6.7.3. Vitamin K

Normal bone mineralization is a highly regulated process, requiring a fine balance between inhibitors and promoters of calcification [195,196]. Among these regulators of mineralization, Matrix Gla Protein (MGP) and osteocalcin (OC) are two proteins reliant on carboxylation for activation and function [196,197]. Gheduzzi et al. described in 2007 high levels of undercarboxylated MGP in the circulation of PXE patients. Uitto et al. also reported the presence of mostly undercarboxylated MGP in the calcified vibrissae of the *Abcc6*−/<sup>−</sup> mice [198]. At about the same time, a remarkably PXE-like phenotype was described in patients carrying mutations in the gamma-glutamyl carboxylase gene (*GGCX*) that encodes an enzyme essential for the carboxylation of MGP and OC as well as clotting factors [199]. Because vitamin K is an essential component in the post-translational carboxylation of glutamate residues (Glu) in these proteins, it was logically proposed that a vitamin K precursor or a conjugated form was the potential substrate(s) for ABCC6 and that insufficient carboxylation of MGP was the cause of abnormal calcification in PXE [200]. The fact that PXE patients have low serum levels of vitamin K [201], and that skin fibroblasts from patients present molecular signatures of impaired vitamin K-dependent carboxylation [202] gave further support to this notion. It was the first hypothesis that not only provided a strong and credible explanation to the calcification phenotype of PXE, but was also easily testable and offered the prospect of an affordable treatment. The PXE scientific community lost no time in developing competing studies using *Abcc6*−/<sup>−</sup> mice to test various active forms of vitamin K, primarily K1 and K2 (i.e., phylloquinone or menaquinone), through dietary supplementation. In quick succession, three publications reported disappointing results, as none of the vitamin K forms tested at high or low concentrations stopped or reversed PXE mineralization [92,140,141]. Despite these negative results, interest in the relationship between vitamin K metabolism and abnormal calcification in PXE and GACI continues and several follow-up studies have since been published [115,116,142,143]. However, neither phylloquinone or menaquinone are considered to be viable treatment options for the time being.
