Piezo1, Integrins, and YAP/TAZ in Osteoporotic Mechanotransduction: Key Pathways, Crosstalk, and Therapeutic Implications.

Osteoporosis is a systemic skeletal disorder fundamentally characterized by an imbalance between bone formation and bone resorption, ultimately leading to reduced bone mass, microarchitectural deterioration, and increased fracture susceptibility. As bone is a highly mechanoresponsive tissue, mechanical stimulation is indispensable for the maintenance of skeletal homeostasis, and insufficient loading is a recognized driver of bone loss. In recent years, Piezo1, integrins, and YAP/TAZ have emerged as key nodes in bone cell mechanotransduction. Piezo1 functions primarily as a mechanosensitive ion channel that converts membrane deformation into calcium-dependent intracellular signaling, integrins mediate extracellular matrix adhesion and focal adhesion-based force transduction, and YAP/TAZ act as nuclear effectors that translate mechanical inputs into transcriptional programs. Increasing evidence indicates that these pathways do not function independently but are organized into a complex and dynamic signaling network that governs osteocyte mechanosensation, osteoblast differentiation, mesenchymal stem cell fate determination, and osteoclast-related remodeling responses. Dysregulation of this mechanotransduction axis has been implicated in aging-related bone loss, estrogen deficiency-induced osteoporosis, and unloading-associated skeletal deterioration. Moreover, these pathways are increasingly being recognized as potential therapeutic targets for osteoporosis, with translational strategies ranging from pharmacological modulation to biomaterial-guided and mechanically assisted interventions. This review summarizes the roles of Piezo1, integrins, and YAP/TAZ in osteoporotic mechanotransduction, emphasizes their crosstalk in the membrane-to-nucleus signaling continuum, and discusses future research priorities, particularly cell specificity, spatiotemporal heterogeneity, and translational applications in precision skeletal medicine. In the revised version, we further distinguish experimentally validated links from proposed models, define the hierarchy of Piezo1-, integrin-, and YAP/TAZ-dependent signaling across osteocytes, osteoblast-lineage cells, BMSCs, and osteoclast/macrophage-lineage cells, and emphasize context-dependent controversies that are essential for therapeutic translation.