4.8 Article

Cobalt ions induce metabolic stress in synovial fibroblasts and secretion of cytokines/chemokines that may be diagnostic markers for adverse local tissue reactions to hip implants

期刊

ACTA BIOMATERIALIA
卷 131, 期 -, 页码 581-594

出版社

ELSEVIER SCI LTD
DOI: 10.1016/j.actbio.2021.06.039

关键词

IL-16; Hip pseudotumors; Metal ions; Mitophagy; Hip arthroplasty; Cytokine storm

资金

  1. Orthopedic Research Excellence Fund (OREF) - Natural Sciences and Engineering Research Council of Canada (NCERC)
  2. Collaborative Health Research Projects (CHRP) - Natural Sciences and Engineering Research Council of Canada (NCERC)
  3. Collaborative Health Research Projects (CHRP) - Canadian Institutes of Health Research (CIHR)
  4. ANID-FONDECYT [1201039]
  5. Iniciativa Cientifica Milenio ANID, Chile
  6. Chilean Bureau of Science and Technology (CONICYT)
  7. Canadian Institutes of Health Research (CIHR)

向作者/读者索取更多资源

Adverse local tissue reactions (ALTRs) in failing metal hip implants are likely caused by CoCrMo corrosion, leading to aseptic necrosis and leukocyte infiltration of synovial tissue. Cobalt ions released by failing hip implants induce mitochondrial stress and cytokine secretion by synovial fibroblasts, initiating ALTR pathogenesis. The inflammatory factors secreted by cobalt-exposed synovial fibroblasts contribute to endothelial activation and monocyte migration in ALTR patients.
Adverse local tissue reactions (ALTRs) are a prominent cause of hip implant failure. ALTRs are characterized by aseptic necrosis and leukocyte infiltration of synovial tissue. The prevalence of ALTRs in hips with failing metal implants, with highest rates occurring in patients with metal-on-metal articulations, suggests a role for CoCrMo corrosion in ALTR formation. Although hypersensitivity reactions are the most accepted etiology, the precise cellular mechanism driving ALTR pathogenesis remains enigmatic. Here we show that cobalt ions released by failing hip implants induce mitochondrial stress and cytokine secretion by synovial fibroblasts: the presumptive initiators of ALTR pathogenesis. We found that in-vitro treatment of synovial fibroblasts with cobalt, but not chromium, generated gene expression changes indicative of hypoxia and mitophagy responses also observed in ALTRs biopsies. Inflammatory factors secreted by cobalt-exposed synovial fibroblasts were among those most concentrated in ALTR synovial fluid. Furthermore, both conditioned media from cobalt-exposed synovial fibroblasts, and synovial fluid from ALTRs patients, elicit endothelial activation and monocyte migration. Finally, we identify the IL16/CTACK ratio in synovial fluid as a possible diagnostic marker of ALTRs. Our results provide evidence suggesting that metal ions induce cell stress in synovial fibroblasts that promote an inflammatory response consistent with initiating ALTR formation.

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