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Inducible expression of Wnt7b promotes bone formation in aged mice and enhances fracture healing
Deye Song1,2, Guangxu He1,2, Fangfang Song3
11Department of Orthopedics, The Second Xiangya Hospital, Central South University, Hunan, 410011 PR China.
Abstract:
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.
Insights
Targeted Wnt7b therapy shows promise for treating osteoporosis and improving fracture healing. This study demonstrates Wnt7b
Area of Science:
- Bone biology and regenerative medicine
- Molecular signaling pathways in skeletal health
Background:
- Aging-related osteoporosis and fracture nonunion present significant unmet clinical needs.
- Wnt signaling is a key pathway for bone formation, with Wnt ligands underexplored as therapeutics.
- Sclerostin inhibitors show potential, but direct Wnt ligand therapy remains largely uninvestigated.
Purpose of the Study:
- To investigate the therapeutic potential of Wnt7b, an endogenous bone anabolic ligand, for aged bone and fracture healing.
- To develop and utilize a doxycycline-inducible system for temporal Wnt7b expression in mouse models.
Main Methods:
- A doxycycline-inducible Wnt7b expression system was established in mice.
- Wnt7b was temporally induced in aged mice (15 months old) for one month.
- The effect of Wnt7b induction on fracture healing was assessed in a murine closed femur fracture model.
Main Results:
- Wnt7b induction in aged mice significantly increased trabecular and endosteal bone formation, leading to higher bone mass.
- In a fracture model, Wnt7b did not alter initial cartilage formation but enhanced mineralization of the bone callus.
- These findings highlight Wnt7b's anabolic effects on bone in different contexts.
Conclusions:
- Temporally controlled Wnt7b expression can effectively stimulate bone formation in aged bone.
- Wnt7b promotes critical mineralization stages during fracture healing.
- Targeted Wnt7b delivery represents a potential therapeutic strategy for osteoporosis and fracture repair.
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