Too much copper in bone cells silences a key enzyme and triggers inflammatory destruction

Copper is essential for building bone. It helps deposit the collagen that gives bone tissue its structural framework, and healthy bones contain measurable traces of the metal. But too much copper inside cells triggers a form of programmed cell death called cuproptosis -- and a team at Wuhan University has now traced a specific molecular pathway from copper overload to the inflammatory bone destruction seen in conditions like rheumatoid arthritis, osteoporosis, and chronic apical periodontitis.

The study, published in the International Journal of Oral Science, examined bone tissue from both mice and humans with chronic apical periodontitis -- a persistent infection at the root tip of a tooth that gradually destroys surrounding jawbone.

Copper silences a critical enzyme

The research team, led by Prof. Lu Zhang, found that excess copper does not just kill cells through cuproptosis. It also directly suppresses Glycogen Synthase 1 (GYS1), the enzyme responsible for converting glucose into glycogen -- the storage form of sugar that cells draw on for energy.

The mechanism is epigenetic. Copper binds to histone proteins in chromosomes, altering the structure of chromatin around the GYS1 gene and effectively silencing it at the transcriptional level. When GYS1 is shut down, cells cannot store glucose as glycogen. Instead, they break down existing glycogen reserves and divert glucose toward energy production through alternative pathways.

This metabolic redirection has a second consequence. Glucose is also normally channeled through the pentose phosphate pathway (PPP), which produces reducing agents that protect cells against oxidative stress. When glucose is rerouted away from the PPP, cells lose that protection and accumulate oxidative damage.

Macrophages become bone destroyers

The oxidative damage and metabolic disruption do not just kill cells -- they transform them. The researchers found that when GYS1 was suppressed, either by copper overload or by chemical inhibitors, macrophages differentiated into osteoclasts: the specialized cells responsible for breaking down bone tissue.

This transformation occurred under both conditions independently. When copper overload and GYS1 inhibitors were combined, the effect was amplified -- cells experienced significantly greater oxidative damage, and more macrophages transformed into osteoclasts. Higher amounts of cuproptosis-associated metabolites correlated with greater weakening of jawbones in the patient samples.

A drug that reverses the damage

The study also tested a potential countermeasure. Tetrathiomolybdate (TTM), a cuproptosis inhibitor that chelates copper, restored GYS1 activity and glycogen synthesis even when copper levels remained elevated. Most importantly, TTM reduced bone degradation in the experimental models.

"Collectively, these findings suggest that both copper and GYS1 may regulate inflammatory pathways," said Prof. Zhang. The dual role of copper -- as both an essential nutrient and a potential driver of inflammatory bone destruction -- makes it a complex but promising therapeutic target.

Implications beyond periodontitis

While the study focused on chronic apical periodontitis as a model system, the pathway it describes is relevant to other inflammatory bone diseases. Altered copper metabolism has been documented in the bones of patients with rheumatoid arthritis and osteoporosis. If the same GYS1-suppression mechanism operates in those conditions, copper-targeted therapies could offer a new approach to treatment.

Current anti-inflammatory treatments for bone diseases often work by broadly suppressing immune system activity, which carries risks of infection and other side effects with long-term use. Therapies that target copper metabolism or restore glycogen synthesis could potentially reduce bone destruction without the immunosuppressive trade-offs.

What remains to be established

The study demonstrates a molecular pathway in mouse models and patient tissue samples, but it does not yet show whether intervening in that pathway produces lasting clinical benefit in living patients. TTM is used clinically for Wilson's disease (a genetic copper overload condition), but its effects on inflammatory bone diseases have not been tested in human trials.

The relationship between dietary copper intake, systemic copper levels, and local copper concentrations in bone tissue is also not straightforward. Whether copper overload in bone reflects a systemic metabolic problem or a localized inflammatory process -- and whether it can be modulated through diet, supplementation, or targeted drug delivery -- are questions the current study does not address.

"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," Prof. Zhang said.