PMID- 35148358
OWN - NLM
STAT- MEDLINE
DCOM- 20220225
LR  - 20220225
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 17
IP  - 2
DP  - 2022
TI  - Oral administration of bovine lactoferrin suppresses the progression of 
      rheumatoid arthritis in an SKG mouse model.
PG  - e0263254
LID - 10.1371/journal.pone.0263254 [doi]
LID - e0263254
AB  - Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammatory 
      bone destruction in which tumor necrosis factor alpha (TNF-alpha) plays a key role. 
      Bovine lactoferrin (bLF) is a multifunctional protein with anti-inflammatory and 
      immunomodulatory properties. This study aimed to clarify the inhibitory effects 
      of bLF on the pathological progression of RA. The mannan-induced arthritis model 
      in SKG mice (genetic RA model) was used. Orally applied liposomal bLF (LbLF) 
      markedly reduced ankle joint swelling and bone destruction. Histologically, 
      pannus formation and osteoclastic bone destruction were prevented in the 
      LbLF-treated animals. Moreover, orally administered LbLF improved the balance 
      between Th17 cells and regulatory T cells isolated from the spleen of 
      mannan-treated SKG mice. In an in vitro study, the anti-inflammatory effects of 
      bLF on TNF-alpha-induced TNF-alpha production and downstream signaling pathways were 
      analyzed in human synovial fibroblasts from RA patients (RASFs). bLF suppressed 
      TNF-alpha production from RASFs by inhibiting the nuclear factor kappa B and 
      mitogen-activated protein kinase pathways. The intracellular accumulation of bLF 
      in RASFs increased in an applied bLF dose-dependent manner. Knockdown of the 
      lipoprotein receptor-related protein-1 (LRP1) siRNA gene reduced bLF expression 
      in RASFs, indicating that exogenously applied bLF was mainly internalized through 
      LRP-1. Immunoprecipitated proteins with anti-TNF receptor-associated factor 2 
      (TRAF2; an adapter protein/ubiquitin ligase) included bLF, indicating that bLF 
      binds directly to the TRAF2-TRADD-RIP complex. This indicates that LbLF may 
      effectively prevent the pathological progression of RA by suppressing TNF-alpha 
      production by binding to the TRAF2-TRADD-RIP complex from the RASFs in the 
      pannus. Therefore, supplemental administration of LbLF may have a beneficial 
      effect on preventive/therapeutic reagents for RA.
FAU - Yanagisawa, Shunryou
AU  - Yanagisawa S
AD  - Department of Oral & Maxillofacial Pathobiology, Graduate School of Biomedical & 
      Health Sciences, Hiroshima University, Hiroshima, Japan.
FAU - Nagasaki, Karin
AU  - Nagasaki K
AD  - Department of Oral & Maxillofacial Pathobiology, Graduate School of Biomedical & 
      Health Sciences, Hiroshima University, Hiroshima, Japan.
AD  - Department of Periodontology and Endodontology, Tohoku University Graduate School 
      of Dentistry, Sendai, Japan.
FAU - Chea, Chanbora
AU  - Chea C
AD  - Department of Oral & Maxillofacial Pathobiology, Graduate School of Biomedical & 
      Health Sciences, Hiroshima University, Hiroshima, Japan.
AD  - Faculty of Dentistry, University of Puthisastra, Phnom Penh, Cambodia.
FAU - Ando, Toshinori
AU  - Ando T
AUID- ORCID: 0000-0002-3141-8173
AD  - Department of Oral & Maxillofacial Pathobiology, Graduate School of Biomedical & 
      Health Sciences, Hiroshima University, Hiroshima, Japan.
AD  - Center of Oral Clinical Examination, Hiroshima University Hospital, Hiroshima, 
      Japan.
FAU - Ayuningtyas, Nurina Febriyanti
AU  - Ayuningtyas NF
AD  - Faculty of Dental Medicine, Airlangga University, Surabaya, Indonesia.
FAU - Inubushi, Toshihiro
AU  - Inubushi T
AD  - Department of Orthodontics and Dentofacial Orthopedics, Graduate School of 
      Dentistry, Osaka University, Osaka, Japan.
FAU - Ishikado, Atsushi
AU  - Ishikado A
AD  - R&D Department, Sunstar Inc., Osaka, Japan.
FAU - Imanaka, Hiromichi
AU  - Imanaka H
AD  - R&D Department, Sunstar Inc., Osaka, Japan.
FAU - Sugiyama, Eiji
AU  - Sugiyama E
AD  - Hiroshima University, Hiroshima, Japan.
FAU - Takahashi, Ichiro
AU  - Takahashi I
AD  - Department of Mucosal Immunology, Graduate School of Biomedical & Health 
      Sciences, Hiroshima University, Hiroshima, Japan.
FAU - Miyauchi, Mutsumi
AU  - Miyauchi M
AUID- ORCID: 0000-0002-7428-9703
AD  - Department of Oral & Maxillofacial Pathobiology, Graduate School of Biomedical & 
      Health Sciences, Hiroshima University, Hiroshima, Japan.
FAU - Takata, Takashi
AU  - Takata T
AD  - Department of Oral & Maxillofacial Pathobiology, Graduate School of Biomedical & 
      Health Sciences, Hiroshima University, Hiroshima, Japan.
AD  - Tokuyama University, Shunan, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220211
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.4.21.- (Lactoferrin)
SB  - IM
MH  - Administration, Oral
MH  - Animals
MH  - Arthritis, Rheumatoid/*drug therapy/metabolism
MH  - Disease Models, Animal
MH  - Disease Progression
MH  - Female
MH  - Humans
MH  - Lactoferrin/*administration & dosage/pharmacology
MH  - Male
MH  - Mice
MH  - Osteoclasts/cytology/drug effects/metabolism
MH  - Osteogenesis/*drug effects
MH  - Synovial Membrane/*cytology/drug effects/metabolism
MH  - Th17 Cells/metabolism
MH  - Tumor Necrosis Factor-alpha/*adverse effects
PMC - PMC8836292
COIS- AI and HI are employees of Sunstar Inc. Besides that, the authors declare no 
      conflicts of interest associated with this manuscript. The funder provided 
      support in the form of salaries for authors [AI and HI] but did not have any 
      additional role in the study design, data collection and analysis, decision to 
      publish, or preparation of the manuscript. The specific roles of these authors 
      are articulated in the 'author contributions' section. This does not alter our 
      adherence to PLOS ONE policies on sharing data and materials. The all authors 
      including AI and HI declare no conflicts of interest associated with this 
      manuscript.
EDAT- 2022/02/12 06:00
MHDA- 2022/02/26 06:00
PMCR- 2022/02/11
CRDT- 2022/02/11 17:11
PHST- 2021/05/20 00:00 [received]
PHST- 2022/01/14 00:00 [accepted]
PHST- 2022/02/11 17:11 [entrez]
PHST- 2022/02/12 06:00 [pubmed]
PHST- 2022/02/26 06:00 [medline]
PHST- 2022/02/11 00:00 [pmc-release]
AID - PONE-D-21-16638 [pii]
AID - 10.1371/journal.pone.0263254 [doi]
PST - epublish
SO  - PLoS One. 2022 Feb 11;17(2):e0263254. doi: 10.1371/journal.pone.0263254. 
      eCollection 2022.