title: 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 unclear how 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 10mg/kg Dkk1-ab or saline every 14days for 14, 28, or 42days. Antibody treatment increased bone formation around the screws and improved their fixation. After 28days, 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 Botulinum 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.
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. fredrik.agholme@liu.se
authors.forename: Fredrik
authors.initials: F
authors.lastname: Agholme
authors.forename: Hanna
authors.initials: H
authors.lastname: Isaksson
authors.forename: Stuart
authors.initials: S
authors.lastname: Kuhstoss
authors.forename: Per
authors.initials: P
authors.lastname: Aspenberg
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D001696:Biomechanical Phenomena / Q000187:drug effects; D001863:Bone Screws; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects*; D005592:Fracture Fixation; D020007:Implants, Experimental; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology*; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013977:Tibia / Q000000981:diagnostic imaging / Q000473:pathology; D016474:Weight-Bearing / Q000502:physiology; D055114:X-Ray Microtomography
chemical_list: D057134:Antibodies, Neutralizing; C531384:Dkk1 protein, rat; D036341:Intercellular Signaling Peptides and Proteins