pH-dependent Osteoimmunomodulation: Molecular mechanisms and therapeutic targeting in bone disorders

The bone microenvironment represents a highly sophisticated ecosystem comprising diverse cellular components-including osteoblasts, osteoclasts, immune cells, endothelial cells, and mesenchymal stem cells-that interact dynamically to maintain skeletal homeostasis and facilitate repair. Emerging insights from osteoimmunology have revealed that acid-base balance serves as a central regulatory node in bone remodeling, working synergistically with other physiological signals to fine-tune osteoclast/osteoblast activity through intricate molecular crosstalk. Notably, even subtle pH fluctuations within this microenvironment can exert profound effects on both bone and immune cell function. This review provides a comprehensive examination of: (1) the physiological principles governing acid-base balance in bone, (2) the pathological consequences of its dysregulation on bone remodeling via osteoimmune networks, and (3) the therapeutic promise of pH-modulating strategies for bone disorders such as osteoporosis and osteoarthritis. Our synthesis positions bone as a precision acid-base regulatory organ while establishing a mechanistic framework for developing targeted therapies that restore pH equilibrium in skeletal tissues.