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J Exp Med. 2009 December 21; 206(13): 2856.
PMCID: PMC2806472

Crippled clock hinders healing

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Bone marrow nerves (arrows) are damaged in diabetic rats, stunting the ability of reparative progenitor cells to exit into circulation.

Diabetic eye damage may start in bone marrow, suggest Busik and colleagues. Damaged bone marrow nerves and disrupted circadian genes hampered the release of progenitor cells that are required to repair diabetes-induced vessel injury in the eye.

Up to 45% of diabetic adults in the US develop retinopathy, a potentially blinding condition. Although high glucose levels and oxidative stress may cause the initial eye injury, Busik et al. suggest that the inability to repair damage causes the real problem. Normally, endothelial progenitor cells (EPCs) exiting the bone marrow help to regenerate damaged vessels during sleep. This nocturnal EPC egress is faulty in patients with diabetes, creating abnormally low levels of nighttime EPCs. Here, the authors show that diabetic rats have similar EPC deficits during the day when they normally sleep.

Diabetic rats showed signs of damage to bone marrow nerves, which trigger the signals required for EPC exit. Nerve damage coincided with a drop in the expression of circadian “clock” genes that control the ebb and flow of EPC migration. With fewer reparative EPCs on the move, damaged eye vessels accumulated in diabetic animals. Circadian rhythm disruption has also been blamed for the glucose and blood pressure complications characteristic of diabetes.

Because nerve damage and clock gene irregularities preceded eye disease, the authors suggest that the resulting EPC malfunction leads to retinopathy. What triggers nerve damage and circadian disruption is not yet known. Senior author Maria Grant suspects a role for nitric oxide, a known regulator of circadian gene transcription that is commonly elevated in patients with diabetes.


Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press