PMID- 35166055
OWN - NLM
STAT- MEDLINE
DCOM- 20220630
LR  - 20230703
IS  - 2326-5205 (Electronic)
IS  - 2326-5191 (Print)
IS  - 2326-5191 (Linking)
VI  - 74
IP  - 7
DP  - 2022 Jul
TI  - The Prominent Role of Hematopoietic Peptidyl Arginine Deiminase 4 in Arthritis: 
      Collagen- and Granulocyte Colony-Stimulating Factor-Induced Arthritis Model in 
      C57BL/6 Mice.
PG  - 1139-1146
LID - 10.1002/art.42093 [doi]
AB  - OBJECTIVE: Genome-wide association studies have connected PADI4, encoding 
      peptidylarginine deiminase 4 (PAD4), with rheumatoid arthritis (RA). PAD4 
      promotes neutrophil extracellular trap (NET) formation. This study was undertaken 
      to investigate the origin of PAD4 and the importance of NET formation in a 
      C57BL/6 mouse model of arthritis. METHODS: To permit the effective use of C57BL/6 
      mice in the collagen-induced arthritis (CIA) model, we introduced the 
      administration of granulocyte colony-stimulating factor (G-CSF) for 4 consecutive 
      days in conjunction with the booster immunization on day 21. Mice with global 
      Padi4 deficiency (Padi4(-/-) ) and mice with hematopoietic lineage-specific Padi4 
      deficiency (Padi4(Vav1Cre/+) ) were evaluated in the model. RESULTS: G-CSF 
      significantly increased the incidence and severity of CIA. G-CSF-treated mice 
      showed elevated citrullinated histone H3 (Cit-H3) levels in plasma, while 
      vehicle-treated mice did not. Immunofluorescence microscopy revealed deposition 
      of Cit-H3 in synovial tissue in G-CSF-treated mice. Padi4(-/-) mice developed 
      less severe arthritis and had lower levels of serum interleukin-6 and plasma 
      Cit-H3, lower levels of Cit-H4 in synovial tissue, and less bone erosion on 
      micro-computed tomography than Padi4(+/+) mice in the G-CSF-modified CIA model. 
      Similarly, Padi4(Vav1Cre/+) mice developed less severe arthritis, compared with 
      Padi4(fl/fl) mice, and presented the same phenotype as Padi4(-/-) mice. 
      CONCLUSION: We succeeded in developing an arthritis model suitable for use in 
      C57BL/6 mice that is fully compliant with high animal welfare standards. We 
      observed a >90% incidence of arthritis in male mice and detectable NET markers. 
      This model, with some features consistent with human RA, demonstrates that 
      hematopoietic PAD4 is an important contributor to arthritis development and may 
      prove useful in future RA research.
CI  - (c) 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC 
      on behalf of American College of Rheumatology.
FAU - Fukui, Shoichi
AU  - Fukui S
AUID- ORCID: 0000-0001-5487-4692
AD  - Children's Hospital and Harvard Medical School, Boston, Massachusetts.
FAU - Gutch, Sarah
AU  - Gutch S
AD  - Boston Children's Hospital, Boston, Massachusetts.
FAU - Fukui, Saeko
AU  - Fukui S
AD  - Boston Children's Hospital, Boston, Massachusetts.
FAU - Cherpokova, Deya
AU  - Cherpokova D
AD  - Children's Hospital and Harvard Medical School, Boston, Massachusetts.
FAU - Aymonnier, Karen
AU  - Aymonnier K
AD  - Children's Hospital and Harvard Medical School, Boston, Massachusetts.
FAU - Sheehy, Casey E
AU  - Sheehy CE
AD  - Boston Children's Hospital, Boston, Massachusetts.
FAU - Chu, Long
AU  - Chu L
AD  - Boston Children's Hospital, Boston, Massachusetts.
FAU - Wagner, Denisa D
AU  - Wagner DD
AD  - Children's Hospital and Harvard Medical School, Boston, Massachusetts.
LA  - eng
GR  - R35 HL135765/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220607
PL  - United States
TA  - Arthritis Rheumatol
JT  - Arthritis & rheumatology (Hoboken, N.J.)
JID - 101623795
RN  - 143011-72-7 (Granulocyte Colony-Stimulating Factor)
RN  - 9007-34-5 (Collagen)
RN  - EC 3.5.3.15 (Padi4 protein, mouse)
RN  - EC 3.5.3.15 (Protein-Arginine Deiminase Type 4)
RN  - EC 3.5.3.15 (Protein-Arginine Deiminases)
SB  - IM
MH  - Animals
MH  - *Arthritis, Experimental/chemically induced/enzymology
MH  - *Arthritis, Rheumatoid/chemically induced/enzymology
MH  - Collagen
MH  - Genome-Wide Association Study
MH  - Granulocyte Colony-Stimulating Factor
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - *Protein-Arginine Deiminase Type 4/metabolism
MH  - Protein-Arginine Deiminases
MH  - X-Ray Microtomography
PMC - PMC9246839
MID - NIHMS1780108
COIS- Competing interests Authors declare no conflict of interest on this research.
EDAT- 2022/02/16 06:00
MHDA- 2022/07/01 06:00
PMCR- 2023/07/01
CRDT- 2022/02/15 05:41
PHST- 2022/01/15 00:00 [revised]
PHST- 2021/08/26 00:00 [received]
PHST- 2022/02/09 00:00 [accepted]
PHST- 2022/02/16 06:00 [pubmed]
PHST- 2022/07/01 06:00 [medline]
PHST- 2022/02/15 05:41 [entrez]
PHST- 2023/07/01 00:00 [pmc-release]
AID - 10.1002/art.42093 [doi]
PST - ppublish
SO  - Arthritis Rheumatol. 2022 Jul;74(7):1139-1146. doi: 10.1002/art.42093. Epub 2022 
      Jun 7.