The mechano-immune-vesicle regulatory circuit: a systems framework for bone homeostasis and regeneration

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Bone remodeling is a mechanically adaptive process that integrates physical loading with immune regulation during homeostasis, repair, and disease. However, the traditional view fails to fully explain how mechanical and immune signals are coordinated across cellular compartments. Emerging evidence indicates that mechanical forces, immune responses, and extracellular vesicles (EVs) function as an integrated communication system rather than independent regulators. Here, we propose a systems-level framework termed the "mechano-immune-vesicle regulatory circuit". In this framework, biophysical cues regulate EV biogenesis and selective cargo sorting through mechanotransduction pathways. These mechanically primed EVs then serve as communication vectors that reprogram osteoimmune responses, specifically by directing macrophage polarization, adaptive immunity, and bone-resident cell differentiation. The resulting immune output feeds back to reshape EV signaling and mechanosensitivity, suggesting a closed regulatory circuit that governs bone remodeling. By synthesizing advances in mechanobiology, osteoimmunology and EV biology, this review reframes bone remodeling as a mechano-immune-vesicle regulatory circuit rather than as a collection of parallel pathways. We further discuss how this framework may guide the design of mechano-responsive biomaterials and engineered EV-based therapies w

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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