Iron(III)-mediated intra-articular crystal deposition in arthritis: a therapeutic role for iron chelators

Crystal deposition in arthritic diseases has attracted much interest. Many reports have established the presence of calcium pyrophosphate (CPPD), hydroxyapatite (HAP) and urate crystals throughout the range of arthritic diseases. In particular, HAP crystals have been detected in 30-60% of synovial fluid (SF) samples from patients suffering from osteoarthritis (OA) and 33% of those suffering from rheumatoid arthritis (RA). In OA, crystal deposition has been linked to greater joint deterioration. The mechanism of intra-articular calcification is unknown. Nucleation is required to transform a 'metastable' phosphate- and calcium-rich biofluid into one that generates crystals. Ferric ions have been demonstrated to induce crystallization of these stable supersaturated solutions via the process of nucleation. The inflamed arthritic joint is prone to iron loading. Microbleeding from compromised vasculature contributes to intra-articular iron loading in arthritic conditions. Low-molecular-mass redox-active iron complexes have been detected in SF in inflammatory joint diseases. These species are credited with mediating oxidative stress via interaction with peroxides and superoxide. In addition, adventitious low-molecular-mass iron complexes can cause nucleation leading to crystal growth within the joint. Decorporating agents capable of removing this misplaced iron from the arthritic joint would have the joint benefit of relieving oxidative stress and preventing crystal nucleation. Systemic side effects could be overcome by the targeting suitable chelators using bioreductive delivery systems that are activated in hypoxic inflamed synovial tissue.