Inhibition of 5-LOX, COX-1, and COX-2 Increases Tendon Healing and Reduces Muscle Fibrosis and Lipid Accumulation After Rotator Cuff Repair
Oak NR, Gumucio JP, Flood MD, Saripalli AL, Davis ME, Harning JA, Lynch EB, Roche SM, Bedi A, Mendias CL. Am J Sport Med. 2014 [Epub ahead of print]
Take-Home Message: Licofelone, a non-steroidal anti-inflammatory treatment, has tissue-specific effects. In a rotator cuff repair rat model, this drug reduces functional muscle regeneration but improves tendon healing.
Rotator cuff tears are often associated with muscle atrophy and fatty degeneration, which can impair tendon repairs. The arachidonic acid cascade, in which arachidonic acid is converted to prostaglandins by cyclooxygenases-1 and -2 (COX-1 and COX-2) or leukotrienes by 5-lipoxygenase (5-LOX), may contribute to the development of fatty infiltration and unfavorable conditions for tissue repair. Licofelone is an anti-inflammatory drug (not yet FDA-approved) that simultaneously inhibits 5-LOX, COX-1, and COX-2. This drug enhanced cartilage and bone regeneration, but its effects have not been tested in other musculoskeletal tissues. The authors of this study were interested in the effects of licofelone on rotator cuff tendon healing in an animal model. Rats underwent detachment of their supraspinatus tendon, which was left to retract, simulating a chronic tear, followed by repair 4 weeks later. After repair, animals received either a control solution or licofelone through oral gavage for 2 weeks. Supraspinatus specimens were used for muscle functional testing, tendon mechanics, histology, and biochemical assays. Licofelone reduced the muscle fiber contractile properties and increased the transition of muscle fiber type IIX to pathological type IIB. Despite these worrisome findings, licofelone increased tendon mechanics (failure load/stress, stiffness), decreased triglycerides and fibrosis within the muscle, and improved the gross appearance of the repair (less inflamed, increased fibrocartilage at the tendon-bone insertion). Gene expression analysis revealed decreased PPARγ and perilipin 1 expression (adipogenic markers), consistent with decreased muscle triglyceride levels, and increased expression of a collagen-degrading enzyme, consistent with reduced collagen content in the muscle.
The findings of this study suggest that licofelone, a LOX-5/COX-1/COX-2 inhibitor, may improve rotator cuff tendon-to-bone healing and reduce muscle fatty degeneration and fibrosis but impair muscle function (decrease contractile properties). Future research could investigate whether postoperative rehabilitation may diminish the loss of muscle function due to licofelone. Future research should also investigate mechanisms responsible for these observations, specifically the role of inflammatory processes in muscle and tendon healing. In humans, muscle fatty atrophy is associated with poor rotator cuff repair outcomes, so developing treatments to reduce this degeneration is an active and important area of research. The investigators of this study chose only a 2 week time point for drug administration and tissue harvest. Other studies suggest that early but not delayed administration of NSAIDs may be detrimental to tendon healing, so future studies should investigate multiple time points. While this is a basic science study, the findings have implications for clinical practice, namely questioning the differential tissue effects of NSAIDs following rotator cuff repairs. Unlike traditional NSAIDs, this novel drug blocks LOX-5 in addition to COX-1 and COX-2. It has been speculated that traditional NSAIDs that block only COX could detrimentally increase production of LOX-5. This study suggests that blocking LOX-5 in addition could enhance rotator cuff tendon-to-bone healing in a chronic tear model, but, similar to traditional NSAIDs, it negatively affects muscle function.
Questions for Discussion: Do you prescribe NSAIDs for tendon and muscle injuries, and if so, will you continue? Do you think that licofelone and other NSAID treatments may have different effects for treating different stages of tendinopathy and rotator cuff tears?
Written by: Sarah Ilkhanipour Rooney
Reviewed by: Stephen Thomas