Tsc1 Regulates the Balance Between Osteoblast and Adipocyte Differentiation Through Autophagy/Notch1/β-Catenin Cascade.

A reduction in trabecular bone mass is often associated with an increase in marrow fat in osteoporotic bones. The molecular mechanisms underlying this inverse correlation are incompletely understood. Here, we report that mice lacking tuberous sclerosis 1 (Tsc1) in Osterix-expressing cells had a significant decrease in trabecular bone mass characterized by decreased osteoblastogenesis, increased osteoclastogenesis, and increased bone marrow adiposity in vivo. In vitro study showed that Tsc1-deficient bone marrow stromal cells (BMSCs) had decreased proliferation, decreased osteogenic differentiation, and increased adipogenic differentiation in association with the downregulation of Wnt/β-catenin signaling. Mechanistically, TSC1 deficiency led to autophagy suppression and consequent Notch1 protein increase, which mediated the GSK3β-independent β-catenin degradation. Together, our results indicate that Tsc1 controls the balance between osteoblast and adipocyte differentiation of BMSCs.