PARP1 Hinders Histone H2B Occupancy at the NFATc1 Promoter to Restrain Osteoclast Differentiation

Abstract

Induction of nuclear factor of activated T cell cytoplasmic 1 (NFATc1) by macrophage colony‐stimulating factor (M‐CSF) and receptor activator of NF‐κB ligand (RANKL) is essential for macrophage differentiation into osteoclasts (OCs), but the underlying mechanisms remain unclear. The ability of poly(ADP‐ribose) polymerase 1 (PARP1) to poly‐ADP‐ribosylate NFATc1 in T cells prompted us to investigate the PARP1 and NFATc1 interaction during osteoclastogenesis. However, extensive studies failed to directly link PARP1 to NFATc1. A combination of transcriptomics and proteomics studies was then used to identify PARP1 targets under these conditions. These unbiased approaches in conjunction with site‐directed mutagenesis studies revealed that PARP1 inhibited NFATc1 expression and OC formation by ADP‐ribosylating histone H2B at serine 7 and decreasing the occupancy of this histone variant at the NFATc1 promoter. The anti‐osteoclastogenic function of PARP1 was confirmed in vivo in several mouse models of PARP1 loss‐of‐function or gain‐of‐function, including a novel model in which PARP1 was conditionally ablated in myeloid cells. Thus, PARP1 ADP‐ribosylates H2B to negatively regulate NFATc1 expression and OC differentiation. © 2019 American Society for Bone and Mineral Research.

Radiation causes tissue damage by dysregulating inflammasome–gasdermin D signaling in both host and transplanted cells

“…The femurs were embedded in 2% agarose gel and scanned at 10 μm, 55 kVp, 145 μA, 8 W, 300-ms integration time using a μCT system (μCT 40; Scanco Medical AG, Zurich, Switzerland) as previously described [70,71]. The regions of interest (ROIs) were defined at 1 mm proximal to the end of the femoral growth plate.…”

“…Mice were euthanized and bone marrow was flushed out from the tibias and femurs. BMDMs were obtained by culturing bone marrow cells in media containing 10% CMG, a source of M-CSF, for up to 5 days in a 10-cm dish as previously described [70,73]. After removing the nonadherent cells by vigorous washes with PBS, adherent cells were plated at 5 to 10 × 10 3 /well in a 96-well plate in culture media containing 2% CMG and 50-100 ng/ml RANKL.…”

Selumetinib - a potential small molecule inhibitor for osteoarthritis treatment

“…The MAPK and NF-κB signaling pathways are associated with the expression of osteoclastogenic transcription factors such as c-Fos and NFATc1. Among these, NFATc1 is a master transcription factor for the downstream effector of RANKL and can lead to increased expression of various osteoclast-related genes ( Cao et al, 2019 ; Wang et al, 2020 ). We found that selumetinib treatment could inhibit RANKL-induced activation of NFATc1 and reduce osteoclast formation.…”

Norcantharidin ameliorates estrogen deficient-mediated bone loss by attenuating the activation of extracellular signal-regulated kinase/ROS/NLRP3 inflammasome signaling

“… Bonar et al (2012) showed that the continuous activation of NLRP3 stimulates osteoclast differentiation in vivo and in vitro , leading to the elevation of bone resorption and subsequent bone loss. In addition, RANKL-induced activation of NLRP3 inflammasomes exerts positive effects on promoting osteoclastic transcription factors, B lymphocyte-induced maturation protein 1 (Blimp1) and NFATc1, facilitating osteoclast differentiation and maturation ( Wang et al, 2016 ; Wang et al, 2020 ). In the present study, we found that the RANKL-induced decrease of NLRP3 expression was rescued with the participation of NCTD, as well as the inhibition of elevated ASC levels.…”