Wnt signaling executes an indispensable performance in osteoblast differentiation

bone development

homeostasis

and remodeling. Wnt signals trigger the intracellular Wnt signaling cascade to initiate regulating the implication of β-catenin in the bone environment. Going through the novel discoveries done via high-throughput sequencing technologies on genetic mouse models

we highlighted the significant contribution of Wnt ligands

co-receptors

inhibitors

their related skeletal phenotypes in mouse models and the similar bone disorders clinically observed in human beings. Moreover

the crosstalk between Wnt signaling pathway and BMP

TGF-β

FGF

Hippo

Hedgehog

Notch and PDGF signaling pathways is thoroughly demonstrated to be the underlying gene regulatory network that orchestrates osteoblast differentiation and bone development. We also introspected the significance of Wnt signaling transduction in the reorganization of cellular metabolism by stimulating glycolysis

glutamine catabolism

and fatty acid oxidation in osteoblast-lineage cells that display an important regulatory arbor in the cellular bioenergetics of the bone. Throughout this evaluation

most to date therapeutical approaches towards osteoporosis and other bone maladies found in human beings

are formulated with an aspiration to holistically revamp the present clinical applications involving various monoclonal antibodies therapies that lack specificity

efficacy

and safety into more requisite advanced therapeutics that satisfy these three requirements for further clinical considerations. Conclusively

our review provides comprehensive scientific findings related to the fundamental significance of Wnt signaling cascades in skeletal system and the underlying gene regulatory network with other signaling pathways enlightening researchers with the possibility to further integrate the identified target molecules into therapeutic strategies for skeletal disorders treatment in the clinic.