The ABCC6 Transporter as a Paradigm for Networking from an Orphan Disease to Complex Disorders

Figure 2

Putative biological pathways related to ABCC6. ABCC6 is mainly expressed in the liver (and the kidneys) and has currently unknown substrates. Furthermore, the molecular mechanisms underlying PXE are still widely unknown but are traditionally explained by the metabolic hypothesis, focusing on the hepatic localization of ABCC6, and the cellular hypothesis, focusing on the role of fibroblasts and peripheral cells. Both are however not necessarily mutually exclusive as shown in this scheme. In the liver, it was shown that ATP is secreted via an ABCC6-dependent mechanism (although ABCC6 itself does not transport ATP). ABCC6 deficiency leads to a hampered transport function, causing a strongly reduced PPi level, which normally inhibits hydroxyapatite growth and hereby mineralization [24]. Further, in PXE, a lower vitamin K (VK) concentration is seen. VK is an essential cofactor of -carboxylation, which is necessary to activate antimineralizing proteins, such as OC and MGP. Ineffective activation of MGP and OC in peripheral cells also leads to a tissue-specific loss of inhibition of ectopic mineralization together with the diminished levels of the systemic calcification inhibitor fetuin-A [25–27]. Next to these findings, an upregulation of 3 proosteogenic pathways, that is, MSX2-WNT, BMP2-RUNX2, and TGF-CTGF, was found in all PXE-affected tissues compared to controls, which further enhance the ectopic mineralization. These pathways are also associated with altered MMP9 and caspase regulation, leading to apoptosis, and altered VEGF regulation, inducing neovascularization [15]. ABCC6: adenosine triphosphate-binding cassette, subfamily C, member 6; AMP: adenosine monophosphate; ATP: adenosine triphosphate; BMP2: bone morphogenetic protein 2; C: carboxyl; ENPP1: ectonucleotide pyrophosphatase/phosphodiesterase 1; GGCX: -glutamyl carboxylase; MGP: matrix Gla protein; MMP9: matrix metalloproteinase; MSX2: muscle segment homeobox, Drosophila, homolog of, 2; NT5E: ecto-5-prime nucleotidase or CD73; OC: osteocalcin; Pi: inorganic phosphate; PPi: inorganic pyrophosphate; RUNX2: runt-related transcription factor; Smad: mothers against decapentaplegic, Drosophila, homolog of; TGF: transforming growth factor ; TNAP: tissue-nonspecific alkaline phosphatase; VEGF: vascular endothelial growth factor; WNT: wingless-type MMTV integration site family.