Sclerostin is expressed almost exclusively by mature osteocytes in bone. Recent findings from this lab indicate that sclerostin targets pre-osteocytes and osteocytes to regulate bone mineralisation1, osteoclast activity2, and, potentially, osteocytic osteolysis3. Sclerostin expression in vivo is associated with the response of osteocytes to mechanical loading and unloading.
The aim of this study was to examine the direct effects of sclerostin on loading-induced bone growth ex vivo. For this, 10mm x 5mm bovine sternum trabecular bone cores were perfused with osteogenic media at 37°C for up to 3 weeks in individual bone culture chambers. The cores were divided into 3 groups; a) mechanically loaded (300 cycles, 4000 µstrain, 1 Hz/day), b) identical loading regime with continuous perfusion of 50 ng/ml recombinant human sclerostin and c) unloaded controls. Loading was accomplished using the Zetos™ long-term bone organ culture and piezo-electric bone loading system. Daily measurements of the bone core stiffness, media pH and ionic calcium concentrations were made. Histomorphometric assessment, including fluorochrome labelling analysis, was made at the end of the experiment.
Bone stiffness increased greatly with mechanical loading but this was attenuated significantly with the addition of sclerostin. The pH of the media after 24 hours decreased and ionic calcium concentrations increased in the presence of sclerostin when compared to mechanical loading alone. Sclerostin also completely abrogated loading-induced calcium/calcein uptake by the bone cores.
Together, the results suggest that an osteocyte/osteoclast response to sclerostin was responsible for these effects. Our results are the first direct evidence for a negative effect of sclerostin on the anabolic response of bone to mechanical loading.