Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma

McNee, Gavin; Eales, Katherine L.; Wei, Wenbin; Williams, D. R.; Barkhuizen, Angelique; Bartlett, David B.; Essex, Sarah; Anandram, Seetharam; Filer, Andrew; Moss, Paul; Pratt, Guy; Basu, Supratik; Davies, Clare C.; Tennant, Daniel A.

doi:10.1038/leu.2016.187

Cited by 45 publications

(47 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1F). In good accord with the previously published data [29], our clinical data showed that the HOXC10 mRNA levels were upregulated in MM-MSCs relative to those from ND (Fig. 1G).…”

Section: Stem Cellssupporting

confidence: 92%

HOXC10 Regulates Osteogenesis of Mesenchymal Stromal Cells Through Interaction with Its Natural Antisense Transcript lncHOXC-AS3

Han

Song

et al. 2018

Stem Cells

View full text Add to dashboard Cite

The characteristics of mesenchymal stromal cells (MSCs) which derived from multiple myeloma (MM) patients are typically impaired in osteogenic differentiation. However, the underlying molecular mechanisms need to be further investigated. lncRNAs are emerging as critical regulation molecules in oncogenic pathways. In this study, we identified that bioactive lncRNA HOXC‐AS3, which is transcribed in opposite to HOXC10, was presented in MSCs derived from bone marrow (BM) of MM patients (MM‐MSCs). HOXC‐AS3 was able to interact with HOXC10 at the overlapping parts and this interaction increased HOXC10 stability, then promoted its expression, conferring osteogenesis repression to MM‐MSCs. In mouse models, intravenously administered siHOXC‐AS3 was proven to be effective in prevention of bone loss, sustained by both anticatabolic activities and bone‐forming. These data showed that lncHOXC‐AS3 was required for osteogenesis in BM‐MSCs by enhancing HOXC10 expression. Our finding thus unveils a novel insight for the potential clinical significance of lncRNA HOXC‐AS3 as a therapeutic target for bone disease in MM. Stem Cells 2019;37:247–256

show abstract

“…1F). In good accord with the previously published data [29], our clinical data showed that the HOXC10 mRNA levels were upregulated in MM-MSCs relative to those from ND (Fig. 1G).…”

Section: Stem Cellssupporting

confidence: 92%

HOXC10 Regulates Osteogenesis of Mesenchymal Stromal Cells Through Interaction with Its Natural Antisense Transcript lncHOXC-AS3

Han

Song

et al. 2018

Stem Cells

View full text Add to dashboard Cite

show abstract

“…PAD2 and PAD4 may be important within B lineage cells for regulating IgG production or other pathways, although expression data for the PADs in B cells is conflicted [9, 14, 15, 52], or important in cells that regulate B cells. For example, PAD2 is upregulated in the bone marrow mesenchymal stem cells of patients with multiple myeloma, a plasma cell malignancy, driving production of IL-6, a molecule that supports plasma cells [53][54]. Perhaps in the absence of PAD2, IL-6 is reduced in the bone marrow microenvironment leading to reduced plasma cells and IgG levels.…”

Section: Discussionmentioning

confidence: 99%

Peptidylarginine deiminase 2 is required for tumor necrosis factor alpha-induced citrullination and arthritis, but not neutrophil extracellular trap formation

Bawadekar

Shim

Johnson

et al. 2017

Journal of Autoimmunity

View full text Add to dashboard Cite

Citrullination, the post-translational conversion of arginines to citrullines, may contribute to rheumatoid arthritis development given the generation of anti-citrullinated protein antibodies (ACPAs). However, it is not known which peptidylarginine deiminase (PAD) catalyzes the citrullination seen in inflammation. PAD4 exacerbates inflammatory arthritis and is critical for neutrophil extracellular traps (NETs). NETs display citrullinated antigens targeted by ACPAs and thus may be a source of citrullinated protein. However, PAD4 is not required for citrullination in inflamed lungs. PAD2 is important for citrullination in healthy tissues and is present in NETs, but its role in citrullination in the inflamed joint, NETosis and inflammatory arthritis is unknown. Here we use mice with TNFα-induced inflammatory arthritis, a model of rheumatoid arthritis, to identify the roles of PAD2 and PAD4 in citrullination, NETosis, and arthritis. In mice with TNFα-induced arthritis, citrullination in the inflamed ankle was increased as determined by western blot. This increase was unchanged in the ankles of mice that lack PAD4. In contrast, citrullination was nearly absent in the ankles of PAD2-deficient mice. Interestingly, PAD2 was not required for NET formation as assessed by immunofluorescence or for killing of Candida albicans as determined by viability assay. Finally, plasma cell numbers as assessed by flow cytometry, IgG levels quantified by ELISA, and inflammatory arthritis as determined by clinical and pathological scoring were all reduced in the absence of PAD2. Thus, PAD2 contributes to TNFα-induced citrullination and arthritis, but is not required for NETosis. In contrast, PAD4, which is critical for NETosis, is dispensable for generalized citrullination supporting the possibility that NETs may not be a major source of citrullinated protein in arthritis.

show abstract

“…Notably, PADI2 is also found to be highly expressed in bone marrow mesenchymal stem cells (BMMSCs) [93]. These BMMSCs are key components for both the normal and transformed bone marrow niche.…”

Section: The Role Of Padi2 In Cancermentioning

confidence: 99%

Peptidyl Arginine Deiminase 2 (PADI2)-Mediated Arginine Citrullination Modulates Transcription in Cancer

Beato

Sharma

2020

IJMS

View full text Add to dashboard Cite

Protein arginine deimination leading to the non-coded amino acid citrulline remains a key question in the field of post-translational modifications ever since its discovery by Rogers and Simmonds in 1958. Citrullination is catalyzed by a family of enzymes called peptidyl arginine deiminases (PADIs). Initially, increased citrullination was associated with autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, as well as other neurological disorders and multiple types of cancer. During the last decade, research efforts have focused on how citrullination contributes to disease pathogenesis by modulating epigenetic events, pluripotency, immunity and transcriptional regulation. However, our knowledge regarding the functional implications of citrullination remains quite limited, so we still do not completely understand its role in physiological and pathological conditions. Here, we review the recently discovered functions of PADI2-mediated citrullination of the C-terminal domain of RNA polymerase II in transcriptional regulation in breast cancer cells and the proposed mechanisms to reshape the transcription regulatory network that promotes cancer progression.

show abstract

Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma

Cited by 45 publications

References 47 publications

HOXC10 Regulates Osteogenesis of Mesenchymal Stromal Cells Through Interaction with Its Natural Antisense Transcript lncHOXC-AS3

HOXC10 Regulates Osteogenesis of Mesenchymal Stromal Cells Through Interaction with Its Natural Antisense Transcript lncHOXC-AS3

Peptidylarginine deiminase 2 is required for tumor necrosis factor alpha-induced citrullination and arthritis, but not neutrophil extracellular trap formation

Peptidyl Arginine Deiminase 2 (PADI2)-Mediated Arginine Citrullination Modulates Transcription in Cancer

Contact Info

Product

Resources

About