258 Journal of Investigative Dermatology (2009), Volume 129
© 2009 The Society for Investigative Dermatology
For the article: http://dx.doi.org/10.1038/jid.2008.212
For discussion and answers: http://network.nature.com/group/jidclub
1. How does PXE manifest clinically?
2. How is a knockout mouse created, and why and how was it used in this study?
3. Describe the method and techniques employed in this study.
4. What are the findings of this study?
5. What insights into PXE do the results imply?
6. What may be the clinical implications of this article?
Pseudoxanthoma elasticum (PXE) is an inherited disorder in which defects in the
ABCC6 gene lead to calcification of connective tissue of the skin, eyes (Bruch’s
membrane of the retina), and blood vessels (Neldner and Struk, 2002). Although the
exact mechanism of how ABCC6 causes disease is not known, several hypotheses
have been generated (Pfendner et al., 2008). The “metabolic hypothesis” suggests that
gene defects lead to the absence of circulating factors normally needed to prevent
mineralization in various tissues (Jiang et al., 2007), whereas the “PXE cell hypothesis”
proposes that resident cells are altered by the genetic abnormality, leading to disease
manifestations (Quaglino et al., 2000).
Although experimental and observational support exists for both hypotheses, a newly developed animal model
clarifies the basis of the disease (Jiang et al., 2007). The PXE knockout mouse model demonstrates a delayed, slow
onset of disease manifestations similar to those observed in patients and consistent with the metabolic hypothesis.
Using this knockout model, in which mineralization of tissue begins about 5 weeks after birth, Jiang et al. (2009,
this issue) were able to graft muzzle skin (with distinct vibrissae that typically mineralize in PXE) onto the back
skin of ABCC6 discordant mice. Grafting experiments were performed in a bidirectional fashion between knockout
and wild-type mice in two different time frames. Grafting experiments performed at 6 weeks enabled investigators
to characterize disease progression and revealed that knockout skin grafted onto wild-type mice did not develop
mineralization of the vibrissae, whereas wild-type skin grafted onto knockout mice did. Grafting experiments
performed at 12 weeks enabled investigators to determine whether disease regression was possible because
mineralization ordinarily occurs before 12 weeks of age. These experiments revealed that mineralized vibrissae from
knockout mice did regress, to some extent, after being grafted onto wild-type mice. In summary, these experiments
support the hypothesis that PXE has features of a metabolic disease.
Through the following questions, we examine this paper in greater detail. For brief answers, please refer to
Jiang Q, Li Q, Uitto J (2007) Aberrant mineralization of connective tissues in a mouse model of pseudoxanthoma elasticum: systemic and local regulatory
factors. J Invest Dermatol 127:1392–402
jiang Q, Endo M, Dibra F, Wang K, uitto j (2009) Pseudoxanthoma elasticum is a metabolic disease. j Invest Dermatol 129:348–54
Neldner KH, Struk B (2002) Pseudoxanthoma elasticum. In: Royce PM, Steinmann B (eds) Connective Tissue and Its Heritable Disorders: Molecular, Genetic
and Medical Aspects. Wiley–Liss: New York, 561–83
Pfendner E, Uitto J, Gerard GF, Terry SF (2008) Pseudoxanthoma elasticum: genetic diagnostic markers. Expert Opin Med Diagn 2:1–17
Quaglino D, Boraldi F, Barbieri D, Croce A, Tiozzo R, Pasquali-Roncherri I (2000) Abnormal phenotype of in vitro dermal fibroblasts from patients with
pseudoxanthoma elasticum (PXE). Biochim Biophys Acta 1501:51–62
Pseudoxanthoma elasticum: new Insights
Robb Marchione1, Nancy Kim1 and Robert S. Kirsner1
Journal of Investigative Dermatology (2009), 129, 258. doi:10.1038/jid.2008.407
1Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
© 2009 Nature Publishing Group
Updated 31 Mar 2009 14:26 UTC
Pfendner E, Uitto J, Gerard GF, Terry SF (2008) Pseudoxanthoma elasticum: genetic diagnostic markers. Expert Opin Med Diagn
Quaglino D, Boraldi F, Barbieri D, Croce A, Tiozzo R, Pasquali-Roncherri I (2000) Abnormal phenotype of in vitro dermal
fibroblasts from patients with pseudoxanthoma elasticum (PXE). Biochim Biophys Acta 1501:51–62
1 Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA