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

Abstract

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.

Epigenetic Regulators Involved in Osteoclast Differentiation

“…PRMT1 expression is increased with RANKL treatment and osteoclasts from Prmt1 +/− mice were smaller and had impaired F-actin ring formation and bone resorption [ 23 ]. PRMT1 was shown to interact with and regulate the transcriptional activity of NF-κB [ 23 ].…”

“…PRMT1 expression is increased with RANKL treatment and osteoclasts from Prmt1 +/− mice were smaller and had impaired F-actin ring formation and bone resorption [ 23 ]. PRMT1 was shown to interact with and regulate the transcriptional activity of NF-κB [ 23 ]. Lastly estrogen was shown to downregulate expression of Prmt1 , which suggests that estrogen may negatively regulate osteoclast differentiation by modulating the expression of Prmt1 [ 23 ].…”

“…PRMT1 was shown to interact with and regulate the transcriptional activity of NF-κB [ 23 ]. Lastly estrogen was shown to downregulate expression of Prmt1 , which suggests that estrogen may negatively regulate osteoclast differentiation by modulating the expression of Prmt1 [ 23 ].…”

Bone Remodeling: Histone Modifications as Fate Determinants of Bone Cell Differentiation

“…It was observed that osteoclast differentiation was blocked in PRMT1 knockdown or PRMT1+/− BMMs compared to PRMT1+/+ BMMs. In addition, PRMT1 haploinsufficiency reduced the enzyme activity of TRAP and increased the BMD in ovariectomized mice [104]. It was reported that methyltransferase G9a regulates osteogenesis via Twist gene repression.…”

Asymmetrical methyltransferase PRMT3 regulates human mesenchymal stem cell osteogenesis via miR-3648

“…PRMT1 is an indispensable regulator of RANKL-induced osteoclast differentiation. PRMT1 activated osteoclast function and led to bone loss in OVX mice 20 . PRMT5 activates RANKL-induced osteoclast differentiation, which involves the regulation of CXCL10 and RSAD2 21 .…”