Bone Regeneration Is Regulated by Wnt Signaling

Abstract

Tissue regeneration is increasingly viewed as reactivation of a developmental process that, when misappropriated, can lead to malignant growth. Therefore, understanding the molecular and cellular pathways that govern tissue regeneration provides a glimpse into normal development as well as insights into pathological conditions such as cancer. Herein, we studied the role of Wnt signaling in skeletal tissue regeneration.Introduction: Some adult tissues have the ability to regenerate, and among these, bone is one of the most remarkable. Bone exhibits a persistent, lifelong capacity to reform after injury, and continual bone regeneration is a prerequisite to maintaining bone mass and density. Even slight perturbations in bone regeneration can have profound consequences, as exemplified by conditions such as osteoporosis and delayed skeletal repair. Here, our goal was to determine the role of Wnts in adult bone regeneration. Materials and Methods: Using TOPgal reporter mice, we found that damage to the skeleton instigated Wnt reporter activity, specifically at the site of injury. We used a skeletal injury model to show that Wnt inhibition, achieved through adenoviral expression of Dkk1 in the adult skeleton, prevented the differentiation of osteoprogenitor cells. Results: As a result, injury-induced bone regeneration was reduced by 84% compared with controls. Constitutive activation of the Wnt pathway resulting from a mutation in the Lrp5 Wnt co-receptor results in high bone mass, but our experiments showed that this same point mutation caused a delay in bone regeneration. In these transgenic mice, osteoprogenitor cells in the injury site were maintained in a proliferative state and differentiation into osteoblasts was delayed. Conclusions: When considered together, these data provide a framework for understanding the roles of Wnt signaling in adult bone regeneration and suggest a feasible approach to treating clinical conditions where enhanced bone formation is desired.

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

“…Importantly, levels of functional Dkk1 predict protection from syndesmophyte formation in patients with AS [18]. Moreover, adenoviral overexpression of Dkk1 was shown to strongly reduce bone healing in mouse, in association with a complete prevention of Runx2 expression and TNAP activity [37]. However, in our hands, Dkk1 failed to reproducibly inhibit TNAP or mineralization.…”

Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones

“…(8) Conversely, inhibition of the Wnt/b-catenin pathway by adenoviral overexpression of Dickkopf 1 has been shown to inhibit the fracture healing process. (8)(9)(10) These results suggest that agents that activate the Wnt/b-catenin signaling pathway may have the potential to improve fracture healing.…”

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

“…By modulating Wnt signaling, it is possible to achieve an anabolic effect in bone. 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].…”