mTORC1 Determines the Hypertrophic Chondrocytes Fate decision via Fatty Acid Synthesis
Abstract
Abstract Hypertrophic chondrocytes (HCs) in the growth plate can transition into osteoblasts, a cell fate switch firmly established by lineage‑tracing studies. Recent work has further demonstrated that HCs become osteoblasts through two distinct routes, either via a skeletal stem cell (SSC) intermediate or through direct conversion, with the SSC‑derived lineage serving as the major source of HC progeny and contributing substantially to trabecular bone formation. However, the molecular mechanisms that govern this lineage choice remain largely undefined. Here, using single‑cell transcriptome analysis, we identify that mTORC1 signaling is highly active in HCs, and immunofluorescence confirmed its strong activation in this population. Deletion of Raptor , an essential component of mTORC1, in chondrocytes led to a notable decrease in HC‑derived progeny and impaired trabecular bone formation. Through an inducible short‑lineage tracing system, we further demonstrated that mTORC1 inactivation impairs the transition from HCs to SSCs while promoting direct conversion to osteoblasts. Mechanistically, the SREBP1–FASN lipogenic axis was identified as a key downstream effector of mTORC1 in HCs. Pharmacological inhibition of FASN recapitulated the shift towards direct osteogenic conversion and phenocopied the trabecular bone defects caused by mTORC1 deficiency. Collectively, these findings establish that mTORC1 controls HC fate choice through FASN‑dependent lipogenesis, steering HCs toward…
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