Inflammatory osteolysis is a condition that involves progressive bone tissue destruction and is observed in many well-known skeletal diseases such as rheumatoid arthritis, osteoporosis, and chronic apical periodontitis. This condition is caused by immune overactivation, a sustained immune response, and an increased number of bone-degrading osteoclasts, which together cause inflammation and weakening of the affected bone tissue.
Bone contains large amounts of copper, as copper is an essential element for the deposition of collagen in bone tissue. However, excess cellular copper disrupts glucose and glycogen metabolic pathways, causing cuproptosis, a form of programmed cell death. Recent studies have found that copper metabolism is altered in the bones of people with arthritis and osteoporosis, suggesting that dysregulation of copper concentrations may contribute to these conditions through copper ptosis.
Can cuproptosis affect bone metabolism and contribute to inflammatory osteolysis? A research team at Wuhan University led by Professor Lu Zhang investigated this question by examining the signs of cuprotinosis and changes in glycogen metabolism in bone tissue affected by chronic apical periodontitis in both mice and humans. Their findings were made available online on February 3, 2026, and were published in Volume 18 of the journal. International Journal of Oral Sciences.
”New research reveals that glycogen metabolism regulates immune cell function, signaling through metabolic intermediates, and energy homeostasis.” Professor Zhang added, “However, The exact mechanism by which glycogen metabolism regulates the progression of cuproptosis remains to be elucidated.”
The research team discovered that leukocoria plays a role in bone weakening seen in chronic apical periodontitis. Higher amounts of cuproptosis-related metabolites correlated with further jaw bone weakness. More importantly, copper was directly involved in the inhibition of glycogen synthase 1 (GYS1), a key enzyme for converting glucose to glycogen. Copper binds to histone proteins on chromosomes and may silence GYS1 at the source. When copper overload occurs, cells break down glycogen into glucose and use it for more energy production. Glucose is also diverted from the pentose phosphate pathway (PPP), which produces reducing agents that reduce oxidative stress within cells.
As a result of these changes, glycogen synthesis is inhibited, increasing intracellular oxidative damage and ultimately leading to cell death. However, suppression of GYS1 had an interesting effect on macrophages, which transformed into osteoclasts and degraded bone tissue. This change occurred both under copper overload conditions and when GYS1 inhibitors were added to bone tissue. Indeed, when copper overload was combined with a GYS1 inhibitor, cells suffered significantly greater oxidative damage and more macrophages were converted to osteoclasts.
Conversely, the cuproptosis inhibitor tetrathiomolybdate (TTM) restored GYS1 activity and glycogen synthesis, ultimately attenuating bone degradation even when copper levels were elevated. ”Taken together, these findings suggest that both copper and GYS1 may regulate inflammatory pathways” said Professor Zhang.
These findings highlight that copper metabolism may represent a novel therapeutic target for inflammatory osteolysis. Inhibiting cuproptosis, restoring glycogen synthesis and PPP, and disrupting copper-histone interactions represent promising routes to new treatments for inflammatory bone diseases. Importantly, such a copper-targeted approach could potentially provide safer, long-term relief without the side effects associated with current anti-inflammatory treatments that suppress immune system activity.
”Elucidating the mechanism of action of cuproptosis inhibitors in inflammatory bone diseases and developing therapeutic agents targeting copper and cuproptosis may provide new directions and strategies for the treatment of inflammatory bone diseases such as rheumatoid arthritis, osteoporosis, and apical periodontitis.” says Professor Zhang in conclusion.
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Reference magazines:
Zhou, L.; Others. (2026). Cuproptosis promotes inflammatory osteolysis via GYS1-mediated glycogen metabolism. International Journal of Oral Sciences. DOI: 10.1038/s41368-025-00408-1. https://www.nature.com/articles/s41368-025-00408-1
