Anti-Interleukin-6 Therapy Decreases Hip Synovitis and Bone Resorption and Increases Bone Formation Following Ischemic Osteonecrosis of the Femoral Head

Yinshi Ren, Zhuo Deng, Vishal Gokani, Michael Kutschke, Thomas Wesley Mitchell, Olumide Aruwajoye, Naga Suresh Adapala, Nobuhiro Kamiya, Yousef Abu-Amer, Harry K Kim

Research output: Contribution to journalArticlepeer-review

Abstract

Legg-Calvé-Perthes disease (LCPD) is a juvenile form of ischemic femoral head osteonecrosis, which produces chronic hip synovitis, permanent femoral head deformity, and premature osteoarthritis. Currently, there is no medical therapy for LCPD. Interleukin-6 (IL-6) is significantly elevated in the synovial fluid of patients with LCPD. We hypothesize that IL-6 elevation promotes chronic hip synovitis and impairs bone healing after ischemic osteonecrosis. We set out to test if anti-IL-6 therapy using tocilizumab can decrease hip synovitis and improve bone healing in the piglet model of LCPD. Fourteen piglets were surgically induced with ischemic osteonecrosis and assigned to two groups: the no treatment group (n = 7) and the tocilizumab group (15 to 20 mg/kg, biweekly intravenous injection, n = 7). All animals were euthanized 8 weeks after the induction of osteonecrosis. Hip synovium and femoral heads were assessed for hip synovitis and bone healing using histology, micro-CT, and histomorphometry. The mean hip synovitis score and the number of synovial macrophages and vessels were significantly lower in the tocilizumab group compared with the no treatment group (p <.0001, p =.01, and p <.01, respectively). Micro-CT analysis of the femoral heads showed a significantly higher bone volume in the tocilizumab group compared with the no treatment group (p =.02). The histologic assessment revealed a significantly lower number of osteoclasts per bone surface (p <.001) in the tocilizumab group compared with the no treatment group. Moreover, fluorochrome labeling showed a significantly higher percent of mineralizing bone surface (p <.01), bone formation rate per bone surface (p <.01), and mineral apposition rate (p =.04) in the tocilizumab group. Taken together, tocilizumab therapy decreased hip synovitis and osteoclastic bone resorption and increased new bone formation after ischemic osteonecrosis. This study provides preclinical evidence that tocilizumab decreases synovitis and improves bone healing in a large animal model of LCPD.

Original languageEnglish (US)
JournalJournal of Bone and Mineral Research
DOIs
StateAccepted/In press - 2020

Keywords

  • AVASCULAR NECROSIS
  • FEMORAL HEAD OSTEONECROSIS
  • INTERLEUKIN-6
  • INTERLEUKIN-6 RECEPTOR INHIBITOR
  • LEGG-CALVÉ-PERTHES DISEASE
  • TOCILIZUMAB

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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