Cytokine receptor-like factor 1 is highly expressed in damaged human knee osteoarthritic cartilage and involved in osteoarthritis downstream of TGF-beta.
Osteoarthritis (OA) is the most prevalent joint disease and is characterized by pain and functional loss of the joint. However, the pathogenic mechanism of OA remains unclear, and no drug therapy for preventing its progress has been established. To identify genes related to the progress of OA, the gene expression profiles of paired intact and damaged cartilage obtained from OA patients undergoing joint substitution were compared using oligo microarrays. Using functional categorization combined with gene ontology and a statistical analysis, five genes were found to be highly expressed in damaged cartilage (HBEGF, ASUS, CRLF1, LOX, CDA), whereas three genes were highly expressed in intact tissues (CHST2, PTPRD, CPAN6). Among these genes, the upregulated expression of CRLF1 was reconfirmed using real-time PCR, and the in vivo expression of CRLF1 was detected in clusters of chondrocytes and fibrocartilage-like cells in damaged OA cartilages using in situ hybridization. In vitro, the transcriptional level of CRLF1 was positively regulated by TGF-beta1 in the mouse chondrogenic cell line ATDC5. Additionally, the CRLF1/CLC complex promoted the proliferation of ATDC5 cells and suppressed the expression level of aggrecan and type II collagen. Our data suggest that the CRLF1/CLC complex disrupts cartilage homeostasis and promotes the progress of OA by enhancing the proliferation of chondrocytes and suppressing the production of cartilage matrix. A component of the complex, CRLF1, may be useful as a biomarker of OA; and the corresponding receptor is a potential new drug target for OA.
Tsuritani
Katsuki
K
Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School of Natural Science and Technology, Kakuma-machi, Kanazawa, Japan. k.tsuritani@po.rd.taisho.co.jp
Takeda
Junko
J
Sakagami
Junko
J
Ishii
Aiko
A
Eriksson
Tore
T
Hara
Toshifumi
T
Ishibashi
Hideaki
H
Koshihara
Yasuko
Y
Yamada
Kiyofumi
K
Yoneda
Yukio
Y
D053674:Aggrecans / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D002358:Cartilage, Articular / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D002460:Cell Line; D049109:Cell Proliferation; D019902:Chondrocytes / Q000378:metabolism; D024043:Collagen Type II / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007719:Knee Joint / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D020370:Osteoarthritis, Knee / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
D053674:Aggrecans; D015415:Biomarkers; D024043:Collagen Type II; D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D016212:Transforming Growth Factor beta; C113554:cytokine-like factor-1