Reciprocal cross-talk between RANKL and interferon-gamma-inducible protein 10 is responsible for bone-erosive experimental arthritis.
OBJECTIVE
Interferon-gamma-inducible protein 10 (IP-10; also called CXCL10), a chemokine important in the migration and proliferation of T cells, is induced in a wide variety of cell types. However, the role of IP-10 in rheumatoid arthritis (RA) remains largely unknown. The purpose of this study was to examine the potential role of IP-10 in bone resorption and RA through examination of a mouse model of collagen-induced arthritis (CIA).


METHODS
The effects of IP-10 on mouse T cells during osteoclast differentiation were examined in migration assays. The bone-erosive activity of IP-10 was determined in vivo in a mouse model of CIA by histologic and immunostaining analyses. Cytokine levels in serum and culture medium were measured with sandwich enzyme-linked immunosorbent assays.


RESULTS
Serum concentrations of IP-10 were significantly higher in mice with CIA than in control mice. RANKL greatly induced IP-10 expression in osteoclast precursors, but not in mature osteoclasts. IP-10 stimulated the expression of RANKL and tumor necrosis factor alpha (TNFalpha) in CD4+ T cells and induced osteoclastogenesis in cocultures of CD4+ T cells and osteoclast precursors. However, IP-10 did not induce RANKL or TNFalpha in CD8+ T cells. Treatment with neutralizing antibody to IP-10 significantly inhibited the infiltration of CD4+ T cells and F4/80+ macrophages into the synovium and attenuated bone destruction in mice with CIA. Furthermore, levels of RANKL and TNFalpha were inhibited by antibody to IP-10. Bone erosion was observed in mice infected with an IP-10 retrovirus.


CONCLUSIONS
Our findings suggest that IP-10 plays a critical role in the infiltration of CD4+ T cells and F4/80+ macrophages into inflamed joints and causes bone destruction. Our results provide the first evidence that IP-10 contributes to the recruitment of inflammatory cells and is involved in bone erosion in inflamed joints.
Kwak
Han Bok
HB
Wonkwang University School of Medicine, Iksan, Republic of Korea.
Ha
Hyunil
H
Kim
Ha-Neui
HN
Lee
Jong-Ho
JH
Kim
Hun Soo
HS
Lee
Seungbok
S
Kim
Hyun-Man
HM
Kim
Jung Yeon
JY
Kim
Hong-Hee
HH
Song
Yeong Wook
YW
Lee
Zang Hee
ZH
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000209:etiology* / Q000276:immunology; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000502:physiology*; D051379:Mice; D008811:Mice, Inbred DBA; D053245:RANK Ligand / Q000502:physiology*
D054357:Chemokine CXCL10; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse