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Activation of Osteoblasts by Cobalt-Chromium Occurs Via a TLR4-Mediated Pathway

Lookup NU author(s): Dr Shannon Jamieson, Amy Mawdesley, Dr Philip Hyde, Emeritus Professor John Kirby, Professor Alison Tyson-Capper


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Total hip replacement (THR) is indicated for patients with osteoarthritis where conservative treatment has failed. Metal alloys used in THR implants such as cobalt-chromium (CoCr) have been known to cause pro-inflammatory reactions in patients, therefore leading to the need for costly revision surgery. This study therefore aimed to investigate the role of TLR4 in the activation of a human osteoblast model in response to CoCr particles in vitro.Human osteoblasts (MG-63 cell line) were seeded at a density of 100,000 cells and treated with 0.5, 5, 50mm3 CoCr particles per cell for 24-hours. Trypan blue and the XTT Cell Proliferation Kit II were then used in conjunction with the cells to assess CoCr-induced cytotoxicity. Cells were pre-treated with a commercially available TLR4-specific small molecule inhibitor (CLI-095) for 6 hours. Untreated cells were used as a negative control and lipopolysaccharide (LPS) was used as a positive control. Following treatment the cell supernatant was collected and used for enzyme-linked immunosorbant assay (ELISA) to measure the secretion of interleukin-8 (IL-8), CXCL10, and interleukin-6 (IL-6).Trypan blue and XTT analysis showed that there was no significant changes to cell viability or proliferation at any dose used of CoCr after 24 hours. There was a significant increase in protein secretion of IL-8 (p<0.001), CXCL10 (p<0.001), and IL-6 (p<0.001) in the cells which received the highest dosage of CoCr. This pro-inflammatory secretory response was ameliorated by TLR4 blockade (p<0.001).CoCr particles are not cytotoxic to osteoblasts but they do induce pro-inflammatory changes as characterised by increased secretion of chemokines IL-8, CXCL10, and IL-6. These responses occur via a TLR4-mediated pathway and upon inhibition they can be effectively ameliorated. This is particularly important as TLR4 could be a potential target for pharmacological intervention used in patients experiencing immunological reactions to metal implant debris.

Publication metadata

Author(s): Jamieson S, Mawdesley A, Hyde P, Kirby J, Tyson-Capper A

Publication type: Conference Proceedings (inc. Abstract)

Publication status: Published

Conference Name: The International Combined Orthopaedic Research Societies (ICORS), World Congress of Orthopaedic Research

Year of Conference: 2022

Pages: 6-6

Print publication date: 04/04/2023

Online publication date: 04/04/2023

Acceptance date: 24/04/2023

ISSN: 2049-4416

Publisher: British Editorial Society of Bone and Joint Surgery


DOI: 10.1302/1358-992X.2023.7.006

Series Title: Orthopaedic Proceedings