TFEB-mediated autophagy stimulation as an anabolic strategy for bone: insights from TFEB activation in the osteoblast lineage

Autophagy in the osteoblast lineage is essential for bone formation and skeletal homeostasis, yet the mechanisms through which it supports bone formation remain unclear. To investigate these mechanisms and evaluate the anabolic potential of autophagy stimulation, we generated a genetic mouse model in which transcription factor EB (<i>Tfeb</i>), a master regulator of autophagy and lysosomal biogenesis, was elevated specifically in osteoblast-lineage cells. <i>Tfeb</i> elevation increased the expression of autophagy and lysosomal genes and enhanced autophagic flux in osteoblasts. Stimulation of autophagy increased bone formation in both cortical and cancellous bone compartments, leading to gains in bone mass and strength. Single-cell RNA sequencing revealed reduced osteoblast apoptosis, suggesting improved cell survival as a contributor to the observed increase in osteoblast number. Our ex vivo studies also suggest that autophagy stimulation increases proliferation of osteoblats lineage cells. In addition to increasing osteoblast number, <i>Tfeb</i> elevation also enhanced osteoblast function, likely by increasing transcription and translation of extracellular bone matrix components. Taken together, these findings demonstrate that elevation of <i>Tfeb</i> in the osteoblast lineage cells stimulates autophagy, promotes bone formation, and leads to increased bone mass and strength, supporting further investigation of TFEB or autophagy activation as a potential therapeutic strategy for osteoporosis.