PXE Disease Origin Theories

There are currently two general hypotheses regarding the cause of PXE – the metabolic theory and the tissue-specific theory.

Metabolic Theory

The metabolic theory is supported by the fact that 80% of people diagnosed with PXE exhibit a loss-of-function mutation in the ABCC6 gene which encodes the atypical, multi-drug associated, transmembrane transporter protein MRP6 (additional information available at http://www.ncbi.nlm.nih.gov/gene/368). This protein is normally expressed predominantly in the liver and kidney.  The metabolic theory claims that the first step in the disease pathway is degradation and bioconjugation of a constituent of the extracellular matrix, specifically elastin.  The theory further suggests that ABCC6 should remove this bio-conjugated metabolite but does not due to the mutation.  Damage and remodeling of the extracellular matrix is then observed due to the elevated levels of this unidentified metabolite.  

See:

Kavukcuoglu NB, Li Q, Pleshko N, Uitto J. Connective tissue mineralization in Abcc6-/- mice, a model for pseudoxanthoma elasticum. Matrix Biol. 2012 May;31(4):246-52. Epub 2012 Mar 6. PubMed PMID: 22421595; PubMed Central PMCID: PMC3340454.  
http://www.ncbi.nlm.nih.gov/pubmed/22421595

Jiang Q, Oldenburg R, Otsuru S, Grand-Pierre AE, Horwitz EM, Uitto J. Parabiotic heterogenetic pairing of Abcc6-/-/Rag1-/- mice and their wild-type counterparts halts ectopic mineralization in a murine model of pseudoxanthoma elasticum. Am J Pathol. 2010 Apr;176(4):1855-62. Epub 2010 Feb 25. PubMed PMID: 20185580; PubMed Central PMCID: PMC2843475.
http://www.ncbi.nlm.nih.gov/pubmed/20185580

Jiang Q, Endo M, Dibra F, Wang K, Uitto J. Pseudoxanthoma elasticum is a metabolic disease. J Invest Dermatol. 2009 Feb;129(2):348-54. Epub 2008 Aug 14. PubMed PMID: 18685618; PubMed Central PMCID: PMC3169309.
http://www.ncbi.nlm.nih.gov/pubmed/18685618

Tissue-specific Theory

The tissue-specific theory is also supported by the fact that 80% of people diagnosed with PXE exhibit a loss-of-function mutation in the ABCC6 gene, transmembrane transporter protein MRP6 in multiple organ and tissue systems, including the liver. In contrast to the metabolic theory, the tissue-specific theory claims that disease manifestations in the multiple organ systems (e.g., ocular, cardio, vascular, and gastrointestinal) and the tissue-dependent loss of expression are associated with extracellular matrix damage observed.  The theory further suggests that the ABCC6 loss of function at the local affected tissues is essential to the disease pathogenesis beyond the metabolic insult resulting from the loss of function in the liver.

See:

Gheduzzi D, Boraldi F, Annovi G, DeVincenzi CP, Schurgers LJ, Vermeer C, Quaglino D, Ronchetti IP. Matrix Gla protein is involved in elastic fiber calcification in the dermis of pseudoxanthoma elasticum patients. Lab Invest. 2007 Oct;87(10):998-1008. Epub 2007 Aug 27. PubMed PMID: 17724449. 
http://www.ncbi.nlm.nih.gov/pubmed/17724449

Boraldi F, Annovi G, Guerra D, Paolinelli Devincenzi C, Garcia-Fernandez MI, Panico F, De Santis G, Tiozzo R, Ronchetti I, Quaglino D. Fibroblast protein profile analysis highlights the role of oxidative stress and vitamin K recycling  in the pathogenesis of pseudoxanthoma elasticum. Proteomics Clin Appl. 2009 Sep;3(9):1084-98. doi: 10.1002/prca.200900007. Epub 2009 Aug 26. PubMed PMID: 21137008.  
http://www.ncbi.nlm.nih.gov/pubmed/21137008

Jiang 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 Jun;127(6):1392-402. Epub 2007 Feb 1. PubMed PMID: 17273159.  
http://www.ncbi.nlm.nih.gov/pubmed/17273159