Experimental studies demonstrate that HIF-1α activation links hypoxia to key osteogenic pathways, including BMP2, RUNX2, and Wnt/β-catenin signalling, thereby influencing phenotypic switching of vascular smooth muscle cells (VSMCs). Hypoxia exerts both stimulatory and suppressive effects on sclerostin depending on local tissue conditions, reflecting a context-dependent regulatory network. Preclinical and clinical data show that sclerostin can act as either a compensatory inhibitor or a pro-calcific mediator, depending on disease stage and metabolic environment. Emerging evidence further highlights natural products such as polyphenols, flavonoids, and marine-derived compounds that modulate sclerostin expression through oxidative, inflammatory, and Wnt-related pathways. Sclerostin sits at a critical intersection between bone and vascular systems, where hypoxia-driven HIF signalling orchestrates its dual effects on mineral metabolism. Understanding the HIF-sclerostin axis provides new insight into the bone-vascular continuum and identifies potential therapeutic targets. Natural bioactive compounds capable of restoring sclerostin-Wnt balance may represent safe, multi-targeted strategies to mitigate VC progression, warranting further mechanistic and translational evaluation.
Yeon et al. (Mon,) studied this question.