| Flexor tendon healing involves a coordinated response of many cells and tissues, with unique temporal and spatial patterns of gene expression. Primary flexor tendon repairs are associated with significant clinical complications, the most notable being formation of fibrous adhesions that decrease the range of motion of the affected digit.;Using a murine model of flexor tendon healing, we have shown that there is a biphasic response of the gelatinolytic matrix metalloproteinases (Mmps) after injury and repair. Mmp-9 (Gelatinase B) is highly expressed on day seven post-repair during the early inflammatory phase and is associated with the degradation of damaged collagen at the injury site. Collagen catabolism sends out chemotactic signals to recruit ECM secreting fibroblasts to the repair site. Th abundant matrix deposition acts to restore tendon integrity, but also results in adhesion formation that limits the gliding function of the tendon. In contrast, Mmp-2 (Gelatinase A) expression is highest at day 21, and breakdown of collagen at this time results in remodeling of the tendon, and a decrease in adhesions.;Loss of Mmp-9 during the tendon healing process using Mmp-9-/- mice resulted in earlier remodeling of adhesions, without any decline in the maximum load at failure of the repaired tendons compared to wild type mice, indicating that this is an important target for therapeutic intervention.;To determine the molecular mechanism of Mmp-9 induction, primary tenocytes were isolated and treated with Prostaglandin E2 (PGE2), which is a modulator of the inflammatory response and is increased after tendon injury.;Tenocytes responded to PGE2 by increasing expression and activity of Mmp-2, however Mmp-9 expression was not altered. Using GFP bone marrow chimeric mice, we have shown that there is an influx of bone marrow derived cells to the repair site after flexor tendon injury, so the response of cultured bone marrow cells to PGE2 was determined. Mmp-9 expression and activity were significantly increased in response to PGE2 in bone marrow cells, and this induction was mediated through the EP4 prostanoid receptor.;To definitively determine that bone marrow cells migrate to the repair site and produce Mmp-9, leading to adhesion formation, Mmp-9-/- (KO) bone marrow was transplanted in to wild type (WT) mice, while WT bone marrow was transplanted in to KO mice. Healing tendons from WT mice with KO bone marrow had a significant decrease in adhesion formation compared to KO mice with WT bone marrow. Additionally, there was no Mmp-9 detected by In situ hybridization in WT animals with KO bone marrow, and there was abundant Mmp-9 detected in Mmp-9-/- mice with WT bone marrow. This highlights a potentially important role for inhibition of Bone Marrow derived Mmp-9 during flexor tendon healing.;Targeting bone marrow derived Mmp-9 during the flexor tendon healing process represents a possible therapeutic intervention to decrease adhesion formation, while not compromising any strength of the repair, which could have significant clinical benefits. |
