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

Abstract

The secreted protein Dickkopf-1 (Dkk1) is an antagonist of canonical Wnt signaling, expressed during fracture healing. It is unknown if it is involved in the mechanical control of bone maintenance. We investigated the response to administration of a Dkk1 neutralizing antibody (Dkk1-ab) in metaphyseal bone under different loading conditions, with or without trauma. In this three part experiment, 120 rats had a screw or bone chamber inserted either unilaterally or bilaterally in the proximal tibia. Mechanical (pull-out) testing, µCT and histology were used for evaluation. The animals were injected with either 10 mg/kg Dkk1-ab or saline every 14 days for 14, 28, or 42 days. Antibody treatment increased bone formation around the screws and improved their fixation. After 28 days, the pull-out force was increased by over 100%. In cancellous bone, the bone volume fraction was increased by 50%. In some animals, one hind limb was paralyzed with Botullinum toxin A (Botox) to create a mechanically unloaded environment. This did not increase the response to antibody treatment with regard to screw fixation, but in cancellous bone, the bone volume fraction increased by 233 %. Thus, the response in unloaded, untraumatized bone was proportionally larger, suggesting that Dkk1 may be up-regulated in unloaded bone. There was also an increase in thickness of the metaphyseal cortex. In bone chambers, the antibody treatment increased the bone volume fraction. The results suggest that antibodies blocking Dkk1 might be used to stimulate bone formation especially during implant fixation, fracture repair, or bone disuse. It also seems that Dkk1 is up-regulated both after metaphyseal trauma and after unloading, and that Dkk1 is involved in mechano-transduction.

Parathyroid hormone-related protein (107-111) improves the bone regeneration potential of gelatin–glutaraldehyde biopolymer-coated hydroxyapatite

“…Furthermore, a previous study demonstrates that systemic or local injection of a DKK1 adenovirus hampered cortical defect healing in the mouse tibial diaphysis [36]. It has also been shown that an anti-DKK1 antibody injection was efficient to stimulate bone healing after trauma caused by a stainless steel screw inserted into the rat tibial metaphysis [44]. Hence, our present findings add credence to the notion that PTHrP (107-111) loaded onto HA Glu scaffolds may promote bone healing through targeting the Wnt pathway.…”

Wnt signaling in bone formation and its therapeutic potential for bone diseases

“…Enhanced fracture healing and orthopedic implant fixation in mice [Agholme et al 2011a;Komatsu et al 2010;Li et al 2011] Reduced osteolytic lesions in myeloma mouse models [Fulciniti et al 2009;Heath et al 2009;Yaccoby et al …”

Efficacy of a sclerostin antibody compared to a low dose of PTH on metaphyseal bone healing

“…1). 14,25 Bone volume/tissue volume (BV/TV) was considered the primary variable. All analyses were performed in a blinded manner.…”