SERPINE1 encodes plasminogen activator inhibitor-1 (PAI-1), a key inhibitor of tissue-type and urokinase-type plasminogen activators. Beyond fibrinolysis, PAI-1 participates in extracellular matrix remodeling, cellular senescence, inflammatory amplification, fibrosis-like repair, metabolic stress responses, and bone-cell coupling. These processes are central to osteoporosis, osteoarthritis, and intervertebral disc degeneration, yet the role of SERPINE1/PAI-1 in skeletal tissues is highly context dependent. In osteoporosis, excessive PAI-1 activity is mainly associated with impaired osteogenesis, osteoblast-lineage senescence, defective repair, and bone loss. In osteoarthritis, PAI-1 shows a context-dependent role: persistent elevation may promote chondrocyte senescence and maladaptive matrix remodeling, whereas experimental loss-of-function studies suggest that PAI-1 may protect cartilage in specific settings by restraining excessive plasmin-MMP-mediated degradation. In intervertebral disc degeneration, emerging evidence links SERPINE1 expression and PAI-1 activity to nucleus pulposus cell senescence, fibrosis-like extracellular matrix remodeling, oxidative/metabolic stress, and matrix dysregulation. This review synthesizes current evidence and proposes a testable conceptual framework in which SERPINE1/PAI-1 may function as a stress-responsive remodeling rheostat rather than as a uniformly pathogenic or protective factor. From a translational perspective, SERPINE1/PAI-1 is unlikely to serve as a stand-alone diagnostic biomarker or a target for uniform systemic inhibition. Instead, its clinical value may lie in molecular stratification, identification of disease-stage- and compartment-specific endotypes, and locally targeted modulation of pathogenic downstream programs. Future studies should integrate spatial multi-omics, time-resolved disease models, human cohort validation, and tissue-specific delivery strategies to determine when SERPINE1/PAI-1 is therapeutically actionable in skeletal degeneration.
