LNGFR promoting osteogenic differentiation of ectomesenchyme stem cells via activation of GHR-JAK-STAT/IGF1 signaling pathway

Ectomesenchymal stem cells (EMSCs) are critical for craniofacial bone development, and low-affinity nerve growth factor receptor (LNGFR) is closely associated with their stemness. However, the specific role of LNGFR in EMSC osteogenesis remains unclear. Here, we investigated this using Lngfr knockout (lngfr^-/-) mice and demonstrated that lngfr^-/-EMSCs exhibited decreased proliferation, migration, and osteogenic differentiation capacities in vitro. Furthermore, impaired skeletal development and reduced mineralization were observed in lngfr^-/- fetal mice in vivo. Circular RNA (circRNA) Sequencing identified the growth hormone (GH) pathway as a key factor involved in LNGFR-regulated osteogenesis of EMSCs. Co-immunoprecipitation (Co-IP) assays further confirmed the interaction between LNGFR and growth hormone receptor (GHR). lngfr^-/-suppressed GHR expression and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) phosphorylation, leading to downregulation of the GH/insulin-like growth factor 1 (IGF-1) signaling pathway. Modulation of the JAK/STAT pathway affected osteogenesis, while exogenous GH rescued the osteogenic defects via the GHR/JAK-STAT/IGF-1 axis. Collectively, these findings demonstrated that LNGFR promoted EMSC osteogenesis by activating the GHR/JAK-STAT/GH-IGF-1 signaling axis, providing new insights into craniofacial development and regenerative medicine.