Hypoxia Potentiates Anabolic Effects of Exogenous Hyaluronic Acid in Rat Articular Cartilage

• Main Authors: Shohei Ichimaru, Shuji Nakagawa, Yuji Arai, Tsunao Kishida, Masaharu Shin-Ya, Kuniaki Honjo, Shinji Tsuchida, Hiroaki Inoue, Hiroyoshi Fujiwara, Seiji Shimomura, Osam Mazda, Toshikazu Kubo
• Format: Article
• Language: English
• Published: MDPI AG 2016-06-01
• Series: International Journal of Molecular Sciences
• Subjects: hypoxia-inducible factor 1 α; hyaluronic acid; CD44; articular cartilage; extracellular matrix
• Online Access: http://www.mdpi.com/1422-0067/17/7/1013

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.