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PLOS ONE  2013 

Cobalt-Alloy Implant Debris Induce HIF-1α Hypoxia Associated Responses: A Mechanism for Metal-Specific Orthopedic Implant Failure

DOI: 10.1371/journal.pone.0067127

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The historical success of orthopedic implants has been recently tempered by unexpected pathologies and early failures of some types of Cobalt-Chromium-Molybdenum alloy containing artificial hip implants. Hypoxia-associated responses to Cobalt-alloy metal debris were suspected as mediating this untoward reactivity at least in part. Hypoxia Inducible Factor-1α is a major transcription factor involved in hypoxia, and is a potent coping mechanism for cells to rapidly respond to changing metabolic demands. We measured signature hypoxia associated responses (i.e. HIF-1α, VEGF and TNF-α) to Cobalt-alloy implant debris both in vitro (using a human THP-1 macrophage cell line and primary human monocytes/macrophages) and in vivo. HIF-1α in peri-implant tissues of failed metal-on-metal implants were compared to similar tissues from people with metal-on-polymer hip arthroplasties, immunohistochemically. Increasing concentrations of cobalt ions significantly up-regulated HIF-1α with a maximal response at 0.3 mM. Cobalt-alloy particles (1 um-diameter, 10 particles/cell) induced significantly elevated HIF-1α, VEGF, TNF-α and ROS expression in human primary macrophages whereas Titanium-alloy particles did not. Elevated expression of HIF-1α was found in peri-implant tissues and synovial fluid of people with failing Metal-on-Metal hips (n = 5) compared to failed Metal-on-Polymer articulating hip arthroplasties (n = 10). This evidence suggests that Cobalt-alloy, more than other metal implant debris (e.g. Titanium alloy), can elicit hypoxia-like responses that if unchecked can lead to unusual peri-implant pathologies, such as lymphocyte infiltration, necrosis and excessive fibrous tissue growths.


[1]  Jacobs JJ, Hallab NJ (2006) Loosening and osteolysis associated with metal-on-metal bearings: A local effect of metal hypersensitivity? J Bone Joint Surg Am 88: 1171–1172.
[2]  Korovessis P, Petsinis G, Repanti M, Repantis T (2006) Metallosis after contemporary metal-on-metal total hip arthroplasty. Five to nine-year follow-up. J Bone Joint Surg Am 88: 1183–1191.
[3]  Milosev I, Trebse R, Kovac S, Cor A, Pisot V (2006) Survivorship and retrieval analysis of Sikomet metal-on-metal total hip replacements at a mean of seven years. J Bone Joint Surg Am 88: 1173–1182.
[4]  Dalal A, Pawar V, McAllister K, Weaver C, Hallab NJ (2012) Orthopedic implant cobalt-alloy particles produce greater toxicity and inflammatory cytokines than titanium alloy and zirconium alloy-based particles in vitro, in human osteoblasts, fibroblasts, and macrophages. J Biomed Mater Res A 100: 2147–2158.
[5]  Hallab NJ, McAllister K, Brady M, Jarman-Smith M (2011) Macrophage reactivity to different polymers demonstrates particle size- and material-specific reactivity: PEEK-OPTIMA((R)) particles versus UHMWPE particles in the submicron, micron, and 10 micron size ranges. J Biomed Mater Res B Appl Biomater.
[6]  Caicedo MS, McAllister K, Reddy A, Jacobs JJ, Hallab NJ (2008) Soluble and particulate Co-Cr-Mo alloy implant metals activate the inflammasome danger signaling pathway in human macrophages: A novel mechanism for implant debris reactivity. J Orthop Res 27: 847–854.
[7]  Goodman SB (2007) Wear particles, periprosthetic osteolysis and the immune system. Biomater 28: 5044–5048.
[8]  Kim SY, Choi YJ, Joung SM, Lee BH, Jung YS, et al. (2010) Hypoxic stress up-regulates the expression of Toll-like receptor 4 in macrophages via hypoxia-inducible factor. Immunology 129: 516–524.
[9]  Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, et al. (2003) HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 112: 645–657.
[10]  Imtiyaz HZ, Simon MC (2010) Hypoxia-inducible factors as essential regulators of inflammation. Curr Top Microbiol Immunol 345: 105–120.
[11]  Murdoch C, Muthana M, Lewis CE (2005) Hypoxia regulates macrophage functions in inflammation. J Immunol 175: 6257–6263.
[12]  Peyssonnaux C, Datta V, Cramer T, Doedens A, Theodorakis EA, et al. (2005) HIF-1alpha expression regulates the bactericidal capacity of phagocytes. J Clin Invest 115: 1806–1815.
[13]  Semenza G (2002) Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol 64: 993–998.
[14]  Spanogle JP, Miyanishi K, Ma T, Epstein NJ, Smith RL, et al. (2006) Comparison of VEGF-producing cells in periprosthetic osteolysis. Biomater 27: 3882–3887.
[15]  Waris V, Sillat T, Waris E, Virkki L, Mandelin J, et al. (2012) Role and regulation of VEGF and its receptors 1 and 2 in the aseptic loosening of total hip implants. J Orthop Res 30: 1830–1836.
[16]  Caicedo MS, Pennekamp PH, McAllister K, Jacobs JJ, Hallab NJ (2010) Soluble ions more than particulate cobalt-alloy implant debris induce monocyte costimulatory molecule expression and release of proinflammatory cytokines critical to metal-induced lymphocyte reactivity. J Biomed Mater Res A 93: 1312–1321.
[17]  Hallab NJ, Anderson S, Caicedo M, Brasher A, Mikecz K, et al. (2005) Effects of soluble metals on human peri-implant cells. J Biomed Mater Res A 74: 124–140.
[18]  Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3: 721–732.
[19]  Pugh CW, Ratcliffe PJ (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9: 677–684.
[20]  Merkel KD, Erdmann JM, McHugh KP, Abu-Amer Y, Ross FP, et al. (1999) Tumor necrosis factor-alpha mediates orthopedic implant osteolysis. Am J Pathol 154: 203–210.
[21]  Schwarz EM, Lu AP, Goater JJ, Benz EB, Kollias G, et al. (2000) Tumor necrosis factor-alpha/nuclear transcription factor-kappaB signaling in periprosthetic osteolysis. J Orthop Res 18: 472–480.
[22]  Kwon YM, Ostlere SJ, Lardy-Smith P, Athanasou NA, Gill HS, et al. (2011) "Asymptomatic" pseudotumors after metal-on-metal hip resurfacing arthroplasty: prevalence and metal ion study. J Arthroplasty 26: 511–518.
[23]  Guyer RD, Shellock J, MacLennan B, Hanscom D, Knight RQ, et al. (2011) Early failure of metal-on-metal artificial disc prostheses associated with lymphocytic reaction: diagnosis and treatment experience in four cases. Spine (Phila Pa 1976) 36: E492–E497.
[24]  Aroukatos P, Repanti M, Repantis T, Bravou V, Korovessis P (2010) Immunologic adverse reaction associated with low-carbide metal-on-metal bearings in total hip arthroplasty. Clin Orthop Relat Res 468: 2135–2142.
[25]  Davies AP, Willert HG, Campbell PA, Learmonth ID, Case CP (2005) An unusual lymphocytic perivascular infiltration in tissues around contemporary metal-on-metal joint replacements. J Bone Joint Surg Am 87: 18–27.


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