| 1 | Augmenting MNK1/2 activation by c-FMS proteolysis promotes osteoclastogenesis and arthritic bone erosion显示文摘Osteoclasts are bone-resorbing cells that play an essential role in homeostatic bone remodeling and pathological bone erosion.Macrophage colony stimulating factor(M-CSF)is abundant in rheumatoid arthritis(RA).However,the role of M-CSF in arthritic bone erosion is not completely understood.Here,we show that M-CSF can promote osteoclastogenesis by triggering the proteolysis of c-FMS,a receptor for M-CSF,leading to the generation of FMS intracellular domain(FICD)fragments.Increased levels of FICD fragments positively regulated osteoclastogenesis but had no effect on inflammatory responses.Moreover,myeloid cell-specific FICD expression in mice resulted in significantly increased osteoclast-mediated bone resorption in an inflammatory arthritis model.The FICD formed a complex with DAP5,and the FICD/DAP5 axis promoted osteoclast differentiation by activating the MNK1/2/EIF4E pathway and enhancing NFATcl protein expression.Moreover,targeting the MNK1/2 pathway diminished arthritic bone erosion.These results identified a novel role of c-FMS proteolysis in osteoclastogenesis and the pathogenesis of arthritic bone erosion. | Se Hwan Mun Seyeon Bae Steven Zeng Brian Oh Carmen Chai Matthew Jundong Kim Haemin Kim George Kalliolias Chitra Lekha Dahia Younseo Oh Tae-Hwan Kim Jong Dae Ji Kyung-Hyun Park-Min | 2021 | Bone Research2021，9，4： | 2 |
| 2 | RANKL-responsive epigenetic mechanism reprograms macrophages into bone-resorbing osteoclasts显示文摘Monocyte/macrophage lineage cells are highly plastic and can differentiate into various cells under different environmental stimuli. Bone-resorbing osteoclasts are derived from the monocyte/macrophage lineage in response to receptor activator of NF-κB ligand (RANKL). However, the epigenetic signature contributing to the fate commitment of monocyte/macrophage lineage differentiation into human osteoclasts is largely unknown. In this study, we identified RANKL-responsive human osteoclast-specific superenhancers (SEs) and SE-associated enhancer RNAs (SE-eRNAs) by integrating data obtained from ChIP-seq, ATAC-seq, nuclear RNA-seq and PRO-seq analyses. RANKL induced the formation of 200 SEs, which are large clusters of enhancers, while suppressing 148 SEs in macrophages. RANKL-responsive SEs were strongly correlated with genes in the osteoclastogenic program and were selectively increased in human osteoclasts but marginally presented in osteoblasts, CD4+ T cells, and CD34+ cells. In addition to the major transcription factors identified in osteoclasts, we found that BATF binding motifs were highly enriched in RANKL-responsive SEs. The depletion of BATF1/3 inhibited RANKL-induced osteoclast differentiation. Furthermore, we found increased chromatin accessibility in SE regions, where RNA polymerase II was significantly recruited to induce the extragenic transcription of SE-eRNAs, in human osteoclasts. Knocking down SE-eRNAs in the vicinity of the NFATc1 gene diminished the expression of NFATc1, a major regulator of osteoclasts, and osteoclast differentiation. Inhibiting BET proteins suppressed the formation of some RANKL-responsive SEs and NFATc1-associated SEs, and the expression of SE-eRNA:NFATc1. Moreover, SE-eRNA:NFATc1 was highly expressed in the synovial macrophages of rheumatoid arthritis patients exhibiting high-osteoclastogenic potential. Our genome-wide analysis revealed RANKL-inducible SEs and SE-eRNAs as osteoclast-specific signatures, which may contribute to the development of osteoclast-specific therapeutic interventions. | Seyeon Bae Kibyeong Kim Keunsoo Kang Haemin Kim Minjoon Lee Brian Oh Kaichi Kaneko Sungkook Ma Jae Hoon Choi Hojoong Kwak Eun Young Lee Sung Ho Park Kyung-Hyun Park-Min | 2023 | Cellular & Molecular Immunology2023，20，1： | 1 |
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