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Phospholipase D (PLD) proteins are major enzymes that regulate various cellular functions, such as cell growth, cell migration, membrane trafficking, and cytoskeletal dynamics. As they are responsible for such important biological functions, PLD proteins have been considered promising therapeutic targets for various diseases, including cancer and vascular and neurological diseases. Intriguingly, emerging evidence indicates that PLD1 and PLD2, 2 major mammalian PLD isoenzymes, are the key regulators of bone remodeling; this suggests that these isozymes could be used as potential therapeutic targets for bone diseases, such as osteoporosis and rheumatoid arthritis. PLD1 or PLD2 deficiency in mice can lead to decreased bone mass and dysregulated bone homeostasis. Although both mutant mice exhibit similar skeletal phenotypes, PLD1 and PLD2 play distinct and nonredundant roles in bone cell function. This review summarizes the physiological roles of PLD1 and PLD2 in bone metabolism, focusing on recent findings of the biological functions and action mechanisms of PLD1 and PLD2 in bone cells.
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