Enhance Rotator Cuff Healing by Stimulating the COX2/PGE2/EP4 Pathway: An In
Vivo and In Vitro Study

Dolkart O, Liron T,
Chechik O, Somjen D, Brosh T, Maman E, Gabet Y.
Am J Sports Med. 2014
Sep 2. [Epub ahead of print]

Home Message: Statins enhance rotator cuff healing following repair through
stimulation of the acute inflammatory phase. Statins may be a useful modality
to improve tendon healing and reduce re-tear rates.

Rotator cuff repair
failure (i.e., gap formation, incomplete healing) is common.  The mechanism by which poor healing occurs is
multifactorial (for example, mechanical, biochemical). One contributing factor
of insufficient healing may be a lack of inflammatory cells at the insertion
site, which reduces the tendon’s natural reparative process.  The use of pharmaceuticals to control
inflammation may improve tendon healing. 
For example, statins, the popular lipid-lowering drugs, are suggested to
modify inflammation.  Therefore, the
objective of this study was to determine the effect of statins on tendon
healing following rotator cuff repair in rats and on tenocyte (a type of cell in tendons) cultures in
a petri dish.  For the first study, 48
rats underwent supraspinatus detachment and repair and were randomized into 4
groups: (1) Atorvastatin
(a statin); (2) Celecoxib, a non-steroidal anti-inflammatory (NSAID);
(3) statin + Celecoxib; or 4) saline control. 
The researchers administered the drugs once a day for 21 days.  All rats were sacrificed and mechanical
testing was performed on the supraspinatus tendon. For the second study,
tenocytes were isolated from 3 rats and 3 humans.  The researchers performed assays to assess RNA
expression, cell proliferation, cell adhesion, and wound healing.  In the first study the researchers
demonstrated an increase in maximal load and stiffness in the statin group
compared with the control, celecoxib, and statin + celecoxib groups.  In the second study they demonstrated
enhanced tenocyte proliferation, migration, and adhesion in the statin group
compared with the control group.

Results from this study
suggest that administration of statins following repair enhances biomechanical
properties of the supraspinatus tendon.  This effect was likely achieved due to
enhanced tenocyte proliferation, adhesion, and migration (as observed in the
second study). Interestingly, the beneficial effect of this statin on tendon
healing was reduced when administered with the anti-inflammatory drug, Celecoxib.
This suggests that the beneficial effect of this statin could be attributed to
the stimulation of acute inflammation following tendon repair. A previous study
(Connizzo et al.) demonstrated that early
administration of Ibuprofen (an NSAID) following tendon repair is detrimental
to healing.  Taken together, the results
from these studies suggest that an early acute inflammatory response may be
important in tendon healing. However, the effect of inflammation on tendon
injury and repair remains controversial and unclear. This study necessitates further
clinical studies to investigate the role of inflammation in tendon healing and to
examine the use of statins as a treatment modality for improving tendon
healing. In the meantime, this study is a nice reminder to clinicians that the
inflammatory response is not always our enemy.

for Discussion: Do you think inflammation is important in tendon healing? Do
your patients who take statins have improved outcomes following rotator cuff

Written by: Katie Reuther
Reviewed by: Jeffrey

Dolkart O, Liron T, Chechik O, Somjen D, Brosh T, Maman E, & Gabet Y (2014). Statins Enhance Rotator Cuff Healing by Stimulating the COX2/PGE2/EP4 Pathway: An In Vivo and In Vitro Study. The American Journal of Sports Medicine PMID: 25184246