Inducible expression of Wnt7b promotes bone formation in aged mice and enhances fracture healing

Deye Song,Matthew J Silva,Zhepeng Wang,Xiaochen Liu,Jiangdong Ni,Fangfang Song,Fanxin Long,Lele Liao,Guangxu He

doi:10.1038/s41413-019-0081-8

Deye Song, Matthew J Silva + Show 7 more

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https://doi.org/10.1038/s41413-019-0081-8

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There remain unmet clinical needs for safe and effective bone anabolic therapies to treat aging-related osteoporosis and to improve fracture healing in cases of nonunion or delayed union. Wnt signaling has emerged as a promising target pathway for developing novel bone anabolic drugs. Although neutralizing antibodies against the Wnt antagonist sclerostin have been tested, Wnt ligands themselves have not been fully explored as a potential therapy. Previous work has demonstrated Wnt7b as an endogenous ligand upregulated during osteoblast differentiation, and that Wnt7b overexpression potently stimulates bone accrual in the mouse. The earlier studies however did not address whether Wnt7b could promote bone formation when specifically applied to aged or fractured bones. Here we have developed a doxycycline-inducible strategy where Wnt7b is temporally induced in the bones of aged mice or during fracture healing. We report that forced expression of Wnt7b for 1 month starting at 15 months of age greatly stimulated trabecular and endosteal bone formation, resulting in a marked increase in bone mass. We further tested the effect of Wnt7b on bone healing in a murine closed femur fracture model. Induced expression of Wnt7b at the onset of fracture did not affect the initial cartilage formation but promoted mineralization of the subsequent bone callus. Thus, targeted delivery of Wnt7b to aged bones or fracture sites may be explored as a potential therapy.

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The adult human skeleton is a dynamic organ that undergoes continuous remodeling throughout life to support whole-body mineral homeostasis while sustaining structural integrity
We have exhibited similar expression patterns, we present here the data previously reported that overexpression of Wnt7b in the from only one of them and propagated this line for osteoblast lineage potently stimulates bone formation in adult subsequent studies
By temporally activating Wnt7b expression in aged mice, we show that Wnt7b potently stimulates bone formation and leads to a marked increase in bone mass

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1234567890();,: INTRODUCTION

The adult human skeleton is a dynamic organ that undergoes continuous remodeling throughout life to support whole-body mineral homeostasis while sustaining structural integrity. GFP was detectable in the postfracture application of Wnt7b notably stimulates hypertrophic chondrocytes (HC), indicating that the BAC transmineralization of the bone callus These results provide gene recapitulated the normal expression pattern of Osx in proof of principle that Wnt7b protein may be explored as a bone skeletal cells, including that in the embryonic HC (Fig. 1d).[27] No anabolic therapy. Mice with the genotype of Osx-rtTA;tetO-Cre;R26-Wnt7b were raised on a regular diet until 10 weeks of age when a fracture was introduced at the diaphysis of the right femur of each mouse; the mice were randomly assigned to two groups with or without Dox supplement in the diet, and allowed to heal for up to 21 days (Fig. 5a). Wnt7b stimulates mineralization of the bone callus with no obvious effect on the callus size

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