Artificial joint replacement is a prosthetic surgery whereby the diseased articular cartilage and bone are replaced with an artificial implant. It has been widely used as an effective treatment for end-stage joint disease[1]. Among the large number of prosthetics available, the metal-on-metal (MOM) artificial joints are the most popular, due to its remarkably high strength and wear resistance[2]. However, due to its high
cobalt-chromium alloy content, MOM often releases a large number of cobalt nano particles (CoNPs) into the human body, due to wear (or physical) and chemical factors[3]. Multiple studies have reported CoNPs to be highly toxic. In particular, they have been shown to stimulate intracellular oxidative stress, DNA damage, tissue inflammatory response, and cyto- and genotoxicity[4–5]. Clinically, the CoNPs side effects present as cobalt cardiomyopathy[6], osteolysis around the prosthesis[7], genetic toxicity[8], hearing and vestibular dysfunction[9], blood system diseases like lupus erythematosus and white blood cell abnormalities[10], malignant tumors, inflammatory pseudotumors, and so on. In the skeletal system, for instance, CoNPs affect the growth and differentiation of osteoblasts, and indirectly up-regulate the dissolution and absorption of bone by osteoclasts, thereby accelerating osteolysis around the prosthesis[11]. Based on ample detrimental evidence, the International Agency for Research on Cancer (IARC) listed CoNPs as potentially carcinogenic to humans and graded it as 2B. Our previous research has also confirmed the toxicity of CoNPs on a variety of cells. However, the underlying mechanism still remains to be investigated.
CoNPs are minute particles, averaging a diameter of 50 nm. They are mostly released from the interface wear of artificial joints. Several factors affect the wear of MOM, including implant type, implant position, swing phase load, fluid chemistry, wear process, and isolation technology[12]. Moreover, with stress bending, scratching, and impact the surface oxide layer of MOM tends to degrade, thereby releasing CoNPs. In addition, both crevice and galvanic corrosions at the prosthetic joints components, under acidic conditions, further accelerates the release of CoNPs[13]. Moreover, CoNPs, that are not absorbed by the bone, can be freely available to multiple organ systems and can exist in forms of particles and corrosion debris, metal-protein complexes, or free metal ions[14]. As a result, CoNPs presence can be detected in multiple organ systems like the liver, kidney, pancreas, myocardium, lung, testis, ovary, and so on. Based on published literature, only a small amount of CoNPs can be eliminated from the body through the kidneys[15–17].
Reactive oxidative stress (ROS) plays a major role in the toxicity of CoNPs. Once CoNPs enter a cell, they stimulate the production of excessive reactive oxygen species through the Fenton reaction, which in turn, oxidizes cell biomolecules, including DNA, causing DNA strand breakage, and induce a series of other oxidative damage[18]. One of the signaling pathways affected by CoNPs is the Keap1-Nrf2-ARE (KNA) antioxidant signaling pathway[19]. ROS is known to activate the KNA pathway, which prompts the activation of a large number of downstream antioxidant enzymes, such as heme oxygenase-1 (HO-1), human quinone peroxidase- 1 (NQO-1), and so on[20]. This is likely the cell’s defense mechanism against the toxicity of CoNPs. As a result, in this study, we suspected that the artificial activation of the KNA pathway to be an effective therapy for CoNPs toxicity.
Bioactive nano selenium (BNS) is a known antioxidant that minimizes oxidative stress in cells[21–23]. It is also responsible for generating strong anti-oxidant selenoproteins in the form of selenocysteine, such as GSH, etc. Given its strong antioxidant property, we suspected that BNS mediates its actions via the KNA pathway, and can be used to antagonize CoNPs toxicity[24–25]. To test this hypothesis, we evaluated oxidative stress and the underlying mechanism in human umbilical vein endothelial cells (HUVECs), exposed to BNS and/or CoNPs. Based on our results, we have confirmed our hypothesis that BNS protects cells from CoNPs-mediated oxidative stress through the activation of the KNA pathway.