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• W1997403604 abstract "Pseudoxanthoma elasticum (PXE) is a pleiotropic multisystem disorder affecting skin, eyes, and the cardiovascular system with progressive pathological mineralization. It is caused by mutations in the ABCC6 gene expressed primarily in the liver and kidneys, and at very low levels, if at all, in tissues affected by PXE. A question has arisen regarding the pathomechanism of PXE, particularly the “metabolic” versus the “PXE cell” hypotheses. We examined a murine PXE model (Abcc6-/-) by transplanting muzzle skin from knockout (KO) and wild-type (WT) mice onto the back of WT and KO mice using mineralization of the connective tissue capsule surrounding the vibrissae as an early phenotypic biomarker. Grafting of WT mouse muzzle skin onto the back of KO mice resulted in mineralization of vibrissae, whereas grafting KO mouse muzzle skin onto WT mice did not. Thus, these findings implicate circulatory factors as a critical component of the mineralization process. This mouse grafting model supports the notion that PXE is a systemic metabolic disorder with secondary mineralization of connective tissues and that the mineralization process can be countered or even reversed by changes in the homeostatic milieu.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article please go to http://network.nature.com/group/jidclub Pseudoxanthoma elasticum (PXE) is a pleiotropic multisystem disorder affecting skin, eyes, and the cardiovascular system with progressive pathological mineralization. It is caused by mutations in the ABCC6 gene expressed primarily in the liver and kidneys, and at very low levels, if at all, in tissues affected by PXE. A question has arisen regarding the pathomechanism of PXE, particularly the “metabolic” versus the “PXE cell” hypotheses. We examined a murine PXE model (Abcc6-/-) by transplanting muzzle skin from knockout (KO) and wild-type (WT) mice onto the back of WT and KO mice using mineralization of the connective tissue capsule surrounding the vibrissae as an early phenotypic biomarker. Grafting of WT mouse muzzle skin onto the back of KO mice resulted in mineralization of vibrissae, whereas grafting KO mouse muzzle skin onto WT mice did not. Thus, these findings implicate circulatory factors as a critical component of the mineralization process. This mouse grafting model supports the notion that PXE is a systemic metabolic disorder with secondary mineralization of connective tissues and that the mineralization process can be countered or even reversed by changes in the homeostatic milieu. JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article please go to http://network.nature.com/group/jidclub knockout pseudoxanthoma elasticum wild type Pseudoxanthoma elasticum (PXE; OMIM 264800) is a multi-system disorder characterized by progressive mineralization of connective tissues, primarily affecting the elastic structures in the skin, Bruch's membrane of the retina, and the mid-layers of the arterial blood vessels (Ringpfeil et al., 2001Ringpfeil F. Pulkkinen L. Uitto J. Molecular genetics of pseudoxanthoma elasticum.Exp Dermatol. 2001; 10: 221-228Google Scholar; Neldner and Struk, 2002Neldner K.H. Struk B. Pseudoxanthoma elasticum.in: Royce P.M. Steinmann B. Connective Tissue and its Heritable Disorders: Molecular, Genetic and Medical Aspects. Wiley-Liss Inc., NY2002: 561-583Google Scholar; Li et al., 2008aLi Q. Jiang Q. Pfendner E. Váradi A. Uitto J. Pseudoxanthoma elasticum: clinical phenotypes, molecular genetics and putative pathomechanisms.Exp Dermatol. 2008Google Scholar). PXE is caused by mutations in the ABCC6 gene which encodes ABCC6, a protein belonging to the family of ATP-binding cassette proteins (Pfendner et al., 2007Pfendner E.G. Vanakker O.M. Terry S.F. Vourthis S. McAndrew P.E. McClain M.R. et al.Mutation detection in the ABCC6 gene and genotype-phenotype analysis in a large international case series affected by pseudoxanthoma elasticum.J Med Genet. 2007; 44: 621-628Google Scholar, Pfendner et al., 2008Pfendner E. Uitto J. Gerard G.F. Terry S.F. Pseudoxanthoma elasticum: genetic diagnostic markers.Expert Opin Med Diagn. 