Osteocyte-Specific Deletion of the α2δ1 Auxiliary Voltage Sensitive Calcium Channel Subunit


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Context: Skeletal unloading due to disuse, disease, or aging increases bone loss and the risk of skeletal fracture. Conversely, mechanical loading is anabolic to the skeleton, promoting skeletal integrity through increased bone formation. As calcium influx is the first measurable response of bone cells to mechanical stimuli, voltage sensitive calcium channels (VSCCs) play a critical role in bone formation. Given VSCC activity is influenced by its auxiliary α2δ1 subunit, regulating the gating kinetics of the channel’s pore-forming (α1) subunit and forward trafficking of VSCCs to cell membranes, the α2δ1 subunit may govern anabolic bone responses. Objective & Design: We hypothesized that osteocyte-specific α2δ1 deletion in a mouse model would impair skeletal development, decrease bone formation and mechanosensitivity. Methods: Generation of an osteocyte-specific α2δ1 knockout was accomplished by crossing mice (C57BL/6) harboring LoxP sequences flanking Cacna2d1, the gene encoding α2δ1, with mice expressing Cre recombinase under the control of the Dmp1 (10Kb) promoter (Cacna2d1fl/fl, Dmp1-Cre+). To assess skeletal phenotype and mechanosensitivity, longitudinal whole body and site-specific DXA, in vivo μCT (10wk old), and two weeks of tibial loading (16wks) will be conducted before femurs are collected at 20 wks for mechanical testing, ex vivo μCT, and quantitative histomorphometry. Results & Conclusion: Preliminary analyses show no differences in whole body or site-specific BMD and BMC values between mice over time, suggesting osteocyte-specific α2δ1 deletion may not influence skeletal development. However, key differences in mechanosensitivity following tibial loading are expected given the potential role of α2δ1 in mechanically-induced bone formation.


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