HIF-2Α Drives Osteoarthritis Development

RESEARCH HIGHLIGHTS OSTEOARTHRITIS HIF-2α drives osteoarthritis development he pathogenesis of osteoarthritis (OA) EPAS1 is driven by the p65 subunit of the WT +/− −/− involves endochondral ossification, transcription factor NFκB, as determined Ta physiological mechanism in which by screening assays and site-directed avascular cartilage tissue converts into mutagenesis. The authors hypothesize that vascularized bone tissue as part of skeletal mechanical stress might induce the NFκB– growth. This process is characterized by HIF-2α signal in joint cartilage, which three fundamental steps—chondrocyte then drives pathological endochondral hypertrophy, cartilage degradation and ossification through the expression of WT +/− vascular invasion, which involve the COL10A1, MMP13 and VEGFA. “The COL10A1, MMP13 and VEGFA genes, NFκB–HIF-2α signal controls not only respectively. Evidence from two studies in the initial chondrocyte hypertrophy, but Nature Medicine now suggests that hypoxia- also subsequent cartilage degradation and inducible factor 2α (HIF-2α), a protein vascular invasion steps of endochondral roup known to be expressed in both hypoxic and ossification in osteoarthritis, and so this G vascularized tissues, is a central mediator of signal might represent a therapeutic endochondral ossification and can promote target,” explains Hiroshi Kawaguchi, the OA development. study’s lead investigator. Taku Saito and colleagues, from the In a separate study, Siyoung Yang University of Tokyo, Japan, screened and co-workers, from three centers © Nature Publishing mouse chondrogenic ATDC5 cells in Korea, identified EPAS1 as a gene by injecting Epas1 into mouse and rabbit and HeLa cells (harboring a COL10A1 induced under pathological conditions knee joints, strongly suggesting that the promoter fragment) with a panel of by screening the human OA cartilage elevated levels of HIF-2α observed in transcription factors, and identified UniGene library. They subsequently human osteoarthritic cartilage are critical HIF-2α as the strongest activator of the showed Epas1 to be upregulated in in the pathogenesis of the disease. COL10A1 promoter. Further analysis primary mouse chondrocytes treated with Collectively, these studies present a revealed that the expression of Epas1, the proinflammatory cytokines. novel role for HIF-2α in endochondral gene encoding HIF-2α, is increased during Further analysis demonstrated that ossification and the development of the differentiation of ATDC5 cells, as HIF-2α mediates the interleukin-1β- OA. Although Epas1+/– mice displayed are the endochondral ossification-related induced expression of various catabolic growth retardation in early life, they had mouse genes Col10a1, Mmp13 and Veg fa. factors in primary rabbit chondrocytes, no gross abnormalities of major organs, Furthermore, Epas1+/– mice—which show including MMP1, MMP3, MMP9, suggesting that inhibition of HIF-2α growth retardation in embryogenesis MMP12, MMP13, ADAMTS4, NOS2 activity might be a viable therapeutic and early life—had decreased Col10a1, and PTGS2. Indeed, expression of these option for OA with minimal adverse Mmp13 and Veg fa gene expression in their factors could be enhanced by ectopic effects on normal skeletal growth. Indeed, chondrocytes in comparison with wild- expression of Epas1 and, conversely, efforts to target the NFκB–HIF-2α signal type mice, which could be restored by blocked through the use of Epas1-specific are underway. “We are now searching for adenoviral overexpression of HIF-2α. small interfering RNA. the extracellular signal that lies upstream Using an OA model in which instability To examine the role of HIF-2α in of HIF-2α and either directly activates is induced in the knee of wild-type and human disease, the researchers compared or suppresses it, because an extracellular Epas1+/– mice, the investigators noted that damaged and undamaged cartilage protein might be easier to target than an HIF-2α deficiency caused a reduction from 20 individuals with OA, and found intracellular transcription factor like in cartilage degradation, osteophyte elevated EPAS1 messenger RNA and HIF-2α,” says Kawaguchi. formation and Col10a1, Mmp13 and HIF-2α protein levels in the damaged Rowan Higgs Veg fa gene expression. Furthermore, tissue. Expression of EPAS1, MMP1, through sequence analysis of data from MMP9, MMP12, MMP13, ADAMTS4, Original articles Saito, T. et al. Transcriptional regulation a Japanese cohort, the research team NOS2 and PTGS2 was also higher of endochondral ossification by HIF-2alpha during skeletal found a significant association (P = 0.013) in damaged osteoarthritic cartilage growth and osteoarthritis development. Nat. Med. 16, between knee OA and the presence of compared with nonosteoarthritic control 678–687 (2010) | Yang, S. et al. Hypoxia-inducible factor- a single nucleotide polymorphism in cartilage. Furthermore, the investigators 2alpha is a catabolic regulator of osteoarthritic cartilage destruction. Nat. Med. 16, 687–694 (2010) the human EPAS1 gene. Expression of could directly induce cartilage destruction NATURE REVIEWS | RHEUMATOLOGY VOLUME 6 | AUGUST 2010 | 435 © 2010 Macmillan Publishers Limited. All rights reserved.

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