Modulation of Wnt signaling influences fracture repair

Abstract

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.

The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions

“…Similar results as those reported for sclerostin antibodies have also been reported with blocking or down regulation of Dkk1 expression. Dkk1 antibodies enhance endochondral bone healing in LRP5 deficient mice [16]. Inhibition of Dkk1 can counter some of the effects of oestrogen deficiency in rats, restoring bone mineral content and density [35].…”

“…Skeletal trauma causes a local increase in Wnt signaling [11] and it has been shown that the pathways involved in bone Wnt signaling are necessary for bone healing [11][12] and for bone formation in general [13][14][15]. Fracture repair can be influenced by blocking Dkk1 in mice [16] and a decrease in Dkk1 gene expression leads to an increase in bone mass and strength [15,17].…”

Autocrine stimulation of osteoblast activity by Wnt5a in response to TNF-α in human mesenchymal stem cells

“…Wnt factors are suspected to relay the early indirect effects of TNF-a in AS [10] and during bone repair [11][12][13]. Wnt proteins are a family of 19 highly conserved secreted glycoproteins that play essential roles during development and tissue homeostasis.…”

CORR Insights®: Does Sclerostin Depletion Stimulate Fracture Healing in a Mouse Model?

“…Next, the current study injects Scl-Ab a week after the fracture, which may have undercut the beneficial effectiveness of the treatment during the first week of healing. Delayed injection post fracture of a different monoclonal antibody of a negative regulator of the Wnt pathway, DKK1, impaired its benefit compared to injections immediately postfracture [3]. Therefore, what are the consequences of early as well as late Scl-Ab treatment?…”