Abcc6 Knockout Rat Model Highlights the Role of Liver in PPi Homeostasis in Pseudoxanthoma Elasticum.

Pseudoxanthoma elasticum, a heritable ectopic mineralization disorder, is caused by mutations in the ABCC6 gene primarily expressed in the liver and the kidneys. The fundamental question on pathogenesis of pseudoxanthoma elasticum, whether lack of ABCC6 expression in liver or kidney is the primary site of molecular pathology in peripheral tissues, has not been addressed. We generated a series of Abcc6 rats as models of pseudoxanthoma elasticum depicting ectopic mineralization in the skin, eyes, and the arterial blood vessels. Plasma inorganic pyrophosphate (PPi) level was reduced (<30%) in the Abcc6 rats leading to a lowered PPi/inorganic phosphate plasma ratio. In situ liver and kidney perfusions were performed to determine the relative contribution of these organs to PPi levels in circulation. PPi levels in the perfusates both in the liver and kidney of Abcc6 rats were significantly reduced, but the PPi levels in the liver perfusates of wild-type rats were 10-fold higher than that in the kidney perfusates. These observations suggest a critical role of hepatic ABCC6 in contributing to plasma PPi levels, identifying liver as a target of molecular correction to counteract ectopic mineralization in pseudoxanthoma elasticum.