Copper metabolism identified as a new therapeutic target for inflammatory osteolysis

Inflammatory osteolysis is a condition involving progressive bone tissue destruction and is observed in many well-known skeletal disorders, including rheumatoid arthritis, osteoporosis, and chronic apical periodontitis. This condition is driven by immune hyperactivation, sustained immune responses, and increased numbers of bone-degrading osteoclast cells, which together cause inflammation and weakening of affected bone tissue.

Copper is a vital element for the deposition of collagen in bone tissue, and hence bones contain significant traces of copper. However, excessive cellular copper disrupts glucose and glycogen metabolism pathways and triggers 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 dysregulated copper levels may contribute to these conditions through cuproptosis.

Could cuproptosis impact bone metabolism and contribute to inflammatory osteolysis? A team of researchers from Wuhan University, led by Professor Lu Zhang, investigated this question by examining signs of cuproptosis and altered 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, in Volume 18 of the International Journal of Oral Science.

"Emerging studies revealed that glycogen metabolism modulates immune cell functionality, signaling through metabolic intermediates, and energy homeostasis," said Prof. Zhang, adding, "However, the precise mechanisms by which glycogen metabolism regulates cuproptosis progression remain to be elucidated."

The team found that cuproptosis was involved in the bone weakening seen in chronic apical periodontitis. Higher amounts of cuproptosis-associated metabolites correlated with greater weakening of jaw bones. More importantly, copper was directly involved in the suppression of Glycogen Synthase 1 (GYS1), an enzyme crucial for converting glucose to glycogen. Copper could bind to histone proteins in chromosomes and silence GYS1 right at the source. When copper overload occurred, cells broke down glycogen into glucose, which they then used for greater energy production. Glucose is also diverted away from the pentose phosphate pathway (PPP), which produces reducing agents that mitigate oxidative stress in cells.

As a result of these changes, disrupting glycogen synthesis increased oxidative damage within cells, ultimately causing cell death. However, suppressing GYS1 had an interesting effect on macrophages - they transformed into osteoclasts and degraded bone tissue. This transformation occurred both under conditions of copper overload and when GYS1 inhibitors were added to bone tissue. In fact, when copper overload was combined with GYS1 inhibitors, cells experienced significantly greater oxidative damage, and more macrophages transformed into osteoclasts.

Conversely, the cuproptosis inhibitor tetrathiomolybdate (TTM) restored GYS1 activity and glycogen synthesis, ultimately reducing bone degradation even when copper levels were elevated. "Collectively, these findings suggest that both copper and GYS1 may regulate inflammatory pathways," said Prof. Zhang.

These findings highlight copper metabolism as a potential new therapeutic target for inflammatory osteolysis. Inhibition of cuproptosis, restoration of glycogen synthesis and PPP, and disruption of copper-histone interactions represent promising avenues for new therapies against inflammatory bone diseases. Importantly, such copper-targeted approaches could offer 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 therapeutics targeting copper and cuproptosis could provide new directions and strategies for treating inflammatory bone diseases, including rheumatoid arthritis, osteoporosis, and apical periodontitis," says Prof. Zhang in conclusion.