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.
Highlights
ADP-ribosyltransferase diphtheria toxin-like 1 (ARTD1, formerly called PARP1) belongs to the family of ADP-ribosyltransferases (ARTs) and utilizes NAD+ for the synthesis of ADP-ribose polymers on acceptor proteins
Early multinucleation was observed in RAW 264.7 cells expressing shMock on day 2 (D2) after RANKL administration, and osteoclast expansion on day 3 (D3)
An even more prominent effect of ARTD1 was found between RANKL-stimulated bone marrow-derived macrophages (BMDM) isolated from WT mice compared to Artd1-deficient (− /− ) mice (Fig. 1B), confirming the results obtained with the engineered RAW 264.7 cells
Summary
ADP-ribosyltransferase diphtheria toxin-like 1 (ARTD1, formerly called PARP1) belongs to the family of ADP-ribosyltransferases (ARTs) and utilizes NAD+ for the synthesis of ADP-ribose polymers on acceptor proteins. A recent study has shown that the methylcytosine dioxygenase ten-eleven translocation 1 (TET1) interacts with PPARγ in an ADP-ribosylation-dependent manner during adipogenesis[12], suggesting a model of active, PAR-dependent DNA demethylation of key adipocyte-specific genes by TET112. RANKL stimulation triggers the induction of the NF-κ B heterodimer p65 (RelA)/ p50 (NF-κ B1), which induces the expression of nuclear factor of activated T-cells (NFATc1), a transcription factor that regulates the terminal RANKL-induced differentiation of osteoclasts[18]. The RANKL-induced NF-κ B pathway controls the transcription of a wide range of pro-inflammatory cytokines, chemokines and growth factors[19] Some of these cytokines such as TNFα , IL-1, IL-17, IL-4, and IFNs have been well documented to modulate the maturation of functionally active osteoclasts in an autocrine feedback loop[20,21]
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