JAK1/STAT3 signalling in cortical bone development, growth and maintenance

STAT3 (Signal Transducer and Activator of Transcription 3) signalling plays essential roles in the development, growth, and maintenance of the thick outer structure of bone (cortical bone). Cytokines using this pathway, particularly IL-6 (Interleukin-6) family members, influence cortical structure through actions on the major cell types of bone, including chondrocytes, osteoblasts, osteocytes and osteoclasts. This review outlines how STAT3 signalling regulates the cellular processes involved in cortical bone development in long bones and calvariae during embryogenesis, and in postnatal life, including consolidation of the cortical structure in growth and response to mechanical load. We discuss how mouse models with global and cell lineage-specific genetic modifications reveal how STAT3 signalling in the osteoblast lineage, which is stimulated by cytokines and subject to negative feedback from SOCS3 (Suppressor of Cytokine Signalling 3), contributes to normal cortical bone maturation and maintenance. We also discuss the potential contributions of STAT3 signalling to age-related cortical bone loss. While these signals are clearly important for both long bone and calvarial cortical development and maintenance, much remains to be resolved. • JAK1/STAT3 signaling is required for cortical bone development and maintenance. • STAT3 hyperactivation increases cortical porosity and vascularization. • Cortical bone consolidation in skull and long bones requires SOCS3 inhibition of STAT3. • Mechanical loading and sex hormones influence STAT3 effects on cortical bone. • JAK1/STAT3 signals may contribute to age-related cortical bone loss and fragility.