BoneKEy Reports | BoneKEy Watch

Osteoblast-secreted Wnt ligands are crucial for bone development


It is well known that signaling via the Wnt/β-catenin pathway is involved in bone development and remodeling during growth and adult life but many questions remain unanswered, such as which specific cell types in the bone microenvironment are responsible for producing each of the 19 proteins in the Wnt family.

In this study, Zhong et al. conditionally inactivated the gene that codes for the Wntless (Wls)/Gpr177 protein using Cre recombinase in conjunction with the osteocalcin promoter. The resulting mice, which were unable to express the Wls gene in mature osteoblasts and osteoclasts, had abnormally low bone mass. This first became apparent within the first three weeks of life and the mice were prone to spontaneous fractures, rarely surviving beyond eight weeks.

Bone analysis revealed reduced cortical and trabecular bone mass. Follow up studies in vitro showed that osteoblasts in mice homozygous for the gene deactivation were unable to mature normally and showed reduced levels of Gpr177 protein and β-catenin. Transcription of Axin2, osterix and Ocn was two-to-fourfold lower, but Runx2 expression was unaffected.

Editor’s comment: This study provides functional significance to genome-wide association studies that recently reported polymorphisms at the Gpr177 locus that are associated with low bone mineral density. The findings further emphasize the crucial importance of Wnt signaling in osteoblast differentiation and bone formation.

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