Chronic Kidney Disease and Osteoarthritis: Current Understanding and Future Research Directions

Abstract

Chronic kidney disease (CKD) is a significant public health concern. Osteoarthritis (OA), a common form of arthritis, has been shown to have a dramatically increased prevalence, particularly among individuals aged 40-50 and older, in the presence of CKD. Furthermore, CKD may exacerbate the progression and impact of OA. A survey study revealed that 53.9% of CKD patients undergoing long-term hemodialysis were diagnosed with OA. These findings underscore the potential association between CKD and OA. Uremic toxins, such as indoxyl sulfate, p-cresyl sulfate, transforming growth factor-β, and advanced glycation end-products, are regarded as potential risk factors in various CKD-related conditions, affecting bone and joint metabolism. However, whether these factors serve as a bridging mechanism between CKD and OA comorbidities, as well as their detailed roles in this context, remains unclear. Addressing the progression of OA in CKD patients and identifying effective treatment and prevention strategies is an urgent challenge that warrants immediate attention. This review focuses on describing and discussing the molecular pathological mechanisms underlying CKD-associated OA and the possible therapeutic strategies.

Keywords: calcium; chronic kidney disease; iron; osteoarthritis; uremic toxins.

Figure 1

The accumulation of uremic toxins (UTs) during chronic kidney disease (CKD) disrupts the intracellular balance of iron and calcium ions in joint cells, such as chondrocytes and synoviocytes, leading to ferroptosis and senescence, ultimately causing osteoarthritis (OA). In addition, the CKD-MBD-related signaling pathways are used for comparison. UTs promote iron uptake, increasing intracellular iron ions, which in turn trigger the Fenton reaction to enhance ROS. This inhibits the antioxidant system and exacerbates lipid peroxidation. Additionally, the increase in intracellular calcium ions induces senescence and activates the Calpain and NF-κB signaling pathways, releasing the senescence-associated secretory phenotype (SASP). Solid lines indicate established pathways. Dashed lines represent signaling pathways that have been speculated but not fully substantiated. Long-chain fatty acid CoA ligase 4, ACSL4; lysophospholipid acyltransferase 3, LPCAT3; lipoxygenase, LOX; polyunsaturated fatty acids, PUFA; cystine, Cys; glutamate, Glu; glutathione, GSH; glutathione peroxidase 4, GPX4; hypoxia-inducible factor 2α, HIF-2α; Piezo-type mechanosensitive ion channel component 1, Piezo1; transient receptor potential melastatin 7, TRPM7; nuclear factor-κB, NF-κB; senescence-associated β-galactosidase, SA-β-Gal; NADPH oxidase 4, Nox4; reactive oxygen species, ROS; interleukin, IL; transforming growth factor-beta, TGF-β; tumor necrosis factor-α, TNF-α; metalloproteinase, MMP; monocyte chemoattractant protein-1, MCP1; chemokine ligand 2, CCL2. Created with BioRender.com.