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.
Highlights
Bone is continuously renewed by replacing old bone with new bone through bone remodeling, which is a turnover process consisting of the interaction and balance between bone-resorbing cells and boneforming cells[1]
To examine the pattern of expression of PRMT1 during osteoclastogenesis, bone marrow-derived macrophages (BMDMs) were treated with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappa B ligand (RANKL) for the indicated periods of time
In the present study, we have demonstrated for the first time that PRMT1 is involved in RANKLinduced osteoclastogenesis and in OVX-induced bone loss using PRMT1 haploinsufficent mice
Summary
Bone is continuously renewed by replacing old bone with new bone through bone remodeling, which is a turnover process consisting of the interaction and balance between bone-resorbing cells (osteoclasts) and boneforming cells (osteoblasts)[1]. The potential imbalance between osteoclasts and osteoblasts plays a fundamental role in the pathogenesis of osteoporosis. Estrogen deficiency in postmenopausal women stimulates osteoclast formation, and this result in the development of postmenopausal osteoporosis[2,3]. It is estimated that estrogen deficiency induced osteoporosis affects 40% of women over the age of 504. Among currently available antiosteoporotic drugs, postmenopausal estrogen replacement therapy has been shown to have the strongest protective effect against osteoporosis in women. Understanding the cellular and molecular mechanisms that govern changes in the activity of cells associated with bone remodeling may identify potential therapeutic targets for osteoporosis and other bone-associated pathology
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