2008; 2: 1-17Google Scholar). ABCC6 is expressed primarily in the basolateral surface of the hepatocytes, to a lesser extent in the proximal tubules of the kidneys, and at a very low level, if at all, in resident cells, such as fibroblasts and smooth muscle cells, in tissues affected by PXE (Belinsky and Kruh, 1999Belinsky M.G. Kruh G.D. MOAT-E (ARA) is a full length MRP/cMOAT subfamily transporter expressed in kidney and liver.Br J Cancer. 1999; 80: 1342-1349Google Scholar; Scheffer et al., 2002Scheffer G.L. Hu X. Pijnenborg A.C. Wijnholds J. Bergen A.A. Scheper R.J. MRP6 (ABCC6) detection in normal human tissues and tumors.Lab Invest. 2002; 82: 515-518Google Scholar; Matsuzaki et al., 2005Matsuzaki Y. Nakano A. Jiang Q.J. Pulkkinen L. Uitto J. Tissue-specific expression of the ABCC6 gene.J Invest Dermatol. 2005; 125: 900-905Google Scholar). On the basis of structural homology with other ABCC transporters, particularly ABCC1, the prototype of C family of these proteins, ABCC6 has been suggested to serve as an efflux transporter molecule, and in vitro experiments have suggested that glutathione-conjugated anionic molecules can serve as transport substrates (Belinsky et al., 2002Belinsky M.G. Chen Z.S. Shchaveleva I. Zeng H. Kruh G.D. Characterization of the drug resistance and transport properties of multi-drug resistance protein 6 (MRP6, ABCC6).Cancer Res. 2002; 62: 6172-6177Google Scholar; Iliás et al., 2002Iliás A. Urban Z. Seidl T.L. Le Saux O. Sinkó E. Boyd C.D. et al.Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6).J Biol Chem. 2002; 277: 16860-16867Google Scholar). However, the precise function of ABCC6 and its physiologic substrates in vivo remain unknown, and the pathomechanistic details leading from ABCC6 mutations to aberrant mineralization in peripheral tissues remain to be explored. Furthermore, PXE shows considerable phenotypic variability, and a number of modifying factors, both genetic and environmental, have been identified (Neldner and Struk, 2002Neldner K.H. Struk B. Pseudoxanthoma elasticum.in: Royce P.M. Steinmann B. Connective Tissue and its Heritable Disorders: Molecular, Genetic and Medical Aspects. Wiley-Liss Inc., NY2002: 561-583Google Scholar; Zarbock et al., 2007Zarbock R. Hendig D. Szliska C. Kleesiek K. Götting C. Pseudoxanthoma elasticum: genetic variations in antioxidant genes are risk factors for early disease onset.Clin Chem. 2007; 53: 1734-1740Google Scholar; Hendig et al., 2007Hendig D. Arndt M. Szliska C. Kleesiek K. Götting C. SPP1 promoter polymorphisms: identification of the first modifier gene for pseudoxanthoma elasticum.Clin Chem. 2007; 53: 829-836Google Scholar, Hendig et al., 2008Hendig D. Zarbock R. Szliska C. Kleesiek K. Götting C. The local calcification inhibitor matrix Gla protein in pseudoxanthoma elasticum.Clin Biochem. 2008; 41: 407-412Google Scholar). Two general mechanisms have been proposed to explain the consequences of the ABCC6 mutations in PXE as manifested by mineralization of the elastic structures and collagen fibers in the skin, the eyes, and the cardiovascular system. “The metabolic hypothesis” postulates that in the absence of functional ABCC6 activity, primarily in the liver, there are changes in the levels of circulating factor(s) that are physiologically required to prevent unwanted mineralization (Uitto et al., 2001Uitto J. Pulkkinen L. Ringpfeil F. Molecular genetics of pseudoxanthoma elasticum: a metabolic disorder at the environment-genome interface?.Trends Mol Med. 2001; 7: 13-17Google Scholar; Jiang et al., 2007Jiang Q. Li Q. Uitto J. Aberrant mineralization of connective tissues in a mouse model of pseudoxanthoma elasticum: systemic and local regulatory factors.J Invest Dermatol. 2007; 127: 1392-4102Google Scholar). The clinical observations and our PXE mouse model studies (see below) support the metabolic hypothesis, indicating that PXE is a late-onset, slowly progressing condition. Demonstrations that serum from PXE patients and mice lack the capacity to prevent calcium/phosphate precipitation in an in vitro assay utilizing smooth muscle cell cultures (Jiang et al., 2007Jiang Q. Li Q. Uitto J. Aberrant mineralization of connective tissues in a mouse model of pseudoxanthoma elasticum: systemic and local regulatory factors.J Invest Dermatol. 