Abstract
Hyaluronic acid (HA) is used clinically to treat osteoarthritis (OA), but its pharmacological effects under hypoxic conditions remain unclear. Articular chondrocytes in patients with OA are exposed to a hypoxic environment. This study investigated whether hypoxia could potentiate the anabolic effects of exogenous HA in rat articular cartilage and whether these mechanisms involved HA receptors. HA under hypoxic conditions significantly enhanced the expression of extracellular matrix genes and proteins in explant culture, as shown by real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and dimethylmethylene blue (DMMB) assays. Staining with Safranin-O and immunohistochemical staining with antibody to type II collagen were also enhanced in pellet culture. The expression of CD44 was increased by hypoxia and significantly suppressed by transfection with siRNAs targeting hypoxia-inducible factor 1 alpha (siHIF-1α). These findings indicate that hypoxia potentiates the anabolic effects of exogenous HA by a mechanism in which HIF-1α positively regulates the expression of CD44, enhancing the binding affinity for exogenous HA. The anabolic effects of exogenous HA may increase as OA progresses.
Highlights
Osteoarthritis (OA) is a disease that negatively affects patients’ quality of life due to the irreversible progression of chronic pain and restriction of joint mobility [1]
To determine the metabolic effects of exogenous Hyaluronic acid (HA) and hypoxia on the extracellular matrix (ECM), explants of rat articular cartilage were cultured for 72 h in the presence or absence of HA under normoxic or hypoxic conditions
Real-time reverse transcription-polymerase chain reaction (RT-PCR) showed that the level of COL2A1 mRNA was significantly higher in explants treated with HA under hypoxic conditions than in the absence of HA under normoxic condition (Figure 1A)
Summary
Osteoarthritis (OA) is a disease that negatively affects patients’ quality of life due to the irreversible progression of chronic pain and restriction of joint mobility [1]. Progressive degeneration of the articular cartilage is associated with age, injury, abnormal alignment, and metabolism disorders. The molecular mechanisms underlying cartilage degeneration caused by aging, mechanical stress, and inflammation have become clear, and risk factors for OA have been identified in a large-scale, population-based cohort study [2,3], curative drug therapy for OA has not yet been developed. Intra-articular injection of N-[N-(3,5-diflurophenylacetate)-L-alanyl]-(S)-phenylglycine t-butyl ester (DAPT), a small compound Notch inhibitor, in a surgical mouse OA model caused suppression of cartilage degradation [6]. These drugs have the potential as a curative agents against OA, but are not yet in clinical use
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