HIF-1-dependent IL-6 activation in articular chondrocytes initiating synovitis in femoral head ischemic osteonecrosis

Ryosuke Yamaguchi, Nobuhiro Kamiya, Naga Suresh Adapala, Hicham Drissi, Harry K.W. Kim

研究成果: ジャーナルへの寄稿学術誌査読

27 被引用数 (Scopus)


Background: Ischemic osteonecrosis of the femoral head in children is associated with chronic hip synovitis and increased levels of the pro-inflammatory cytokine interleukin-6 (IL-6) in the synovial fluid due to unknown mechanisms. The purpose of this study was to investigate hypoxia-inducible factor-1 (HIF-1) activation as a molecular mechanism linking the induction of ischemic osteonecrosis to IL-6 production and the initiation of hip synovitis. Methods: Ischemic osteonecrosis was surgically induced in the right femoral head of 6 piglets. A histologic score, synovial fluid volume, and IL-6 level were used to assess hip synovitis. IL-6 immunostaining of articular cartilage and synovial tissue was performed as well. To study the role of HIF-1 in IL-6 activation, in vitro experiments using an HIF- 1a activator (deferoxamine) and inhibitor (HIF-1 small interfering-RNA [siRNA]) were carried out. Synovial cell responses to hypoxic chondrocyte-conditioned media with and without an IL-6 receptor blocker (tocilizumab) were assessed on the basis of IL-1b and tumor necrosis factor-alpha (TNF-a) gene expressions and with a synovial cell-proliferation assay. Results: Induction of ischemic osteonecrosis produced hip synovitis and increased IL-6 levels in the synovial fluid. Immunostaining and protein analysis demonstrated articular chondrocytes as a source of increased IL-6 production. When articular chondrocytes were cultured under hypoxic conditions, significantly increased HIF-1a and IL-6 expressions were observed. Under hypoxic culture conditions, IL-6 gene expression was significantly increased by HIF-1a activation using deferoxamine and inhibited by HIF-1a inhibition using HIF-1 siRNA. Synovial cells exposed to hypoxic chondrocyteconditioned medium showed significant increases in IL-1b and TNF-a gene expressions and cell proliferation, which were inhibited by the IL-6 receptor blocker tocilizumab. Conclusions: Induction of ischemic osteonecrosis results in IL-6 production in the articular cartilage through an HIF-1-dependent pathway. IL-6 produced by hypoxic articular chondrocytes stimulates inflammatory cytokine responses in synovial cells, which were significantly decreased by tocilizumab.

ジャーナルJournal of Bone and Joint Surgery - American Volume
出版ステータス出版済み - 7月 6 2016

!!!All Science Journal Classification (ASJC) codes

  • 外科
  • 整形外科およびスポーツ医学


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