*5.2. The Murine DCC Phenotype and Other PXE Mouse Models*

In the past years, two groups of investigators have found that ABCC6 deficiency causes an acute and inducible dystrophic cardiac calcification phenotype (DCC) affecting several strains of inbred mice, including C3H/HeJ, 129S1/SvJ, and DBA/2J [12,14,100]. DCC is an autosomal recessive trait that was described decades ago [101,102]. DCC can either occur spontaneously over the long-term, be initiated by a specific dietary regimen, or be triggered into an acute phenotype by direct injury [103,104] or ischemia [13]. Of note, arteries (most notably the aorta) as well as skeletal muscles, are also susceptible to dystrophic calcification [100,105] (Le Saux et al., unpublished results). DCC is caused by a single *Abcc6* gene mutation in C3H/HeJ, 129S1/SvJ, and DBA/2J mice [12], while it is absent in C57BL/6J mice that are DCC-resistant. Note that the *Abcc6*−/<sup>−</sup> mice that have been used thus far were all backcrossed into C57BL/6J. This is important as there are 3 other minor loci affecting the penetrance and the expression of DCC mapping to chromosomes 4, 12, and 14 [104].

Remarkably, DCC-susceptible C3H/HeJ mice develop an attenuated version of the murine PXE phenotype as compared to the *Abcc6*−/<sup>−</sup> animals, while the DBA/2J mice present little or no manifestations [106]. It is interesting to note that the murine PXE manifestations reported in KK/H1J mice are remarkably severe [107]. These mice show systemic age-dependent ectopic mineralization, hyperplasia, and fibro-osseous lesions [108]. Calcification mostly affects vibrissae (as for *Abcc6*−/<sup>−</sup> animals), but also the heart, the lung and many other organs to a lesser degree. Pancreatic islet hyperplasia was observed as well as fibro-osseous lesions in several bones. More interesting is that these strains of mice carry the exact same *Abcc6* gene mutation and have similar plasma PPi levels (Figure 2), which clearly underlie the possible role of other factors such as the environment [19] and/or modifier genes in the development of ectopic calcification [109,110].

*− − − −* μ **Figure 2.** Plasma pyrophosphate levels do not correlate with the calcification phenotype in mice. Plasma pyrophosphate levels in *Abcc6*−/<sup>−</sup> mice (C57BL/6J background), and in C3H/H1J mice with a naturally occurring *Abcc6* mutation are virtually identical and significantly lower than wild type C57BL/6J mice. However, at 12 months of age, *Abcc6*−/<sup>−</sup> mice present a much more pronounced vibrissae calcification as shown on this µCT scan rendering (right, arrows). Plasma PPi results are shown as means +SEM. *p*-values were determined by Student's *t*-test. \*\* *p* < 0.01, \*\*\*\* *p* < 0.0001. Derived from [111].
