Mechanical regulation of mesenchymal stem cell osteogenesis, bone matrix homoeostasis, and skeletal pathology

Osteogenesis is the process by which mesenchymal stem/stromal cells (MSCs) differentiate into mature osteoblasts, forming a mineralised bone matrix. This process is regulated by soluble factors, mechanical stimuli, and the extracellular matrix (ECM), which together maintain bone and mineral homoeostasis. Mechanotransduction, the conversion of physical cues into intracellular signals, is crucial for MSC fate determination and orchestrates bone matrix remodelling, balancing formation and resorption. Continuous mechanical loading supports optimal osteogenic differentiation, whereas mechanical unloading (sub-physiological mechanical loading) disrupts this equilibrium and increases bone loss risk. These processes involve complex crosstalk among local and systemic factors, immune cells, and osteoblast-osteoclast interactions in response to mechanical cues. This review discusses key biomechanical factors regulating MSC osteogenic differentiation and bone remodelling, and synthesises evidence on skeletal immobilisation and other unloading-associated conditions that contribute to skeletal anomalies. It further emphasises nanovibrational stimulation as a novel approach to enhance MSC osteogenesis and mitigate skeletal anomalies.