Inhibition of 5-LOX, COX-1, and COX-2
Increases Tendon Healing and Reduces Muscle Fibrosis and Lipid Accumulation
After Rotator Cuff Repair
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]
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.
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.
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.
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?
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
Sarah Ilkhanipour Rooney
Reviewed
by: Stephen Thomas
by: Stephen Thomas
Related
Posts:
Posts:
Oak NR, Gumucio JP, Flood MD, Saripalli AL, Davis ME, Harning JA, Lynch EB, Roche SM, Bedi A, & Mendias CL (2014). Inhibition of 5-LOX, COX-1, and COX-2 Increases Tendon Healing and Reduces Muscle Fibrosis and Lipid Accumulation After Rotator Cuff Repair. The American Journal of Sports Medicine PMID: 25245131