Abstract
Accumulating evidence demonstrates that the Wnt/β-catenin signaling pathway plays a dominant role in bone repair. However, the role of Wnt/β-catenin signaling in the remodeling phase during bone fracture healing is currently unknown. In the present study, β-catenin was activated at different levels or deleted in mice at the late stage of fracture healing, and the effects on healing quality were investigated. Deletion of β-catenin disturbed bone remodeling, as confirmed by increased bone resorption and decreased bone formation, and significantly decreased bone strength compared with wildtype mice. In addition, the constitutive activation of β-catenin significantly increased the bone mass and delayed the bone remodeling process, resulting in slightly impaired bone strength. In contrast, a slight activation of β-catenin significantly increased bone formation and slightly hindered bone resorption. These effects lead to improved bone fracture healing quality compared with wildtype mice. In summary, the present study provides the first demonstration showing that Wnt/β-catenin signaling should be maintained at a slightly activated level during the late stage of fracture healing to ensure better bone fracture repair.
Highlights
Secondary bone healing is the most common type of fracture healing observed in a clinical setting
The mRNA expression levels of β-catenin and its target genes in fracture sites after the injection of tamoxifen were examined by RT-PCR, and the results revealed that the β-catenin expression level in β-catenin-knockout (β-catenin-KO) mice were approximately 35.2% of that detected in wildtype (WT) mice, whereas the levels obtained after constitutive and slight activation of β-catenin (CA-β-catenin and SA-β-catenin) were 2.31- and 1.21-fold higher than that found in WT mice, respectively (Fig. 1A)
The bone volume (BV) and tissue volume fraction (BV/total volume (TV)) decreased significantly and the transverse sections of the microCT images showed decreased bone volume with a significant bone void in β-catenin-KO mice compared with WT mice (Fig. 2Q and R)
Summary
Secondary bone healing is the most common type of fracture healing observed in a clinical setting. The protein controls the relationship between the numbers of osteoblasts and chondrocytes that arise from pluripotent mesenchymal cells Both too much and too little β-catenin can be detrimental to bone healing at this stage. Β-catenin promotes the differentiation of osteoblasts and enhances their production of the bone matrix; too little β-catenin at this stage impairs healing[4, 7], whereas β-catenin levels increased by the administration of the above-mentioned Wnt agonist or neutralizing antibodies could improve healing[4, 7, 13, 15]. Our previous studies indicated that constitutive activation of β-catenin impairs the terminal differentiation of osteoblasts[16, 17] This effect might reduce the final bone fracture healing quality. Β-catenin was constitutively activated, slightly activated or deleted in mice, and the effects of β-catenin on the bone remodeling phase and eventual bone fracture healing quality were investigated
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