Clear evidence: PXE is a metabolic disease

SEPTEMBER 15, 2008
By Emilie Lamb, Research Assistant, PXE International

Lay summary of: 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. Free article in PubMed. PMID: 18685618

This article was first published in the Fall 2008 PXE International MemberGram.

In August of 2008, Dr. Jouni Uitto, along with Dr. Qiujie Jiang, Masayuki Endo, Florian Dibra, and Krystle Wang, published an article presenting the results of multiple studies that represents strong evidence that PXE is a metabolic disorder and not a connective tissue disease as previously thought.  This article was published in the Journal of Investigative Dermatology on August 7, 2008.

Dr. Uitto's experiments involved comparing a knockout (KO) mouse and a wild type (WT) mouse. A KO mouse has the ABCC6 gene function “knocked out” by mutations or deletions, so that the gene does not function properly and it can mimic PXE in the human. A WT mouse has no mutations and therefore the ABCC6 gene functions normally. Dr. Uitto´s research team was able to perform two major experiments. They first looked at the possible prevention of skin mineralization that is characteristic in PXE. The second study was conducted to determine if mineralization could be reversed.

The first experiment looked at the prevention question by performing skin grafts on three combinations of KO and WT mice. The mice were all 4 weeks old, and there was no mineralization at this young age. In the first combination, the researchers took a piece of skin off of the muzzle of a WT mouse and grafted it onto the back of a KO mouse. In the second combination, muzzle skin from a KO mouse was grafted onto the back of a WT mouse. The third combination was designed as a comparison, and skin was grafted from one WT mouse onto the back of another WT mouse. 

Two months after the surgeries were completed, the researchers examined the skin grafts to see if mineralization was prevented. The team found that the WT skin on the back of the KO mouse, which was not mineralized at the start, became mineralized in 28.6% of the mice after it was grafted on the skin of the KO mice. However, in the second combination, the KO skin was not mineralized at all after it was grafted on to the WT mouse´s back. The third combination of mice had no mineralization, therefore revealing that surgery itself had not mineralized the skin. 

The second study was designed to determine if mineralization already present in the skin could be reversed. In this experiment, the grafts were performed at 12 weeks of age when the muzzle skin of the KO mouse already showed mineralization. In this experiment, the muzzle skin from the KO mouse was grafted on to the backs of both a WT mouse and a KO mouse. Again, two months after the surgery, the grafted skin was examined. Dr. Uitto found that the KO skin grafted on to the WT mouse was less mineralized than it was at the time of grafting, and the KO skin grafted onto the KO mouse was more than twice as mineralized as it was at the time of grafting.

Based on these two experiments, Dr. Uitto determined that the cause of the mineralization seen in these mice is not specific to the skin tissue, but is related to the metabolism of the KO mouse. After a piece of skin is grafted from one animal to another, the skin is supplied by new blood vessels from the recipient mouse instead of the blood from the donor mouse. Because the skin grafts receive blood from the recipient mice, Dr. Uitto determined that it must be something in the blood of the recipient mice that either prevents or reverses the mineralization. 

These experiments show that something circulating in the bloodstream, called a metabolite (a byproduct of metabolism), is important to the mineralization seen in PXE. While Dr. Uitto and his research group have not yet identified the actual metabolite(s) that is involved, these experiments are strong evidence that PXE is a metabolic disease involving the whole body and not a specific problem with the tissue of the skin, eyes, and arteries. This research is very exciting because understanding the cause of the mineralization seen in PXE is an important step towards trying to find a treatment and cure. 

Defining the Terms

ABCC6 Knockout Mouse: a mouse that does not have a functioning copy of the ABCC6 gene because the gene has been deleted or mutated.

Wild Type Mouse: a mouse with a non-mutated copy of the ABCC6 gene that functions normally. 

ABCC6 gene: the piece of genetic material (DNA) that is responsible for making the ABCC6 protein. Mutations in this piece of DNA lead to the symptoms of PXE.

Muzzle: the area around the nose and mouth of an animal. 

Skin Graft: the surgical removal of a piece of skin and its movement to another location.

Metabolite: a molecule or chemical that can be found in the blood stream.

Metabolism: the chemical reactions that occur in the body, mostly in the liver, that help create or break down molecules and transport them throughout the body.

Metabolic Disease: a disease that is caused by a problem with the chemical reactions in the body or he transportation of chemicals and molecules around the body.