2007; 127: 1392-4102Google Scholar) further support of this hypothesis. In addition, serum from patients with PXE has been shown to modulate the elastin biosynthetic profile in cultured dermal fibroblasts, further implicating circulatory factors in the disease process (LeSaux et al., 2006LeSaux O. Bunda S. Van Wart C.M. Douet V. Got L. Martin L. et al.Serum factors from pseudoxanthoma elasticum patients alter elastic fiber formation in vitro.J Invest Dermatol. 2006; 126: 1497-1505Google Scholar). On the other hand, “the PXE cell hypothesis” postulates that the lack of ABCC6 expression in the resident cells alters their biosynthetic capacity and biological profile (Quaglino et al., 2000Quaglino D. Boraldi F. Barbieri D. Croce A. Tiozzo R. Pasquali-Ronchetti I. Abnormal phenotype of in vitro dermal fibroblasts from patients with pseudoxanthoma elasticum (PXE).Biochim Biophys Acta. 2000; 1501: 51-62Google Scholar, Quaglino et al., 2005Quaglino D. Sartor L. Garbisa S. Boraldi F. Croce A. Passi A. et al.Dermal fibroblasts from pseudoxanthoma elasticum patients have raised MMP-2 degradative potential.Biochim Biophys Acta. 2005; 1741: 42-47Google Scholar). Specifically, cultured fibroblasts derived from the skin of patients with PXE demonstrate increased extracellular matrix expression, enhanced degradative potential, and altered cell–cell and cell–matrix interactions, associated with changes in their proliferative capacity. In support of this postulate are also the histopathological and ultrastructural observations demonstrating that the elastic structures that become mineralized in the skin of patients with PXE are not normal elastic fibers but appear to have a changed composition. Nevertheless, both hypotheses lack strong experimental evidences and remain to be confirmed. We have developed an Abcc6-/- knockout (KO) mouse by targeted ablation of the corresponding gene (Klement et al., 2005Klement J.F. Matsuzaki Y. Jiang Q.-J. Terlizzi J. Choi H.Y. Fujimoto N. et al.Targeted ablation of the ABCC6 gene results in ectopic mineralization of connective tissues.Mol Cell Biol. 2005; 25: 8299-8310Google Scholar). These mice show normal natal and postnatal development and are morphologically and histologically indistinguishable from their wild-type (WT) counterparts during the early postnatal period. However, at ∼5 weeks of age, progressive mineralization affecting soft connective tissues ensues in homozygous Abcc6-/- mice, but not in their heterozygous littermates or WT counterparts. Electron microscopy revealed that the mineralization process affects both elastic structures and collagen fibers (Klement et al., 2005Klement J.F. Matsuzaki Y. Jiang Q.-J. Terlizzi J. Choi H.Y. Fujimoto N. et al.Targeted ablation of the ABCC6 gene results in ectopic mineralization of connective tissues.Mol Cell Biol. 2005; 25: 8299-8310Google Scholar). Specifically, these mice demonstrate extensive mineralization of connective tissues in the skin, eyes, and cardiovascular system, that is, tissues affected in PXE. Thus, these mice recapitulate the genetic, histopathologic, and ultrastructural features of human PXE. An intriguing feature of these mice is that the first site of mineralization is the connective tissue capsule surrounding the bulb of vibrissae, which then serves as an early biomarker of the PXE mineralization process in these mice (Klement et al., 2005Klement J.F. Matsuzaki Y. Jiang Q.-J. Terlizzi J. Choi H.Y. Fujimoto N. et al.Targeted ablation of the ABCC6 gene results in ectopic mineralization of connective tissues.Mol Cell Biol. 2005; 25: 8299-8310Google Scholar; Jiang et al., 2007Jiang Q. Li Q. Uitto J. Aberrant mineralization of connective tissues in a mouse model of pseudoxanthoma elasticum: systemic and local regulatory factors.J Invest Dermatol. 