Role of estrogen receptor signaling in low-magnitude high-frequency vibration-induced effects on bone fracture healing
Final Report Abstract
Postmenopausal osteoporosis is known to disturb fracture healing, while the underlying mechanisms remain largely unknown. Ovariectomized (OVX) mice are widely used to investigate the molecular pathways that are involved in osteoporosis development. To improve osteoporosis-induced compromised fracture healing, many treatments are currently under investigation. Among them, external biomechanical stimulation by low-magnitude highfrequency vibration (LMHFV) was shown to significantly improve fracture healing in OVX mice, but delays healing in non-OVX mice. It is further known that ERα signaling is required for mediating the vibration-induced effects on bone fracture healing, however it was not known on which cell types the ERα might be crucial for mechanotransduction during bone healing. We hypothesized that osteoblast-lineage cells might be the main drivers of the LMHFV-induced effects, therefore we first generated a mouse-line lacking the ERα in late chondrocytes and osteoblast lineage-specific cells (Runx2-Cre/ERαflox) and studied if the deletion affects the skeletal bone phenotype of these mice. Having established that, we further aimed to investigate if the deletion of ERα on osteoblastic cells is involved in the effects of LMHFV on fracture healing in skeletally healthy non-OVX and osteoporotic, OVX mice. Male Cre+ mice displayed a significantly increased cortical bone mass and flexural rigidity of the femurs compared to age-matched controls with no active Cre-transgene. By contrast, female Cre+ mice exhibited significant trabecular bone loss, whereas in cortical bone periosteal and endosteal diameters were reduced. Our results indicate that the ERα in osteoblast progenitors and late chondrocytes differentially contributes to bone mass regulation in male and female mice and improve our understanding of ERα signaling in bone cells in vivo. Our fracture healing study using non-OVX and OVX female mice which were subjected to vibration indicated a critical role of the ERα in osteoprogenitor cells during mechanotransduction in the fracture callus both under estrogen-deficient and -sufficient conditions. Additional in vitro experiments revealed that prostaglandin and Wnt signaling pathways seems to be important for vibration-induced effects on osteogenic cells under estrogen-deficient conditions. Furthermore, by performing in vitro experiments with vibrated osteogenic cells in estrogen-supplemented media and utilizing ERαAF-2 mice which lack ligand-dependent ERα signaling, we were able to conclude that the AF-2 domain is involved in the negative effects of vibration during bone fracture healing in skeletally healthy mice. These results could be used to develop treatment strategies to combine whole-body-vibration with selective estrogen receptor mediators to treat fracture healing complications in the clinics. Further studies should investigate the translational potential of our findings.
Publications
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Influence of Low-Magnitude High-Frequency Vibration on Bone Cells and Bone Regeneration. Frontiers in Bioengineering and Biotechnology, 8.
Steppe, Lena; Liedert, Astrid; Ignatius, Anita & Haffner-Luntzer, Melanie
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Estrogen Receptor α Signaling in Osteoblasts is Required for Mechanotransduction in Bone Fracture Healing. Frontiers in Bioengineering and Biotechnology, 9 (2021, 12, 7).
Steppe, Lena; Krüger, Benjamin Thilo; Tschaffon, Miriam Eva Angelica; Fischer, Verena; Tuckermann, Jan; Ignatius, Anita & Haffner-Luntzer, Melanie
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Bone Mass and Osteoblast Activity Are Sex-Dependent in Mice Lacking the Estrogen Receptor α in Chondrocytes and Osteoblast Progenitor Cells. International Journal of Molecular Sciences, 23(5), 2902.
Steppe, Lena; Bülow, Jasmin; Tuckermann, Jan; Ignatius, Anita & Haffner-Luntzer, Melanie
