Abstract
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.
Highlights
Osteoarthritis (OA) is a degenerative disease of the articular cartilage, impairing activity of daily living and quality of life due to arthralgia, limitation of the range of joint motion, and joint swelling.Mechanical loading is considered to be strongly involved in degeneration of articular cartilage.Takahashi et al [1] showed that continuous hydrostatic pressure inhibited proteoglycan synthesis in a human chondrocyte-like cell line and Nakamura et al [2] showed that induced apoptosis depending on pressure amplitude and/or duration in chondrocytes cultured on alginate beads
Hydrostatic pressure was exposed to primary cultured chondrocytes measuring gene expression related to hypertrophic differentiation
The levels of NF-κB, Hypoxia-inducible factor (HIF)-2α, matrix metalloproteinase (MMP)-13, MMP-3, and vascular endothelial growth factor (VEGF) gene expression were significantly increased by 5.0, 3.7, 26.5, 1356, and 1.5-fold, respectively, by inflammatory stress (Figure 1)
Summary
Osteoarthritis (OA) is a degenerative disease of the articular cartilage, impairing activity of daily living and quality of life due to arthralgia, limitation of the range of joint motion, and joint swelling. Mechanical loading is considered to be strongly involved in degeneration of articular cartilage. Excessive mechanical stress induces degeneration and destruction of articular cartilage, causing OA. Hypertrophic differentiation characterized by secretion of type 10 collagen is involved in the initiation of OA. Hypertrophic differentiated chondrocytes product matrix metalloproteinase (MMP)s, resulting in progression of cartilage degeneration. Hypoxia-inducible factor (HIF)-2α is a transcription factor that strongly induces type 10 collagen in chondrocytes [3,4]. HIF-2α induces expression of a wide range of factors involved in endochondral ossification, such as MMPs, vascular endothelial growth factor (VEGF), and Indian hedgehog signals, in articular chondrocytes. It was reported that pressure amplitude influences HIF-2α expression in murine endothelial cells [5,6]. The present study was performed to analyze the influence of hydrostatic pressure on hypertrophic differentiation-related gene expression in cultured chondrocytes
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