Mannose-6-phosphate, an inhibitor of transforming growth factor-beta, 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-beta) is a key cytokine in the pathogenesis of tissue fibrosis. In this study, the effects of two natural inhibitors of TGF-beta, 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-beta along with increasing doses of decorin or mannose-6-phosphate. Collagen-I 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-beta 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-beta 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.
Bates
Steven J
SJ
Stanford University Medical Center, 770 Welch Road, Suite 400, Stanford, CA 94304, USA.
Morrow
Ellen
E
Zhang
Andrew Y
AY
Pham
Hung
H
Longaker
Michael T
MT
Chang
James
J
D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis; D058575:Decorin; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D016326:Extracellular Matrix Proteins / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008360:Mannosephosphates / Q000494:pharmacology*; D011509:Proteoglycans / Q000494:pharmacology; D011817:Rabbits; D016059:Range of Motion, Articular / Q000187:drug effects*; D013710:Tendons / Q000166:cytology / Q000601:surgery*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
D024042:Collagen Type I; D058575:Decorin; D016326:Extracellular Matrix Proteins; D008360:Mannosephosphates; D011509:Proteoglycans; D016212:Transforming Growth Factor beta; C027693:mannose-6-phosphate