Inoue Hiroaki, Arai Yuji, Kishida Tsunao, Terauchi Ryu, Honjo Kuniaki, Nakagawa Shuji, Tsuchida Shinji, Matsuki Tomohiro, Ueshima Keiichirou, Fujiwara Hiroyoshi, Mazda Osam, Kubo Toshikazu
Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
Department of Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
Int J Mol Sci. 2015 Jan 5;16(1):1043-50. doi: 10.3390/ijms16011043.
Hypoxia-inducible factor (HIF)-2α is considered to play a major role in the progression of osteoarthritis. Recently, it was reported that pressure amplitude influences HIF-2α expression in murine endothelial cells. We examined whether hydrostatic pressure is involved in expression of HIF-2α in articular chondrocytes. Chondrocytes were cultured and stimulated by inflammation or hydrostatic pressure of 0, 5, 10, or 50 MPa. After stimulation, heat shock protein (HSP) 70, HIF-2α, nuclear factor kappa B (NF-κB), matrix metalloproteinase (MMP)-13, MMP-3, and vascular endothelial growth factor (VEGF) gene expression were evaluated. The levels of all gene expression were increased by inflammatory stress. When chondrocytes were exposed to a hydrostatic pressure of 5 MPa, HIF-2α, MMP-13, and MMP-3 gene expression increased significantly although those of HSP70 and NF-κB were not significantly different from the control group. In contrast, HIF-2α gene expression did not increase under a hydrostatic pressure of 50 MPa although HSP70 and NF-κB expression increased significantly compared to control. We considered that hydrostatic pressure of 5 MPa could regulate HIF-2α independent of NF-κB, because the level of HIF-2α gene expression increased significantly without upregulation of NF-κB expression at 5 MPa. Hydrostatic pressure may influence cartilage degeneration, inducing MMP-13 and MMP-3 expression through HIF-2α.
缺氧诱导因子（HIF）-2α被认为在骨关节炎进展中起主要作用。最近，有报道称压力幅度会影响小鼠内皮细胞中HIF-2α的表达。我们研究了流体静压力是否参与关节软骨细胞中HIF-2α的表达。培养软骨细胞，并分别用炎症或0、5、10或50兆帕的流体静压力进行刺激。刺激后，评估热休克蛋白（HSP）70、HIF-2α、核因子κB（NF-κB）、基质金属蛋白酶（MMP）-13、MMP-3和血管内皮生长因子（VEGF）的基因表达。炎症应激会使所有基因表达水平升高。当软骨细胞暴露于5兆帕的流体静压力时，HIF-2α、MMP-13和MMP-3的基因表达显著增加，尽管HSP70和NF-κB的基因表达与对照组无显著差异。相比之下，在50兆帕的流体静压力下，HIF-2α基因表达并未增加，尽管与对照组相比，HSP70和NF-κB表达显著增加。我们认为5兆帕的流体静压力可独立于NF-κB调节HIF-2α，因为在5兆帕时，HIF-2α基因表达水平显著增加，而NF-κB表达并未上调。流体静压力可能通过HIF-2α影响软骨退变，诱导MMP-13和MMP-3表达。
