Connexin 43 deficiency may protect against bed rest-associated bone loss

By Laura Cowen

Mice lacking connexin 43 (Cx43), the most abundant gap junction protein in bone, have a decreased susceptibility to the effects of mechanical unloading on bone, US researchers report.

Therefore, "Cx43 may represent a novel therapeutic target for investigation as a countermeasure for age-related and unloading-induced bone loss," Henry Donahue (Penn State College of Medicine, Hershey, Pennsylvania, USA) and co-authors of the study remark in the Journal of Bone and Mineral Research.

Cx43 is has previously been shown to play a key role in skeletal homeostasis. To further investigate its role in mechanical unloading, the researchers subjected skeletally mature mice with a bone-specific deletion of Cx43 (cKO) to 3 weeks of hindlimb suspension (HLS). This technique mimics the effects of skeletal unloading due to prolonged bed rest, reduced activity associated with aging, and spaceflight microgravity, they explain.

At baseline, the cortical bone of cKO mice displayed an osteopenic phenotype, with a significantly greater cortical bone area, decreased cortical thickness, decreased bone mineral density, and increased porosity, compared with wild-type (WT) mice. By contrast, there were no significant differences between WT and cKO mice in any of the trabecular bone parameters.

However, after 3 weeks of HLS, WT mice experienced substantial declines in trabecular bone volume fraction ([you don't need the '-' if you are saying declines]67%), connectivity density (64%), trabecular thickness (35%), and trabecular tissue mineral density (3%). These deleterious effects were significantly attenuated in cKO mice, with respective reductions of 53%, 50%, 21%, and 1%.

The effect of HLS on cortical bone was modest compared with that on trabecular bone, and there was no difference in loss of cortical microstructure between WT and cKO mice for any of the parameters assessed by micro-computed tomography.

Analysis of histomorphometry data demonstrated a substantial decrease in bone formation rate, mineralizing surface, and mineral apposition rate following HLS in WT micebut not in cKO mice, where parameters were maintained at baseline levels.

Interestingly, mechanical testing of femurs revealed a greater loss of strength and rigidity for cKO than for WT mice during HLS.

"Taken together, the results of the present study indicate that Cx43 deficiency desensitizes bone to the effects of mechanical unloading, and that this may be due to an inability of mechanosensing osteocytes to effectively communicate the unloading state to osteoblasts to suppress bone formation," Donahue et al conclude.

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