Musculoskeletal complications associated with pathological iron toxicity and its molecular mechanisms

Iron is fundamental for several biological functions, but when in excess can lead to the development of toxic events. Some tissues and cells are more susceptible than others, but systemic iron levels can be controlled by treating patients with iron-chelating molecules and phlebotomy. An early diagnostic can be decisive to limit the progression of musculoskeletal complications like osteoarthritis and osteoporosis because of iron toxicity. In iron-related osteoarthritis, aggravation can be associated to a few events that can contribute to joints articular cartilage exposure to high iron concentrations, which can promote articular degeneration with very little chance of tissue regeneration. In contrast, bone metabolism is much more dynamic than cartilage, but progressive iron accumulation and ageing can be decisive factors for bone health. The iron overload associated with hereditary diseases like hemochromatosis, hemophilias, thalassemias and other hereditary anaemias increase the negative impact of iron toxicity in joints and bone, as well as in life quality, even when iron levels can be controlled. The molecular mechanisms by which iron can compromise cartilage and bone have been illusive and only in the last 20 years studies have started to shed some light into the molecular mechanisms associated with iron toxicity. Ferroptosis and the regulation of intracellular iron levels is instrumental in the balance between detoxification and induced cell death. In addition, these complications are accompanied with multiple susceptibility factors that can aggravate iron toxicity and should be identified. Therefore, understanding tissues microenvironment and cell communication is fundamental to contextualize iron toxicity.