The role of palmitoylation modifications in the regulation of bone cell function, bone homeostasis, and osteoporosis

Osteoporosis a is a metabolic bone disease caused by an imbalance in bone homeostasis, which is regulated by osteoblasts and osteoclasts. Protein palmitoylation modification is a post-translational modification that affects protein function, localization, and targeting by attaching palmitoyl groups to specific amino acid residues of proteins. Recent studies have shown that protein palmitoylation is involved in the regulation of osteoclast overproduction, osteoblast migration, osteogenic differentiation, dysfunctional autophagy, and endocrine hormone membrane receptors in osteoporosis. Exactly to what extent palmitoylation modifications can regulate osteoporosis, and whether palmitoylation inhibition can delay osteoporosis, is a key question that needs to be investigated urgently. In this review, we observed that palmitoylation modifications act mainly through two target cells – osteoblasts and osteoclasts – and that the targets of palmitoylation modifications are focused on plasma membrane proteins or cytosolic proteins of the target cells, which tend to assume the role of receiving extracellular signals. We also noted that different palmitoyl transferases acting on different substrate proteins exert conflicting regulation of osteoblast function. We concluded that the regulation of osteocyte function, bone homeostasis, and osteoporosis by palmitoylation modifications is multidimensional, diverse, and interconnected. Perfecting the palmitoylation modification network can enhance our ability to utilize post-translational modifications to resist osteoporosis and lay the foundation for targeting palmitoyl transferases to treat osteoporosis in the future. Cite this article: Bone Joint Res 2025;14(5):420–433.