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.