Mice Lacking the a2d1 Auxiliary Voltage Sensitive Calcium Channel Subunit Have Impaired Bone Quantity and Decreased Lean Mass

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Medicine and Health Sciences


Mechanical loading is critical for bone remodeling. Voltage sensitive calcium channels (VSCCs) influence bone development and responses to loading. The α2δ1 VSCC subunit regulates osteocyte mechanosensation. Here we used α2δ1 knockout mice to determine the role of this subunit in bone development. Dual energy x-ray absorptiometry (DEXA) analyses (n=6/genotype) included male and female mice. Cacna2d1 KO mice had reduced body weight, compared to control mice, by an average of 17.85% (p<0.01) over the ages examined (6, 9, 12, 15, and 18 weeks). Absolute lean mass was reduced in KO mice by an average of 20.68% (p<0.0001). When normalized to body weight, lean mass was reduced in Cacna2d1 KO mice by 7.62% (p<0.01). Whole body bone mineral density (BMD) and bone mineral content (BMC) were reduced by 8.95% (p<0.001) and 26.04% (p<0.0001) respectively. BMD and BMC of the femur was reduced in KO mice by an average of 15.01% (p<0.0001) and 28.62% (p<0.0001) respectively. BMD and BMC of L3-L5 vertebrae were reduced by an average of 11.67% and 23.53% respectively (p<0.0001). μCT analysis of the cancellous compartment of distal femoral metaphyses (n=3 per genotype) revealed that KO mice had decreased trabecular BV/TV (40.43%), decreased trabecular connectivity (77.89%), decreased trabecular number (17.17%), and increased trabecular spacing (22.4%) (p<0.05). Total BMC was decreased in Cacna2d1 KO mice by 18.54%, while cortical BMC was reduced by 13.75% (p=0.0525). Here we show that deletion of α2δ1 in C57BL/6 mice decreased whole body BMC and BMD prominently in trabecular bone, while lean mass was also reduced. We have previously shown that the α2δ1 subunit supports osteocyte responses to force in vitro, thus this subunit may regulate load-induced bone formation. Additionally, as the α2δ1 subunit is the receptor for the antiepileptic drug gabapentin, future work seeks to reveal the mechanisms underlying gabapentin-associated bone loss.


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