Mechanical Vibration Induces Differentiation of Mesenchymal Stem Cells to Osteoblasts at the Expense of Adipocyte Differentiation through Activation of Wnt Pathway and Inhibition of PPARgamma Nuclear Hormone Receptor in Osteoporotic Bone
Introduction. Osteoporosis (OP) in post-menopausal women causes abnormally low bone mineral density, bone fragility, and high bone marrow adipocyte content. With 54 million currently afflicted in the United States and another 120 million predicted to suffer from OP by 2050 in China1, substantial efforts have been directed towards the generation of safe and effective therapies for OP. The standard treatment involves hormone replacement in post-menopausal women and use of the antiresorptive agents such as bisphosphate. This approach is associated with increased risk of atypical femur fracture and osteonecrosis of the mandible2. Disrupted hormonal homeostasis in OP results in the loss of the capacity for mesenchymal stem cells (MSC) to differentiate into osteoblasts. The resultant effect is increased differentiation of MSCs to adipocytes resulting in that higher fat content and diminished capacity to maintain bone tissue3. One possible approach to safely enhance osteogenic differentiation of MSCs is mechanical stimulation through exposure to vibration and this has been explored in model systems. Methods. To model OP, female rodents were ovariectomized (OVX). The control group underwent sham OVX by removal similar sized piece of adipose. The animal models were then subject to mechanical vibration. Rats were euthanized allowing tissue to be subjected to further testing. Results. Alikani et al. reported that application of vibration resulted in up-regulation of Wingless pathway components LRP6, β-catenin, BMP2, and Wnt3a while down regulating Wnt inhibitor SOST promoting an osteogenic differentiation in OP mice. This resulted in preserved bone quality.4 In Li et al., some rats received estradiol (E2) and some received vibration. The OVX rats that received vibration exhibited a pro-osteogenic state with upregulation of ERα, Wnt3a and β-catenin as well as down regulation of PPARγ and RANKL. Bone was tested post-mortem and revealed that vibration restored density and strength of bone more than in the group receiving E2.5 Conclusion. Upregulation of pro-osteogenic signals (Wnt3a, Lrp6 and β-catenin) along with the downregulation of inhibitors (SOST and PPARγ) of the canonical Wnt/β-catenin pathway resulted in maintenance of bone density in rodents with OP. Low intensity mechanical vibration has been shown to treat the pathologies of OP through activation of the canonical Wnt/β-catenin pathway and inhibition of PPARγ pathway thus driving the differentiation of MSCs into osteoblasts. Though the mechanism by which vibration increases Wnt signaling is not understood, the novel therapy could lead to safe treatments of OP without the need for of drugs or hormone replacement.
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