Modulation of Wnt signaling influences fracture repair

• Published in: Journal of orthopaedic research Vol. 28; no. 7; pp. 928 - 936
• Main Authors: Komatsu, David E., Mary, Michelle N., Schroeder, Robert Jason, Robling, Alex G., Turner, Charles H., Warden, Stuart J.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.07.2010
• Subjects: Absorptiometry, Photon; Animals; Antibodies - pharmacology; Biomechanical Phenomena; Bony Callus - diagnostic imaging; Bony Callus - metabolism; Bony Callus - physiopathology; Dkk1; Female; Femoral Fractures - diagnostic imaging; Femoral Fractures - metabolism; Femoral Fractures - physiopathology; Fracture Healing - physiology; fracture repair; Intercellular Signaling Peptides and Proteins - immunology; Intercellular Signaling Peptides and Proteins - metabolism; LDL-Receptor Related Proteins - genetics; LDL-Receptor Related Proteins - metabolism; Low Density Lipoprotein Receptor-Related Protein-5; Lrp5; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Signal Transduction - physiology; Wnt; Wnt Proteins - metabolism
• ISSN: 0736-0266; 1554-527X
• DOI: 10.1002/jor.21078

While the importance of Wnt signaling in skeletal development and homeostasis is well documented, little is known regarding its function in fracture repair. We hypothesized that activation and inactivation of Wnt signaling would enhance and impair fracture repair, respectively. Femoral fractures were generated in Lrp5 knockout mice (Lrp5−/−) and wild‐type littermates (Lrp5+/+), as well as C57BL/6 mice. Lrp5−/− and Lrp5+/+ mice were untreated, while C57BL/6 mice were treated 2×/week with vehicle or anti‐Dkk1 antibodies (Dkk1 Ab) initiated immediately postoperatively (Day 0) or 4 days postoperatively (Day 4). Fractures were radiographed weekly until sacrifice at day 28, followed by DXA, pQCT, and biomechanical analyses. Lrp5−/− mice showed impaired repair compared to Lrp5+/+ mice, as evidenced by reduced callus area, BMC, BMD, and biomechanical properties. The effects of Dkk1 Ab treatment depended on the timing of initiation. Day 0 initiation enhanced repair, with significant gains seen for callus area, BMC, BMD, and biomechanical properties, whereas Day 4 initiation had no effect. These results validated our hypothesis that Wnt signaling influences fracture repair, with prompt activation enhancing repair and inactivation impairing it. Furthermore, these data suggest that activation of Wnt signaling during fracture repair may have clinical utility in facilitating fracture repair. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:928–936, 2010