Bone strength is partially determined during corticalisation, a two-step process comprising coalescence of peripheral trabecular bone and its progressive mineralisation. Hyperactivation of STAT3 phosphorylation in osteocytes, by targeted deletion of suppressor of cytokine signalling 3 (Socs3), delays corticalisation leading to high cortical porosity, low mineralisation and low bone strength. Since multiple bone-active cytokines activate STAT3 including leptin, IL-6 family cytokines, and G-CSF, we evaluated whether blocking leptin signalling in osteocytes of Dmp1creTg.Socs3fl/fl mice would rectify their cortical bone deficit.
We generated mice deficient in both Socs3 and Leptin Receptor (LepR), using Dmp1creTg. Dmp1creTg.Socs3fl/fl.LepRfl/fl mice (DSL) were compared to cousin Dmp1creTg.Socs3fl/fl (DS) controls by micro-computed tomography. We also generated Dmp1creTg.LepRfl/fl mice to assess the effect of leptin signalling at physiological STAT3 levels, using Dmp1creTg as controls; these mice showed no detectable bone phenotype.
Between 6 and 12 weeks of age, although corticalisation was delayed, male and female DS control mice showed some maturation of the cortex, including a 64% reduction in cortical porosity and a 200% increase in high-density bone. Six-week-old DSL mice showed the same phenotype as DS control mice. At 12-weeks of age, male DSL and DS mice showed the same pattern of skeletal maturation, however, female DSL mice showed no reduction in cortical porosity since 6 weeks, and a 32% greater proportion of low-density bone mass than age-matched DS controls. Between 6 to 12 weeks, female DSL mice accrued half the amount of medium- and high-density bone than that accrued during the same period in DS mice. This indicates that absence of LepR in mice with STAT3 hyperactivation further delays bone corticalisation.
This identifies a new role for leptin signalling in bone. Although LepR within osteocytes had no irreplaceable physiological role in cortical bone development, in the context of STAT3 hyperactivation, leptin receptor signalling promotes cortical bone consolidation.