Researchers traced a complete chain of defects from Lamin B1 loss to mitochondrial failure in aging bone stem cells that weakens bones, and identified an approved drug that interrupts it
Researchers traced a complete chain of defects from Lamin B1 loss to mitochondrial failure in aging bone stem cells that weakens bones, and identified an approved drug that interrupts it
In an October 8 paper, biologists at Sun Yat-sen University in Shenzhen used patient cells and mice to trace how age-related loss of Lamin B1 activates the SLC7A11 gene, damages actin, a protein that forms the cell’s internal framework, through excess disulfide bonds, and halts mitochondrial division. Among approved drugs, they identified naldemedine, a treatment for constipation caused by opioid painkillers, as an inhibitor of this step.
Bone is constantly renewed: some cells break it down, while bone marrow stem cells build new bone. In older people, breakdown outpaces formation, leading to senile osteoporosis. Why stem cells become less able to build bone, however, was unclear.
The authors began with Lamin B1, a nuclear envelope protein whose loss is considered a marker of cellular aging. It normally anchors regions of DNA to the nuclear envelope and keeps them inactive. When Lamin B1 is lost, DNA becomes less tightly packed, allowing a “super-enhancer” to form: a cluster of regulatory elements that strongly activates a particular gene. Among the genes in these regions, only SLC7A11 was abnormally active in both aging and osteoporosis. It encodes a transporter that brings the amino acid cystine into the cell.
Excess SLC7A11 brings in more cystine than the cell can process. The cell runs short of the reducing agent NADPH, and cystine causes abnormal disulfide bonds to form in actin. This process was discovered in cancer cells in 2023 and named disulfidptosis; the paper reporting the discovery has already received nearly a thousand citations. In cancer cells, this requires a shortage of glucose in the surrounding environment. Aging bone cells take up less glucose and produce less NADPH even in a nutrient-rich environment, so the process can occur without an external glucose shortage.
The collapsed actin framework can no longer hold DRP1, the protein responsible for mitochondrial division. Without division, damaged mitochondrial segments cannot be removed. Mitochondria then produce less energy, leaving the cell with insufficient energy to become a bone-forming cell.
To establish causality, the authors bred mice lacking Lamin B1 in bone cells. These mice developed osteoporosis more rapidly. In a separate experiment, they inactivated SLC7A11 in 18-month-old mice, an advanced age for mice. These animals were protected from the bone loss seen in ordinary aged mice. In the decisive experiment, the researchers also inactivated SLC7A11 in mice lacking Lamin B1, and bone loss did not occur. This places SLC7A11 downstream of Lamin B1 in the pathway: its activity is required for Lamin B1 loss to cause bone loss. The same chain of events was confirmed in bone marrow from older patients, and a genomic analysis linked LMNB1 variants to osteoporosis risk.
Lamin B1 is a structural protein, which makes it difficult to target with a drug. SLC7A11 is a membrane transporter with a known three-dimensional structure. The researchers screened a library of approved drugs against that structure and identified naldemedine, a drug from the Japanese pharmaceutical company Shionogi that blocks opioid receptors in the gut to treat constipation caused by opioid painkillers. A 30-day course restored bone mass in mice with osteoporosis and accelerated healing of a skull defect, without changing blood parameters or measures of liver, kidney, and heart function.
SLC7A11 also has a protective role: in cancer cells, it prevents ferroptosis, another form of cell death. Excessive inhibition could therefore leave cells vulnerable to ferroptosis. The authors consequently describe naldemedine dosing as requiring careful adjustment, and its interaction with SLC7A11 as an inference from docking and simulation. Biologists in California have linked the waning effects of osteoporosis drugs to their stimulation of bone turnover as a whole rather than direct action on the bone stem cell pool. Naldemedine’s target lies within that pool, and its safety has already been tested, although so far for a different indication.