Cortical bone develops and changes in response to mechanical load, which is sensed by osteocytes in the skeleton. The bone formation response to load depends on STAT3 intracellular signals, which are upregulated after loading, and are subject to negative feedback from Suppressor of Cytokine Signaling 3 (Socs3). Mice with prolonged and elevated STAT3 activation in osteocytes, caused by Dmp1Cre-targeted knockout of Socs3, have delayed cortical bone maturation. Here we determined whether Dmp1Cre.Socs3f/fmice have an altered response to physiological mechanical load (treadmill running) and experimental loading (tibial compression).
Daily treadmill running for 5 weeks did not change cortical bone mass in control mice, but further delayed cortical development in Dmp1Cre.Socs3f/f mice. Cortical bone was thinner than gene-matched sedentary controls and contained less high density bone.
Tibial compression in control (Socs3f/f) and Dmp1Cre.Socs3f/fmice increased to a similar extent average cortical bone thickness and periosteal perimeter in the loaded tibia compared to the contralateral limb. However, 360˚ radial analysis revealed that, at the site of greatest compressive strain, the increase in cortical thickness in Dmp1Cre.Socs3f/fmice was significantly greater than that observed in controls. Calcein labeling confirmed that more new bone was deposited in loaded Dmp1Cre.Socs3f/ftibiae at both periosteal and endocortical surfaces at this site, than in loaded controls. This included formation of abundant woven bone, similar to that seen when bone is loaded at high strains. This suggests Dmp1Cre.Socs3f/fmice have a greater sensitivity to mechanical load.
In summary, mice with targeted SOCS3 deletion and immature cortical bone have an exaggerated response to both physiological and experimental loading. We conclude that there is an optimal level of osteocytic response to load required for cortical bone maturation and that load-induced bone formation may be enhanced by limiting the SOCS3 negative feedback loop in osteocytes.