ARTD1 regulates osteoclastogenesis and bone homeostasis by dampening NF-κB-dependent transcription of IL-1β

Abstract

While ADP-ribosyltransferase diphtheria toxin-like 1 (ARTD1, formerly PARP1) and its enzymatic activity have been shown to be important for reprogramming and differentiation of cells, such as during adipogenesis, their role and mechanism in regulating osteoclastogenesis and bone homeostasis are largely unknown. Here, in cell culture-based RANKL-induced osteoclastogenesis models, we show that silencing of ARTD1 or inhibition of its enzymatic activity enhances osteoclast differentiation and function. As a consequence of ARTD1 silencing or inhibition, the recruitment of p65/RelA to the IL-1β promoter, which is associated with transcriptionally active histone marks, IL-1β expression and inflammasome-dependent secretion of IL-1β are enhanced. This subsequently promotes sustained induction of the transcription factor Nfatc1/A and osteoclastogenesis in an autocrine manner via the IL-1 receptor. In vivo, Artd1-deficient mice display significantly decreased bone mass as a consequence of increased osteoclast differentiation. Accordingly, the expression of osteoclast markers is enhanced in mutant compared to wild-type mice. Together, these results indicate that ARTD1 controls osteoclast development and bone remodelling via its enzymatic activity by modulating the epigenetic marks surrounding the IL-1β promoter and expression of IL-1β and subsequently also Nfatc1/A.

Chronic inflammation triggered by the NLRP3 inflammasome in myeloid cells promotes growth plate dysplasia by mesenchymal cells

“…We also found that PARP1 regulates skeletal development 24, 32 , but whether PARP1 interacts with NLRP3 during this process remains unknown. Here, we used Parp1 D214N/D214N mice to investigate the interplay between this protein and NLRP3.…”

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

“…PARP1 loss‐of‐function mutations promote the differentiation of macs into OCs, whereas PARP1 gain‐of‐function mutations impair this process . Thus, PARP1 is the most important intracellular ARTD to regulate the biology and commitment of macs to the OC lineage, but the underlying mechanisms are not understood.…”

“…NFATc1 and NF-κB are not ADP-ribosylated in cells of the OC lineage PARP1 loss-of-function mutations promote the differentiation of macs into OCs, whereas PARP1 gain-of-function mutations impair this process. (23,24) Thus, PARP1 is the most important intracellular ARTD to regulate the biology and commitment of macs to the OC lineage, but the underlying mechanisms are not understood. Evidence suggesting that PARP1 modifies NFATc1 and NF-κB, (68)(69)(70)(71) which are key OC transcription factors, provided a rationale for studying the interplay among these pathways in the OC lineage.…”

“…To reinforce the notion that PARP1 acted primarily in myeloid cells, we generated novel Parp1 fl/fl mice and conditionally deleted this gene in myeloid cells using Lysozyme M-Cre (Parp1 cKO mice). Mice with global ablation of Parp1 (Parp1 KO mice), which exhibited low bone mass due to increased OC differentiation (23) were used as additional controls. Parp1 KO mice and Parp1 cKO mice indistinguishably displayed a low bone mass phenotype (Fig.…”

“…(9)(10)(11) This differentiation program is governed by a few transcriptional factors, including NFATc1, NF-κB, c-Fos, and B lymphocyte-induced maturation protein 1 (Blimp-1), (12) and is modulated by post-translational modifications (PTMs), including phosphorylation, (13,14) methylation, (15,16) acetylation, (17) ubiquitination, (18,19) SUMOylation, (20) and ADP-ribosylation. (21)(22)(23)(24)(25) ADP-ribosylation is the transfer of either a single ADP-ribose unit (mono-ADP-ribosylation or MARylation) or several ADPribose units (poly-ADP-ribosylation or PARylation) from nicotinamide adenine dinucleotide (NAD + ) to acceptor proteins; this PTM impacts cell fate determinations and outcomes. (26)(27)(28)(29) Poly-ADP-ribosylation is carried out by ADP-ribosyltransferases (ARTDs, also known as poly[ADP-ribose] polymerases [PARPs]) of which ARTD1/PARP1 is the archetypal member.…”