PMID- 27385686 OWN - NLM STAT- MEDLINE DCOM- 20170323 LR - 20170817 IS - 1535-1386 (Electronic) IS - 0021-9355 (Linking) VI - 98 IP - 13 DP - 2016 Jul 6 TI - HIF-1-Dependent IL-6 Activation in Articular Chondrocytes Initiating Synovitis in Femoral Head Ischemic Osteonecrosis. PG - 1122-31 LID - 10.2106/JBJS.15.01209 [doi] AB - 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-1alpha 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-1beta and tumor necrosis factor-alpha (TNF-alpha) 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-1alpha and IL-6 expressions were observed. Under hypoxic culture conditions, IL-6 gene expression was significantly increased by HIF-1alpha activation using deferoxamine and inhibited by HIF-1alpha inhibition using HIF-1 siRNA. Synovial cells exposed to hypoxic chondrocyte-conditioned medium showed significant increases in IL-1beta and TNF-alpha 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. CLINICAL RELEVANCE: This study provides new insight into the inherent relationship between the induction of ischemia and the initiation of hip synovitis following ischemic osteonecrosis and suggests a potential therapeutic target in the treatment of the synovitis. CI - Copyright (c) 2016 by The Journal of Bone and Joint Surgery, Incorporated. FAU - Yamaguchi, Ryosuke AU - Yamaguchi R AD - Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, Texas Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas. FAU - Kamiya, Nobuhiro AU - Kamiya N AD - Faculty of Budo and Sport Studies, Tenri University, Tenri, Nara, Japan. FAU - Adapala, Naga Suresh AU - Adapala NS AD - Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, Texas Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas. FAU - Drissi, Hicham AU - Drissi H AD - Department of Orthopaedic Surgery, University of Connecticut Health Center, Farmington, Connecticut. FAU - Kim, Harry K W AU - Kim HK AD - Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, Texas Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas Harry.Kim@tsrh.org. LA - eng PT - Journal Article PL - United States TA - J Bone Joint Surg Am JT - The Journal of bone and joint surgery. American volume JID - 0014030 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Interleukin-1beta) RN - 0 (Interleukin-6) RN - 0 (Receptors, Interleukin-6) RN - 0 (Tumor Necrosis Factor-alpha) RN - I031V2H011 (tocilizumab) SB - IM MH - Animals MH - Antibodies, Monoclonal, Humanized/pharmacology MH - Cartilage, Articular/drug effects/*metabolism/pathology MH - Cell Proliferation/drug effects/physiology MH - Chondrocytes/drug effects/*metabolism/pathology MH - Disease Models, Animal MH - Femur Head Necrosis/*metabolism/pathology MH - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism MH - Interleukin-1beta/metabolism MH - Interleukin-6/*metabolism MH - Receptors, Interleukin-6/antagonists & inhibitors MH - Signal Transduction/drug effects/physiology MH - Swine MH - Synovial Fluid/*metabolism MH - Synovial Membrane/drug effects/metabolism/pathology MH - Synovitis/*metabolism/pathology MH - Tumor Necrosis Factor-alpha/metabolism EDAT- 2016/07/08 06:00 MHDA- 2017/03/24 06:00 CRDT- 2016/07/08 06:00 PHST- 2016/07/08 06:00 [entrez] PHST- 2016/07/08 06:00 [pubmed] PHST- 2017/03/24 06:00 [medline] AID - 98/13/1122 [pii] AID - 10.2106/JBJS.15.01209 [doi] PST - ppublish SO - J Bone Joint Surg Am. 2016 Jul 6;98(13):1122-31. doi: 10.2106/JBJS.15.01209.