Bone Abstracts

Mechanosenstitive osteocytes in bone supress the local production of sclerostin in response to mechanical loading, to increase osteoblast differentiation and bone mass. In addition, sclerostin is secreted from osteocytes into the circulation. Serum sclerostin has been shown to correlate with osteoporosis and low bone mass, however there is limited evidence by which to determine whether serum sclerostin is acting either a biomarker or rather functionally to regulate bone mass. Our research attempted to address this in a conditional mouse model, producing localised sclerostin knockout, and reduced circulating sclerostin levels.

Limb-specific sclerostin null mice (Prrx1-Cre Sost^f/f) were generated, which retained sclerostin expression in the axial skeleton. These were compared to wild type mice and constitutive sclerostin null mice (Sost^−/−). The whole body dual-energy X-ray absorptiometry (DXA) was performed longitudinally to measure bone mineral content (BMC) and bone mineral density (BMD), as well as determination of lumbar and hind limb-specific measures. The three genotypes of mice were culled at 16 wk age to collect blood, femurs, and spine for further analyses.

We found that the serum sclerostin was reduced by 1.7-fold in Prrx1-Cre Sost^f/f compared to control mice, but was undetectable in Sost^−/− mice. The DXA results showed that greater BMD and BMC were present only in the hind limbs (limb BMD mean(SE) g/cm², control 0.05 (0.0007) Prrx1 0.069 (0.002), P<0.0002) but not in the lumbar spine of Prrx1-Cre Sost^f/f mice (spine BMD, control 0.051 (0.0004) Prrx1 0.050 (0.0007), ns) whereas Sost^−/− mice showed greater BMD and BMC both in the limb and spine. Micro-computed tomography showed greater cortical bone mass in femurs of Prrx1-Cre Sost^f/f and Sost^−/− mice compared to control mice. Importantly, cancellous bone mass in vertebra did not differ between Prrx1-Cre Sost^f/f and control mice, despite the significant reduction in serum sclerostin in Prrx1-Cre Sost^f/f.

In conclusion, our results indicate that the local production of sclerostin is the primary factor in the modulation of skeletal bone density.