The emerging role of lactate in skeletal homeostasis and disorders: Integrated mechanisms and translational opportunities
Abstract
Lactate has evolved from a metabolic byproduct to a central regulator of skeletal homeostasis and disorders, integrating metabolic flux with epigenetic reprogramming. Within the skeletal system, it modulates the processes of osteogenesis, osteoclastogenesis, chondrogenesis, and matrix synthesis by regulating the physiological activities of bone marrow mesenchymal stem cells, osteoblasts, osteoclasts, chondrocytes, and intervertebral disc cells, thereby maintaining skeletal homeostasis. Dysregulated lactate signaling is increasingly recognized as a pivotal pathological mechanism in degenerative, inflammatory, and neoplastic skeletal disorders. The presence of pathogenic lactate flux has been shown to drive disease-specific mechanisms, including, in osteoporosis, it disrupts osteoblast-osteoclast coupling; in osteoarthritis, it amplifies chondrocyte inflammation and matrix degradation; in rheumatoid arthritis, excess lactate enhances fibroblast invasiveness; in intervertebral disc degeneration, lactate accumulation induces acidosis and cell death; and in malignancies, lactate simultaneously nourishes osteoclasts and suppresses anti-tumor immunity. Currently, emerging preclinical evidence indicates that therapeutic strategies targeting lactate metabolism, transport, receptor signaling, and lactylation show promise. However, challenges such as cell-type-specific effects, metabolic compensation, and systemic off-target risks persist.
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