2007; 127: 1392-4102Google Scholar). In this study, we have addressed the “metabolic hypothesis” of PXE utilizing the Abcc6-/- mice as a model system. Specifically, we have grafted muzzle skin containing the vibrissae from WT and KO mice onto the back of KO and WT mice. The degree of mineralization was evaluated by histopathology, including special stains for calcium and phosphate, followed by computerized morphometric analysis. Two experimental designs were utilized: one of them was used to examine potential prevention of ectopic mineralization, whereas the second one was aimed at examining the potential of reversal of the mineralization. In the prevention study, muzzle skin from WT or KO mice at the age of 4 weeks (before development of mineral deposits) was transplanted onto the back of both KO and WT mice; in the reversal study, muzzle skin from KO mice at the age of 12 weeks (after development of mineralization) was transplanted onto WT or KO mice. Both designs utilized skin grafts from the muzzle skin either from WT or Abcc6-/- KO mice, which were transplanted onto the back of either WT or KO mice (Figure 1). The overall success rate and persistence of the grafts was 83%. At the time points indicated below, the grafts together with surrounding recipient skin were removed and examined by hematoxylin and eosin stain to assess the presence and viability of the graft. Specifically, the presence of cross sections of vibrissae, as shown in Figure 1b, was characteristic of the donor muzzle skin, whereas the adjacent back skin of the recipient did not have these structures, indicating the persistence of the graft. The origin of the graft was also verified by genomic PCR. Specifically, the grafts which originated from the KO mice demonstrated the presence of a 320bp PCR product representing the Abcc6-/- allele, whereas the grafts originating from WT mice clearly demonstrated the presence of 430bp WT allele of Abcc6 (Figure 1c, groups 1 and 2, respectively). In order to establish the reference points of mineralization for the grafting studies, the progressive nature of ectopic mineralization of the connective tissue capsule of vibrissae was examined in Abcc6+/+ and Abcc6-/- mice (Figure 2). As reported previously (Klement et al., 2005Klement J.F. Matsuzaki Y. Jiang Q.-J. Terlizzi J. Choi H.Y. Fujimoto N. et al.Targeted ablation of the ABCC6 gene results in ectopic mineralization of connective tissues.Mol Cell Biol. 2005; 25: 8299-8310Google Scholar), no mineralization can be noted in Abcc6+/+ mice even up to 2 years of age, and this was confirmed in our study. Specifically, there was no evidence of mineralization in Abcc6+/+ mice at 24 weeks when the capsules were stained with hematoxylin and eosin, Alizarin Red, or von Kossa stain (Figures 2a,e, and i). In Abcc6-/- mice, no evidence of mineralization was noted at 4 weeks, but foci of mineralization were detected at the age of 12 weeks and the mineralization progressively increased in the subsequent 12 weeks (Figure 2). In the first set of experiments (prevention) addressing the metabolic hypothesis of PXE, muzzle skin grafts were placed onto the back of mice at the age of 4 weeks, a time point that did not show any degree of mineralization in the Abcc6-/- mice. Three different experimental groups were studied. Group 1: muzzle skin from Abcc6+/+ mouse (donor) was grafted onto the back of gender- and age-matched Abcc6-/- mouse (recipient). Group 2: the same setup as in Group 1, except that the Abcc6-/- mouse was the donor and the Abcc6+/+ mouse was the recipient. Group 3: both donor and recipient were Abcc6+/+ mice. The grafts were then examined at 2 months subsequent to the placement of the graft. When WT mouse muzzle skin was transplanted onto the back of a recipient KO mouse, evidence of mineralization could be noted in the connective tissue capsule surrounding the vibrissae in each mouse (Figures 3a–c, arrows), although not every vibrissa showed mineralization, the total percent of mineralized vibrissae being 28.6% of all examined (Table 1). In contrast, placement of KO mouse muzzle skin onto the back of WT mice did not reveal any evidence of mineralization at 2 months post operatively (Figures 3d–f). Finally, placement of WT mouse muzzle skin onto the back of another WT mouse did not result in mineralization (Figures 3g–i), indicating that the mineralization noted in the KO mouse is not due to surgical manipulation. The