Trabecular bone and cortical bone have different bone remodeling levels, and the underlying mechanisms are not fully understood. In the present study, the expression of Wnt/β-catenin signaling and its downstream molecules along with bone mass in trabecular and cortical bone were compared in wild-type mice, constitutive activation of β-catenin (CA-β-catenin) mice and β-catenin deletion mice. It was found that the expression level of most of the examined genes such as Wnt3a, β-catenin, osteocalcin and RANKL/OPG ratio were significantly higher in trabecular bone than in cortical bone in wild-type mice. CA-β-catenin resulted in up-regulated expression of the above-mentioned genes except for RANKL/OPG ratio, which were down-regulated. Also, CA-β-catenin led to increased number of osteoblasts, decreased number of osteoclasts and increased bone mass in both the trabecular bone and cortical bone compared with wild-type mice; however, the extent of changes was much greater in the trabecular bone than in the cortical bone. By contrast, null β-catenin led to down-regulated expression of the above-mentioned genes except for RANKL/OPG ratio. Furthermore, β-catenin deletion led to decreased number of osteoblasts, increased number of osteoclasts and decreased bone mass when compared with wild-type mice. Again, the extent of these changes was more significant in trabecular bone than cortical bone. Taken together, we found that the expression level of Wnt/β-catenin signaling and bone remodeling-related molecules were different in cortical bone and trabecular bone, and the trabecular bone was more readily affected by changes in the Wnt/β-catenin signaling pathway. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:812-819, 2017.
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.
Accumulating evidence suggests that Wnt/β-catenin signaling plays a central role in controlling bone mass. We previously reported that constitutive activation of β-catenin (CA-β-catenin) in osteoblasts potentially has side effects on the bone growth and bone remodeling process, although it could increase bone mass. The present study aimed to observe the effects of osteoblastic CA-β-catenin on bone quality and to investigate possible mechanisms of these effects. It was found that CA-β-catenin mice exhibited lower mineralization levels and disorganized collagen in long bones as confirmed by von Kossa staining and sirius red staining, respectively. Also, bone strength decreased significantly in CA-β-catenin mice. Then the effect of CA-β-catenin on biological functions of osteoblasts were investigated and it was found that the expression levels of osteocalcin, a marker for the late differentiation of osteoblasts, decreased in CA-β-catenin mice, while the expression levels of osterix and alkaline phosphatase, two markers for the early differentiation of osteoblasts, increased in CA-β-catenin mice. Furthermore, higher proliferation rate were revealed in osteoblasts that were isolated from CA-β-catenin mice. The Real-time PCR and western blot examination found that the expression level of c-myc and cyclin D1, two G1 progression-related molecules, increased in osteoblasts that were isolated from the CA-β-catenin mice, and the expression levels of CDK14 and cyclin Y, two mitotic-related molecules that can accelerate cells entering into S and G2/M phases, increased in osteoblasts that were isolated from the CA-β-catenin mice. In summary, osteoblastic CA-β-catenin kept osteoblasts in high proliferative state and impaired the terminal osteoblast differentiation, and this led to changed bone structure and decreased bone strength.
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