Region- and Compartment-Specific Elevation of Bone Mass in Mice Following Tsc1 Deletion in 8-kb Dmp1-Cre-Expressing Cells

Tuberous sclerosis complex 1 (TSC1) is a negative regulator of mTORC1 signaling, a key pathway in skeletal homeostasis, but its region- and compartment-specific effects on bone remain unclear. Here, we examined the skeletal impact of Tsc1 deletion using the 8-kb Dmp1-Cre line, which targets mature osteoblasts and osteocytes. Cre activity in Ai14 reporter mice showed comparable recombination in craniofacial, appendicular, and axial bones. Conditional Tsc1 deletion resulted in greater bone mass at multiple sites, but with marked regional and compartmental variations. In the craniofacial skeleton, the frontal bone showed the most robust elevation in thickness and volume, the parietal bone displayed intermediate elevation, and the mandible exhibited the smallest elevation but reduced bone volume fraction and tissue mineral density, consistent with greater porosity. In femurs, both trabecular and cortical bone mass was augmented. Histomorphometric analysis of femoral trabecular bone revealed increased osteoblast number and surface together with reduced osteoclast parameters. In vertebrae, Tsc1 deletion produced modest trabecular bone accrual but > 100% expansion of both outer and inner cortical bone, indicating a predominant cortical effect. Comparative analysis showed stronger trabecular bone response in the femur and greater cortical response in the vertebra. p-S6 immunostaining confirmed mTORC1 activation across skeletal sites. Comparison with Osterix-Cre–mediated Tsc1 deletion showed similar trabecular responses but milder cortical effects in Dmp1-Cre meditated Tsc1 deletion, suggesting stage-specific regulation within the osteoblast lineage. These findings reveal pronounced regional variation among craniofacial bones and distinct compartmental responses to Tsc1 deletion, highlighting the role of local bone context in shaping skeletal outcomes of mTORC1 hyperactivation.