocytes were clustered at the tendon-bone interface, and more extracellular matrixes were produced in the MF/HA group. The interface of the MF/HA group appeared similar with the normal tendon-bone interface.ConclusionHA may play a crucial role in the acceleration of tendon-to-bone healing which might be through inhibiting inflammation. Rotator cuff repair using MF along with HA led to better tendon-bone healing and a subsequent increase of biomechanical strength at the repair site.The translational potential of this articleHA injection is very common for patients with rotator cuff disease because of its antiinflammatory action and adhesion prevention preoperatively. The HA injection during surgery provides an antiinflammatory effect during tendon-bone healing process and leads to better tendon-bone healing postoperatively.

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

Publications

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

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