Hypoxia-inducible factor-1 alpha maintains mouse articular cartilage through suppression of NF-κB signaling
Hypoxia-inducible factor-1 alpha maintains mouse articular cartilage through suppression of NF-κB signaling
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DOI：
10.1038/s41598-020-62463-4
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发表时间：
2020-03-25
影响因子：
4.6
通讯作者：
Saito, Taku
中科院分区：
文献类型：
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作者：
Okada, Keita;Mori, Daisuke;Saito, Taku
缺氧诱导因子-1α(HIF-1α)是低氧条件下软骨细胞发育所必需的转录因子，但其在关节软骨细胞中的表达和作用尚不清楚。我们使用最先进的低氧探针检测了HIF-1α蛋白的表达和小鼠骨关节炎(OA)发展过程中的低氧状态，发现其表达随着OA的进展而减少，这与关节软骨的低氧状态的变化相一致。细胞培养实验中HIF-1α的获得和功能丧失实验表明，HIF-1α抑制分解代谢基因，如Mmp13和HIF2A。我们通过测量体外培养的野生型和条件性基因敲除小鼠股骨头释放的糖胺多糖来证实这些抗代谢作用。我们继续通过手术在软骨细胞特异性缺失HIF1a的小鼠中诱导骨性关节炎，发现骨性关节炎的发展加剧。在基因敲除的小鼠中，分解代谢因子的表达增加和核因子-kappaB信号的激活明显。基因芯片分析表明，C1qtnf3是HIF-1α的下游分子，实验表明其通过抑制核因子-kappaB发挥抗分解代谢作用。结论：HIF-1α通过抑制核因子-kappaB信号通路在维持关节软骨功能中具有抗分解代谢作用。
HIF-1 alpha, an essential transcription factor under hypoxic condition, is indispensable for chondrocytes during skeletal development but its expression and roles in articular chondrocytes are yet to be revealed. We examined HIF-1 alpha protein expression and the hypoxic condition during mouse osteoarthritis (OA) development using state of the art hypoxic probes and found that its expression decreased as OA progressed, coinciding with the change in hypoxic conditions in articular cartilage. Gain- and loss-of-function of HIF-1 alpha in cell culture experiments showed that HIF-1 alpha suppressed catabolic genes such as Mmp13 and Hif2a. We confirmed these anticatabolic effects by measuring glycosaminoglycan release from wild type and conditional knock-out mice femoral heads cultured ex vivo. We went on to surgically induce OA in mice with chondrocyte-specific deletion of Hif1a and found that the development of OA was exacerbated. Increased expression of catabolic factors and activation of NF-kappa B signalling was clearly evident in the knock-out mice. By microarray analysis, C1qtnf3 was identified as a downstream molecule of HIF-1 alpha, and experiments showed it exerted anti-catabolic effects through suppression of NF-kappa B. We conclude that HIF-1 alpha has an anti-catabolic function in the maintenance of articular cartilage through suppression of NF-kappa B signalling.