Role of estrogen receptor signaling in low-magnitude high-frequency vibration-induced effects on bone fracture healing

• Applicant: Professorin Dr. Melanie Haffner-Luntzer
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 413253470

Due to its osteoanabolic effects, low-magnitude high-frequency whole-body vibration (LMHFV) is supposed to provide a non-invasive, cost-effective and safe treatment to increase bone mass and improve bone quality in osteoporotic patients. Much less is known about the effects of LMHFV on bone fracture healing. Experimental studies reported contradictory results. It has been shown that LMHFV supports bone regeneration in estrogen-deficient rodents, whereas, in estrogen-competent animals, no or negative effects were observed. This indicates a major role for estrogen in mechanostimulation of bone repair and implies that LMHFV might only be beneficial in confined target populations. However, the underlying molecular mechanisms remain poorly understood. In preliminary work for this proposal, we studied the role of estrogen receptor (ER) signaling in LMHFV-induced effects on fracture healing using ER alpha- and ER beta-knockout mice. Our results suggest a critical role of ER alpha-, but not of ER beta-signaling. However, remaining open questions which should be addressed by the proposed project are, if ligand-dependent or ligand-independent ER alpha-signaling is responsible for the effects of LMHFV and which cell types in the fracture callus are the targets for mechanostimulation. To answer the first question, we will use ER alpha-AF1-0 and ER alpha-AF2-0 mice for fracture healing studies, since the AF-1 domain is responsible for ligand-dependent and -independent signaling, whereas AF-2 exerts only ligand-dependent signaling. To identify the involved cell types, we will use cell-specific ER alpha-knockout mice. Additional in vivo and in vitro experiments will be performed to identify molecular targets of ER alpha signaling during LMHFV and if ER alpha- signaling interact with other pathways, such as Wnt/beta-catenin-signaling, during mechanotransduction. The results of the proposed project might be clinically relevant to establish LMHFV-based treatment options for fracture patients.

• DFG Programme: Research Grants