PRMT1 mediates RANKL-induced osteoclastogenesis and contributes to bone loss in ovariectomized mice

Protein arginine methylation is a novel form of posttranslational modification mediated by protein arginine methyltransferase (PRMTs). PRMT1, a major isoform of the PRMT family, is responsible for various biological functions, including cellular differentiation. Although the important function that PRMT1 plays in various tissues is being increasingly recognized, its role in receptor activation of NF-κB ligand (RANKL)-induced osteoclastogenesis or osteoporosis has not yet been described. Here, we show that PRMT1 is essential for RANKL-induced osteoclastogenesis in vitro and for bone loss in vivo. RANKL treatment increased the expression of PRMT1 and its nuclear localization in bone marrow-derived macrophages (BMDMs) in a c-Jun N-terminal kinase (JNK)-dependent manner. Silencing PRMT1 attenuated RANKL-induced osteoclastogenesis by decreasing tartrate-resistant acid phosphatase (TRAP)-positive cells and inhibiting F-actin ring formation and bone resorption, which was confirmed in a separate experiment using haploinsufficient cells from PRMT1+/- mice. Our results also revealed that PRMT1 regulates the transcription activity of NF-κB by directly interacting with it in RANKL-treated BMDMs. An in vivo study showed that the haploinsufficiency of PRMT1 reduced the enzyme activity of TRAP and increased the bone mineral density in the metaphysis of ovariectomized (OVX) mice. Finally, treatment with estrogen (E2) downregulated the RANKL-induced expression of PRMT1, suggesting that estrogen may exert an inhibitory effect on osteoclastogenesis by suppressing PRMT1 expression. Our results suggest that PRMT1 plays an important role in the progression of osteoporosis and that it might be a good therapeutic target for postmenopausal osteoporosis.
Osteoporosis: protein trigger for postmenopausal bone loss identified A protein that helps trigger bone loss in postmenopausal osteoporosis could be a potential therapeutic target. After the menopause, decreases in estrogen hormone levels can lead to bone diseases including osteoporosis. Osteoporosis occurs when the bone remodeling process breaks down, and bone resorption by cells called osteoclasts outweighs bone formation. In a mouse model of postmenopausal osteoporosis, Jong-Hwan Park at Chonnam National University, Gwangju, South Korea and co-workers identified key players in the progression of the disease. The team focused on factors influencing the RANKL protein, a known controller of bone remodeling. They found that RANKL triggers the formation of osteoclasts via interaction with another protein, PRMT1. Suppression of PRMT1 by estrogen appears to inhibit excessive osteoclast formation, suggesting it could be a potential therapeutic target for treating osteoporosis.