results illustrated in Figure 3 were based on survey of 56, 42, and 12 vibrissae in Groups 1, 2, and 3, respectively. As shown in Table 1, 16 out of 56 vibrissae grafted from the muzzle skin of Abcc6+/+ mice onto the back of Abcc6-/- mice (Group 1) developed characteristic mineralization, whereas no mineralization was observed in any of the 42 and 12 vibrissae examined in Groups 2 and 3, respectively. The connective tissue mineralization could also be visualized by transmission electron microscopy of the graft from WT mice muzzle skin placed on the back of KO mice. Examination of different areas of tissue revealed that both collagen fibers and elastic tissue depicted characteristic electron dense mineral deposits (Figures 3j and k), similar to that seen in humans with PXE (Ringpfeil et al., 2001Ringpfeil F. Pulkkinen L. Uitto J. Molecular genetics of pseudoxanthoma elasticum.Exp Dermatol. 2001; 10: 221-228Google Scholar; Neldner and Struk, 2002Neldner K.H. Struk B. Pseudoxanthoma elasticum.in: Royce P.M. Steinmann B. Connective Tissue and its Heritable Disorders: Molecular, Genetic and Medical Aspects. Wiley-Liss Inc., NY2002: 561-583Google Scholar).Table 1Mineralization of vibrissae in grafted skin1Tissue samples of muzzle skin from the donor mice were grafted on the wound bed on the back of recipient mice at the age of 4 weeks, as shown in Figure 1. The grafts were analyzed for mineralization two months post grafting by staining with hematoxylin and eosin, Alizarin Red, and von Kossa, as shown in Figures 3a–i.Group (donor → recipient)Total vibrissae2n, number of vibrissae examined. (n)Mineralized vibrissae2n, number of vibrissae examined. (n)Percent mineralized (%)1.WT → KO (n=8)561628.62.KO → WT (n=7)42003.WT → WT(n=4)1200Abbreviations: KO, knockout (Abcc6-/-) mice; WT, wild-type mice.1 Tissue samples of muzzle skin from the donor mice were grafted on the wound bed on the back of recipient mice at the age of 4 weeks, as shown in Figure 1. The grafts were analyzed for mineralization two months post grafting by staining with hematoxylin and eosin, Alizarin Red, and von Kossa, as shown in Figures 3a–i.2 n, number of vibrissae examined. Open table in a new tab Abbreviations: KO, knockout (Abcc6-/-) mice; WT, wild-type mice. The above prevention studies were performed utilizing 8 and 7 individual pairs of mice in Groups 1 and 2, respectively. The pairs represented the same litter, and the mice were originally developed on mixed C57/J129 background and had been crossbred toward C57 genetic homogeneity for six generations. Nevertheless, 2 and 1 mice in Groups 1 and 2, respectively, showed histologic evidence of inflammation, suggesting minor immune incompatibility. Consequently, similar experiments were performed with immune deficient Rag 1 mice (Abcc6+/+; Mombaerts et al., 1992Mombaerts P. Iacomini J. Johnson R.S. Herrup K. Tonegawa S. Papaioannou V.E. RAG-1-deficient mice have no mature B and T lymphocytes.Cell. 1992; 68: 869-877Google Scholar) as the recipients of muzzle skin grafts from Abcc6-/- mice (n=3). Examination of these grafts did not reveal any evidence of immune reaction and there was no mineralization, validating the original observations in the KO → WT group of mice (Group 2). Collectively, these data clearly imply that PXE does not result from a localized defect based on abnormalities in the resident cells in affected tissues, but rather from a change of metabolite(s) in serum that would physiologically prevent the mineralization process in ectopic tissue sites. In general, mineralization develops in several stages: amorphous calcium phosphate is deposited at the early stages of the process and then gradually transforms into the less soluble crystalline apatite-like compounds (Carson, 1997Carson F.L. Histotechnology: A Self-Instructional Text. American Society of Clinical Pathology, Chicago1997: 222Google Scholar). Therefore, in the second set of experiments, aimed at evaluation of the potential for reversal of the mineralization, muzzle skin from Abcc6-/- mice at the age of 12 weeks, that is, after the development of mineralization had commenced (see Figure 2), was transplanted onto the back of Abcc6+/+ or Abcc6-/- mice. As a control, the muzzle skin from Abcc6-/- mice at the age of 3 months was also examined. Quantitation of mineralization of the connective tissue capsule surrounding the vibrissae revealed clear evidence of mineralization in KO mice (n=11) at the age of 3 months, that is, at the time the grafting procedure was initiated. The difference in the degree of mineralization among the three groups was significant (P=0.0154; Kruskal–Wallis test; Table 2). Examination of the grafts originating from the Abcc6-/- mice and placed on the back of WT mice showed significantly less mineralization than those grafts placed on the back of KO mice (P<0.05; Dunn's multiple comparison test). In contrast, the grafts originating from KO mice and placed on the back of Abcc6-/- indicated close to a 2.5-fold increase in the degree of mineralization in the subsequent 3 months after grafting, as compared to the 3-month-old mice. However, due to individual variability, this difference did not reach statistical significance (P>0.05; Table 2). The mean degree of mineralization in the KO → WT group was about 60% less than that noted in the muzzle skin of KO mice at the age of 3 months, but this difference was not statistically significant (P>0.05; Table 2).Table 2Quantitation of mineralization of vibrissae 3 months after being grafted1Skin sections from KO mice at the age of 3 months were grafted onto the back of either WT or KO mice. Three months post grafting, the grafts were removed, stained with hematoxylin and eosin, and examined for mineralization by light microscopy followed by quantitative computerized morphometric analysis. For comparison, KO mice at 3m of age were examined similarly for mineralization.Experimental group (donor → recipient)Total vibrissae per graft2n, numbers of vibrissae examined. (n)Mineralized vibrissae per graft2n, numbers of vibrissae examined. (n)Percent mineralized (%)Total area per graft3Units are expressed as pixels per μm2 reflecting the intensity of hematoxylin and eosin stain. (U × 103)Mineralized area per graft3Units are expressed as pixels per μm2 reflecting the intensity of hematoxylin and eosin stain. (U × 103)Area of mineralization per total area4Values presented as mean±s.e.m. as well as median; range in parenthesis. (%)Fold5Calculated using the KO → KO group as 1.0.P-value (P=0.0156The total exact P-value for the Kruskal–Wallis test.)KO → WT (6 months, n=6)20.173.3321.118.5970.1340.52±0.24 (0.34; 0–1.28)0.16<0.057P-value for comparison between KO → WT and KO → KO groups (Dunn's multiple comparison test).>0.058P-value for comparison between KO → WT and KO groups (Dunn's multiple comparison test).KO → KO (6 months, n=4)14.256.7547.932.3660.9213.19±1.28 (2.32; 1.17–6.94)1.0KO (3 months, n=11)10.005.6459.282.2580.9961.21±0.19 (1.20; 0.37–2.40)0.40>0.059P-value for comparison between KO → KO and KO groups (Dunn's multiple comparison test).Abbreviations: KO, knockout (Abcc6-/-) mice; WT, wild-type (Abcc6+/+) mice.1 Skin sections from KO mice at the age of 3 months were grafted onto the back of either WT or KO mice. Three months post grafting, the grafts were removed, stained with hematoxylin and eosin, and examined for mineralization by light microscopy followed by quantitative computerized morphometric analysis. For comparison, KO mice at 3m of age were examined similarly for mineralization.2 n, numbers of vibrissae examined.3 Units are expressed as pixels per μm2 reflecting the intensity of hematoxylin and eosin stain.4 Values presented as mean±s.e.m. as well as median; range in parenthesis.5 Calculated using the KO → KO group as 1.0.6 The total exact P-value for the Kruskal–Wallis test.7 P-value for comparison between KO → WT and KO → KO groups (Dunn's multiple comparison test).8 P-value for comparison between KO → WT and KO groups (Dunn's multiple comparison test).9 P-value for comparison between KO → KO and KO groups (Dunn's multiple comparison test). Open table in a new tab Abbreviations: KO, knockout (Abcc6-/-) mice; WT, wild-type (Abcc6+/+) mice. In this study, we have utilized mouse skin transplantation using a mouse PXE model (Abcc6-/-). After grafting, vascular capillaries in the graft regress, whereas new vascular ingrowth occurs from the wound bed to replace the regressing vessels (Capla et al., 2006Capla J.M. Ceradini D.J. Tepper O.M. Callaghan M.J. Bhatt K.A. Galiano R.D. et al.Skin graft vascularization involves precisely regulated regression and replacement of endothelial cells through both angiogenesis and vasculogenesis.Plast Reconstr Surg. 2006; 117: 836-844Google Scholar; Matsuo et al., 2007Matsuo S. Kurisaki A. Sugino H. Hashimoto I. Nakanishi H. Analysis of skin graft survival using green fluorescent protein transgenic mice.J Med Invest. 