Musculoskeletal complications associated with pathological iron toxicity and its molecular mechanisms

Abstract

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.

D‐mannose alleviates osteoarthritis progression by inhibiting chondrocyte ferroptosis in a HIF‐2α‐dependent manner

“…It is known that articular cartilage damage is the most obvious pathologic feature leading to joint dysfunction. Earlier research reported several ferroptosis‐related features, such as abnormal iron metabolism, 10 , 11 , 37 , 38 lipid peroxidation 39 , 40 and mitochondrial dysfunction, 41 , 42 are closely correlated with accelerating cartilage destruction. It is only recently that Yao et al 9 first demonstrated that chondrocyte ferroptosis contributes to the progression of osteoarthritis.…”

Interplay Between Iron Overload and Osteoarthritis: Clinical Significance and Cellular Mechanisms

“…The condition of iron overload is frequently associated with the osteoarthritic phenotypes (such as progressive cartilage erosion, altered subchondral bone microarchitecture, and biomechanics, persistent joint inflammation, proliferative synovitis, and synovial pannus) (Heiland et al, 2010;Simão et al, 2019). Evidence from clinical studies and animal models suggests that iron overload is associated with OA (Husar-Memmer et al, 2014;Kiely, 2018;Simão and Cancela, 2021). At present, iron chelators can be used in the field of first-line therapeutic therapy to eliminate iron overload in vital organs, and osteochondral tissue, and synovium (Rao, 2013;Jansová and Šimůnek, 2019).…”

“…Iron overload is also associated with OA of the joints in patients suffering from diseases associated with iron overload (such as hereditary hemochromatosis (HH), thalassemia, hemophilia, sickle cell disease (SCD)). Iron overload can also result in aging and estrogen deficiency (Dallos et al, 2013;Chehade and Adams, 2019;Simão and Cancela, 2021). HH is the leading case of primary iron overload (Powell et al, 2005), while secondary iron overload is usually caused by the introduction of excess iron in the body.…”

New Insights into the Regulatory Role of Ferroptosis in Ankylosing Spondylitis via Consensus Clustering of Ferroptosis-Related Genes and Weighted Gene Co-Expression Network Analysis

“…The role of ferroptosis in musculoskeletal diseases has been well documented [ 50 ]. Ferroptosis in chondrocytes leads to progression of osteoarthritis, which can be alleviated by inhibiting chondrocyte ferroptosis [ 51 , 52 ].…”