Abstract
Osteoarthritis (OA) and rheumatoid arthritis (RA) are inflammatory articular conditions with different aetiology, but both result in joint damage. The nutritionally essential metal zinc (Zn2+) and the non-essential metal cadmium (Cd2+) have roles in these arthritic diseases as effectors of the immune system, inflammation, and metabolism. Despite both metal ions being redox-inert in biology, they affect the redox balance. It has been known for decades that zinc decreases in the blood of RA patients. It is largely unknown, however, whether this change is only a manifestation of an acute phase response in inflammation or relates to altered availability of zinc in tissues and consequently requires changes of zinc in the diet. As a cofactor in over 3000 human proteins and as a signaling ion, zinc affects many pathways relevant for arthritic disease. How it affects the diseases is not just a question of zinc status, but also an issue of mutations in the many proteins that maintain cellular zinc homoeostasis, such as zinc transporters of the ZIP (Zrt-/Irt-like protein) and ZnT families and metallothioneins, and the multiple pathways that change the expression of these proteins. Cadmium interferes with zinc’s functions and there is increased uptake under zinc deficiency. Remarkably, cadmium exposure through inhalation is now recognized in the activation of macrophages to a pro-inflammatory state and suggested as a trigger of a specific form of nodular RA. Here, we discuss how these metal ions participate in the genetic, metabolic, and environmental factors that lead to joint destruction. We conclude that both metal ions should be monitored routinely in arthritic disease and that there is untapped potential for prognosis and treatment.
Highlights
Among the common rheumatic diseases, osteoarthritis (OA) and rheumatoid arthritis (RA) are thought to be the most prevalent ones, with approximately 11% (10% OA and 1% RA) of the world’s population being affected [1]
It is thought that a series of events or triggers from non-genetic factors such as age, gender, trauma, and malalignment of the joint, high body-mass index (BMI), diet, infection, and cigarette smoking in combination with an arthritis-prone genetic profile are responsible for the onset of arthritic disease
Considering the three facts that (i) cadmium is similar to zinc and the biological actions of cadmium(II) ions have been described by some as ionic mimicry with regard to zinc(II) ions, (ii) ZIP8 can be a portal for cadmium entry into cells, and iii) ZIP8 expression in lungs depends on the NF-κB pathway, it is contended that ZIP8 plays a significant role in cadmium toxicity, and the subsequent effects on zinc metabolism, in the smoking-induced lung disease [100]
Summary
Among the common rheumatic diseases, osteoarthritis (OA) and rheumatoid arthritis (RA) are thought to be the most prevalent ones, with approximately 11% (10% OA and 1% RA) of the world’s population being affected [1]. People living in industrialised countries are more likely to suffer from these forms of arthritis when compared to developing countries, with Europe and the US leading as these forms are more common in Caucasians [2] Both conditions affect later stages in life (>45 years), with OA prevalence rising indefinitely with age. Three different subtypes of RA are mainly determined by the levels of synovial and systemic inflammation (high, low, mixed) based on histology and gene expression profiles [10] Another distinct subtype only recently postulated is a form of nodular RA, which is characterized by pulmonary rheumatoid nodule formation and generation of RA-associated autoantibodies caused by cadmium inhalation [11]. We attempt to explain this discrepancy and discuss the involvement of these metals in the pathogenesis of arthritis
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