Halofuginone ameliorates autoimmune arthritis in mice by regulating the balance between Th17 and Treg cells and inhibiting osteoclastogenesis.
OBJECTIVE
The small molecule halofuginone has been shown to inhibit fibrosis, angiogenesis, and tumor progression. This study was undertaken to evaluate the effects of halofuginone in preventing autoimmune arthritis in mice.


METHODS
The effects of halofuginone on joint diseases were assessed by clinical scoring and histologic analysis. Protein expression levels were confirmed by immunohistochemistry, enzyme-linked immunosorbent assay, flow cytometry, and/or Western blotting. The expression levels of messenger RNA (mRNA) for various molecules were determined by real-time polymerase chain reaction (PCR). Proliferation of osteoclast precursors was assessed by bromodeoxyuridine uptake. Osteoclast differentiation and activity were determined by quantifying tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and area of resorbed bone.


RESULTS
Treatment with halofuginone suppressed the development of autoimmune arthritis and reciprocally regulated Th17 cells and FoxP3+ Treg cells. These effects of halofuginone on Th17 differentiation involved increased signaling of ERK and reduction of STAT-3 and NF-ATc1 expression. Furthermore, halofuginone induced the expression of indoleamine 2,3-dioxygenase (IDO) in dendritic cells, leading to reduced production of Th17 cells. In addition, halofuginone prevented the formation and activity of osteoclasts through suppression of transcription factors, such as activator protein 1 and NF-ATc1, and inhibited cell cycle arrest by the committed osteoclast precursors via expression of Ccnd1 encoding cyclin D1.


CONCLUSIONS
Taken together, our results suggest that halofuginone is a promising therapeutic agent for the treatment of Th17 cell-mediated inflammatory diseases and bone diseases.
Catholic University of Korea, Seoul, South Korea.
Mi-Kyung
MK
Park
Jin-Sil
JS
Park
Eun-Mi
EM
Park
Mi-Ae
MA
Lim
Sung-Min
SM
Kim
Dong-Gun
DG
Lee
Seung-Ye
SY
Baek
Eun-Ji
EJ
Yang
Jung-Won
JW
Woo
Jennifer
J
Lee
Seung-Ki
SK
Kwok
Ho-Youn
HY
Kim
Mi-La
ML
Cho
Sung-Hwan
SH
Park
D000818:Animals; D001168:Arthritis / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D001327:Autoimmune Diseases / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D018450:Disease Progression; D051858:Forkhead Transcription Factors / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology*; D053244:Osteoprotegerin / Q000494:pharmacology / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D052999:Quinazolinones / Q000494:pharmacology / Q000627:therapeutic use*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000473:pathology*; D058504:Th17 Cells / Q000187:drug effects / Q000473:pathology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050778:NFATC Transcription Factors; D053244:Osteoprotegerin; D010880:Piperidines; D011500:Protein Synthesis Inhibitors; D052999:Quinazolinones; D050796:STAT3 Transcription Factor; C010176:halofuginone