Telomerase reverse transcriptase mediates bone formation for osteoporosis via activating BMP4/Smad1 pathway

Background: The role of telomerase reverse transcriptase (TERT) in bone metabolism remains poorly defined. This study investigates its function in osteoporosis (OP) pathogenesis and its therapeutic potential. Methods: TERT expression was analyzed in clinical OP specimens and ovariectomized (OVX) mice. Mechanisms were probed using RNA-seq, gain/loss-of-function studies, and pathway inhibition. Exosomes derived from TERT-overexpressing BMSCs (TERT-Exo) were functionalized with a bone-targeting aptamer (Apt-TERT-Exo) and evaluated in OVX mice. Results: TERT was downregulated in OP, correlating with impaired osteogenesis. TERT was identified as a novel upstream activator of the BMP4/Smad1 pathway, essential for its pro-osteogenic effect. Apt-TERT-Exo exhibited enhanced bone accumulation and systemic administration effectively restored trabecular bone mass in OVX mice by promoting BMSC osteogenesis. Conclusion: TERT is a novel upstream regulator of osteogenesis via BMP4/Smad1. The Apt-TERT-Exo platform represents a promising targeted, cell-free therapeutic approach for osteoporosis. The translational potential statement: The Translational Potential of this Article.The Apt-TERT-Exo platform presents a targeted, cell-free strategy for osteoanabolic therapy. Its design addresses key translational challenges by enabling precise delivery to bone tissue, potentially minimizing systemic side effects and offering a promising new avenue for treating osteoporosis.