2007; 54: 267-275Google Scholar). The survival of skin grafts is, therefore, dependent on the reestablishment of an adequate blood circulation ingrown from the recipient animal. New established capillaries were also observed in our study (data not shown). Thus, all survived grafts were supplied by the blood of the recipient mice. If PXE is a metabolic disorder, one would expect that the Abcc6-/- mouse skin graft would not develop mineralization on the Abcc6+/+ mouse, but the skin from WT mouse would be mineralized after grafting onto Abcc6-/- mouse. This was indeed observed in our experiments, suggesting that circulating factor(s) in the recipient's blood are critical in determining the degree of mineralization of the graft, irrespective of graft genotype. It is important to note that our studies do not shed light on the chemical characteristics or the mechanistic details of action of the circulatory factors important in the pathologic mineralization in PXE. Previously, a number of serum proteins, including matrix gla protein, fetuin-A, and ankylosis protein, have been shown to prevent unwanted mineralization under physiologic conditions of mineral homeostasis (see Jiang et al., 2007Jiang Q. Li Q. Uitto J. Aberrant mineralization of connective tissues in a mouse model of pseudoxanthoma elasticum: systemic and local regulatory factors.J Invest Dermatol. 2007; 127: 1392-4102Google Scholar). More recently, low-molecular-weight compounds, such as vitamin K derivatives, alone or conjugated with glutathione, have emerged as potential effector molecules (Li et al., 2008aLi Q. Jiang Q. Pfendner E. Váradi A. Uitto J. Pseudoxanthoma elasticum: clinical phenotypes, molecular genetics and putative pathomechanisms.Exp Dermatol. 2008Google Scholar). Finally, the mechanistic details of the mineralization process, whether humoral or cellular, are not clear. A possibility, potentially bridging the observations in support of “metabolic” versus “PXE cell” hypothesis, is that the circulatory factors, or the lack thereof, influence the metabolic profile of target cells, such as fibroblasts, in the peripheral connective tissues, thus eliciting the processes leading to ectopic mineralization (Gheduzzi et al., 2007Gheduzzi D. Boraldi F. Annovi G. DeVincenzi C.P. Schurgers L.J. Vermeer C. et al.Matrix Gla protein is involved in elastic fiber calcification in the dermis of pseudoxanthoma elasticum patients.Lab Invest. 2007; 87: 998-1008Google Scholar)." @default.
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• W1997403604 title "Pseudoxanthoma Elasticum Is a Metabolic Disease" @default.
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• W1997403604 cites W1983904961 @default.
• W1997403604 cites W1989417694 @default.
• W1997403604 cites W1989680708 @default.
• W1997403604 cites W2007097439 @default.
• W1997403604 cites W2012043021 @default.
• W1997403604 cites W2021481602 @default.
• W1997403604 cites W2030564290 @default.
• W1997403604 cites W2044835168 @default.
• W1997403604 cites W2058254839 @default.
• W1997403604 cites W2059575042 @default.
• W1997403604 cites W2063863692 @default.
• W1997403604 cites W2065930800 @default.
• W1997403604 cites W2070669725 @default.
• W1997403604 cites W2077260227 @default.
• W1997403604 cites W2079028287 @default.
• W1997403604 cites W2103521480 @default.
• W1997403604 cites W2108998829 @default.
• W1997403604 cites W2113613489 @default.
• W1997403604 cites W2117715660 @default.
• W1997403604 cites W2128271989 @default.
• W1997403604 cites W2140489687 @default.
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