Attenuated Response to In Vivo Mechanical Loading in Mice With Conditional Osteoblast Ablation of the Connexin43 Gene (Gja1)

Abstract

In vitro data suggest that gap junctional intercellular communication mediated by connexin43 (Cx43) plays an important role in bone cell response to mechanical stimulation. We tested this hypothesis in vivo in a model of genetic deficiency of the Cx43 gene (Gja1). Four-month-old female mice with a conditional Gja1 ablation in osteoblasts (ColCre;Gja1(-/flox)), as well as wildtype (Gja1(+/flox)) and heterozygous equivalent (Gja1(-/flox)) littermates (eight per genotype), were subjected to a three-point bending protocol for 5 d/wk for 2 wk. Microstructural parameters and dynamic indices of bone formation were estimated on sections of loaded and control contralateral tibias. ColCre;Gja1(-/flox) mice had significantly thinner cortices, but larger marrow area and total cross-sectional area in the tibial diaphysis, compared with the other groups. The ColCre;Gja1(-/flox) mice needed approximately 40% more force to generate the required endocortical strain. In Gja1(+/flox) mice, the loading regimen produced abundant double calcein labels at the endocortical surface, whereas predominantly single labels were seen in ColCre;Gja1(-/flox) mice. Accordingly, mineral apposition rate and bone formation rate were significantly lower (54.8% and 50.2%, respectively) in ColCre;Gja1(-/flox) relative to Gja1(+/flox) mice. Intermediate values were found in Gja1(-/flox) mice. Gja deficiency results in thinner but larger tibial diaphyses, resembling changes occurring with aging, and it attenuates the anabolic response to in vivo mechanical loading. Thus, Cx43 plays an instrumental role in this adaptive response to physical stimuli.