Full metadata record
| DC Field | Value | Language |
|---|---|---|
| dc.contributor | Department of Biomedical Engineering | en_US |
| dc.contributor.advisor | Wen, Chunyi (BME) | en_US |
| dc.creator | Zou, Zhou | - |
| dc.identifier.uri | https://theses.lib.polyu.edu.hk/handle/200/14605 | - |
| dc.language | English | en_US |
| dc.publisher | Hong Kong Polytechnic University | en_US |
| dc.rights | All rights reserved | en_US |
| dc.title | Endothelin-1/ETB receptor signalling drives PRX1+ skeletal STEM cell senescence and osteoporotic bone loss | en_US |
| dcterms.abstract | Skeletal and vascular ageing are closely interconnected, with increasing evidence highlighting the role of vascular factors in regulating tissue-specific ageing. Endothelin-1 (ET-1), a potent vasoconstrictor, is essential for maintaining vascular tone and blood pressure. However, excessive ET-1 expression leads to endothelial dysfunction and cellular senescence, contributing to age-related diseases. Although the bone marrow is highly vascularised, the impact of elevated ET-1 secretion from the endothelial cells on the function of perivascular skeletal stem cells (SSCs) during skeletal ageing remains unclear. | en_US |
| dcterms.abstract | Senescence of SSCs is an important but underexplored driver of osteoporosis. In this study, we identified ET-1/Endothelin B receptor (ETBR) signalling as a key mediator of osteoporosis. In both aged and ovariectomized (OVX) mice, increased ETBR expression was associated with bone loss and reactive oxygen species (ROS)-induced SSC senescence. Transgenic mice overexpressing ET-1 (TET-1) exhibited endothelial dysfunction and accelerated skeletal ageing, particularly in vascular-rich bone regions. Through RNA sequencing of SSCs, we found ET-1 induced senescence related to the PI3K/akt/mTOR signalling pathway. Notably, conditional knockout of ETBR in SSCs (Prx1-Cre::ETBRfl/fl) prevented ET-1-induced senescence, reduced ROS accumulation, and alleviated osteoporotic degeneration in OVX mice. Similarly, pharmacological inhibition of ETBR with BQ788 similarly rejuvenated bone in both aged and OVX mice. | en_US |
| dcterms.abstract | These findings reveal a direct ET-1/ETBR-ROS axis that governs SSC senescence and skeletal ageing, positioning ETBR inhibition as a promising therapeutic strategy. To translate these insights into clinical applications, we developed drug-loaded alginate-based hydrogels (Macitentan/Alg@Sr) for vascular and bone tissue regeneration. The hydrogels effectively reduced cellular senescence and inflammation. By elucidating the link between vascular dysfunction and skeletal ageing, this study advances our understanding of osteoporosis pathogenesis and identifies a precision target for combating age-related bone loss, with broad implications for the treatment of degenerative skeletal disorders. | en_US |
| dcterms.extent | xiv, 251 pages : color illustrations | en_US |
| dcterms.isPartOf | PolyU Electronic Theses | en_US |
| dcterms.issued | 2026 | en_US |
| dcterms.educationalLevel | Ph.D. | en_US |
| dcterms.educationalLevel | All Doctorate | en_US |
| dcterms.accessRights | open access | en_US |
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