The finding that both gain- and loss-of-function mutations in the Lrp5 receptor regulate bone mass in humans highlighted the important role of Wnt signaling in skeletal biology. The information from various genetic mouse models expanded our knowledge about the extensive involvement of this signaling pathway in regulating skeletal development. Various in vitro studies further enriched our understanding with regard to how Wnt signaling might regulate skeletogenesis. However, many questions still remain unanswered.
It is proposed that Wnt regulates osteoblastogenesis through the canonical, β-beta;-catenin dependent pathway. There is some supporting evidence for this statement. However, the recent finding that Wnt3a and Wnt7b promote bone formation through G protein-linked PKCδ activation challenged this view. It will be necessary to gather more information about the effect of this pathway on in vivo bone formation. The detailed molecular mechanism of other “canonical Wnts,” such as Wnt1 and Wnt10b, in the regulation of osteoblastogenesis needs further investigation.
Studies using transgenic and knockout mice have provided tremendous information about the role of Wnt signaling in skeletal development, in vivo. Although mice models manipulating the β-catenin exist, the β-catenin dependent pathway may not be the sole or critical pathway for the effect of some Wnts on the skeletal system. It is expected that gain- and loss-of-function mouse models targeting specific skeletal component will greatly help elucidate the role of Wnt signaling in skeletal development. Because of possible functional redundancy, the development of skeletal conditional double or triple knockout mice models will be necessary
We are starting to understand the role of Wnt signaling in osteoclastogenesis. To date, the majority of the data points to the indirect role of Wnt signaling in osteoclasts via a regulation of the RANKL-OPG pathway by osteoblasts. However, it is largely unknown whether and by what means Wnt signaling affects osteoclasts. Mice models with osteoclast specific overexpression or deletion of the Wnt signaling components would provide valuable information for this.
The molecular mechanisms for the different responses to canonical Wnt signaling in various cells and stages of differentiation need further study. In particular, it’s important to know how Wnt signaling promotes or inhibits mesenchymal stem cell differentiation towards osteoblast lineage. The underlying mechanism that is responsible for the inhibition of osteogenic differentiation of MSCs by Wnt1 or Wnt3a is not clear. Although the canonical Wnt signaling plays a critical role in bone development, targeting the canonical Wnt signaling pathway may not be useful for improving the osteogenic potential of MSCs. Targeting non-canonical Wnt singaling to enhance osteogenic differentiation of MSCs needs further study.