Mannose-6-phosphate, an inhibitor of transforming growth factor-β, improves range of motion after flexor tendon repair

Background: Adhesion formation between the flexor tendon and its surrounding fibro-osseous sheath results in a decreased postoperative range of motion in the hand. Transforming growth factor-beta (TGF-β) is a key cytokine in the pathogenesis of tissue fibrosis. In this study, the effects of two natural inhibitors of TGF-β, decorin and mannose-6-phosphate, were investigated in vitro and in vivo. Methods: In the in vitro investigation, primary cell cultures from rabbit flexor tendon sheath, epitenon, and endotenon were established and each was supplemented with TGF-β along with increasing doses of decorin or mannose-6-phosphate. Collagen-1 production was measured with enzyme-linked immunosorbent assay (ELISA). For the in vivo study, rabbit zone-II flexor tendons were transected and then immediately repaired. Single intraoperative graded doses of decorin, mannose-6-phosphate, or phosphate-buffered saline solution (control) were added to the repair sites, and the forepaws were tested for the range of motion and repair strength at eight weeks postoperatively. Results: Decorin and mannose-6-phosphate both reduced TGF-β upregulated collagen production. Intraoperative application of low-dose mannose-6-phosphate significantly improved the range of motion of the operatively treated digits. The effect on breaking strength of the tendon repair was inconclusive. Conclusions: Mannose-6-phosphate is effective in reducing TGF-β upregulated collagen production in an in vitro model. This finding correlated with our in vivo finding that a single intraoperative dose of mannose-6-phosphate improved the postoperative range of motion. Clinical Relevance: Mannose-6-phosphate is ubiquitous, nonimmunogenic, and easily produced, making it an ideal candidate for clinical application to reduce adhesion formation after flexor tendon repair.