Statins 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]
Take 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.
Questions for Discussion: Do you think inflammation is important in tendon healing? Do your patients who take statins have improved outcomes following rotator cuff repair?
Written by: Katie Reuther
Reviewed by: Jeffrey Driban