HIF-2α-induced chemokines stimulate motility of fibroblast-like synoviocytes and chondrocytes into the cartilage-pannus interface in experimental rheumatoid arthritis mouse models.
BACKGROUND
Pannus formation and resulting cartilage destruction during rheumatoid arthritis (RA) depends on the migration of synoviocytes to cartilage tissue. Here, we focused on the role of hypoxia-inducible factor (HIF)-2α-induced chemokines by chondrocytes in the regulation of fibroblast-like synoviocyte (FLS) migration into the cartilage-pannus interface and cartilage erosion.


METHODS
Collagen-induced arthritis (CIA), K/BxN serum transfer, and tumor necrosis factor-α transgenic mice were used as experimental RA models. Expression patterns of HIF-2α and chemokines were determined via immunostaining, Western blotting and RT-PCR. FLS motility was evaluated using transwell migration and invasion assays. The specific role of HIF-2α was determined via local deletion of HIF-2α in joint tissues or using conditional knockout (KO) mice. Cartilage destruction, synovitis and pannus formation were assessed via histological analysis.


RESULTS
HIF-2α and various chemokines were markedly upregulated in degenerating cartilage and pannus of RA joints. HIF-2α induced chemokine expression by chondrocytes in both primary culture and cartilage tissue. HIF-2α -induced chemokines by chondrocytes regulated the migration and invasion of FLS. Local deletion of HIF-2α in joint tissues inhibited pannus formation adjacent to cartilage tissue and cartilage destruction caused by K/BxN serum transfer. Furthermore, conditional knockout of HIF-2α in cartilage blocked pannus formation in adjacent cartilage but not bone tissue, along with inhibition of cartilage erosion caused by K/BxN serum transfer.


CONCLUSIONS
Our findings suggest that chemokines induced by IL-1β or HIF-2α in chondrocytes regulate pannus expansion by stimulating FLS migration and invasion, leading to cartilage erosion during RA pathogenesis.
BioImaging and Cell Dynamics Research Center, Gwangju Institute of Science and Technology, 123 Cheomdangwagi-ro, Buk-gu, Gwangju, 61005, Republic of Korea. yhuh@gist.ac.k.
Yun Hyun
YH
Huh
Cell Dynamics Research Center and School of Life Science, Gwangju Institute of Science and Technology, 123 Cheomdangwagi-ro, Buk-gu, Gwangju, 61005, Republic of Korea. gslee@gist.ac.kr.
Gyuseok
G
Lee
Department of Orthopedic Surgery, Chonnam National University Medical School and Hospital, 42 Jebong-ro, Dong-gu, Gwangju, 61469, Republic of Korea. kbleeos@chonnam.ac.kr.
Keun-Bae
KB
Lee
Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea. jtkoh@chonnam.ac.kr.|Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea. jtkoh@chonnam.ac.kr.
Jeong-Tae
JT
Koh
Cell Dynamics Research Center and School of Life Science, Gwangju Institute of Science and Technology, 123 Cheomdangwagi-ro, Buk-gu, Gwangju, 61005, Republic of Korea. jschun@gist.ac.kr.
Jang-Soo
JS
Chun
Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea. jesryu@jnu.ac.kr.|Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea. jesryu@jnu.ac.kr.
Je-Hwang
JH
Ryu
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051792:Basic Helix-Loop-Helix Proteins / Q000276:immunology*; D015153:Blotting, Western; D002358:Cartilage, Articular / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000276:immunology; D018925:Chemokines / Q000276:immunology; D019902:Chondrocytes / Q000276:immunology* / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D005347:Fibroblasts / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D018925:Chemokines; D000099162:Endothelial PAS Domain-Containing Protein 1