Similar genes found in Dupuytren's and Peyronie's

Dupuytren's and Peyronie's disease are believed to be related, to share a common genetic starting point. This has been an assumption, not hard fact: the genetic starting points of these conditions are not yet known, much less known to be the same. Doctors have been wrong on these issues in the past: in the 1800's, it was an accepted "fact" that Dupuytren's and gout were related. They are not: the only relationship is demographic overlap. We now have better tools to find genetic similarities of Dupuytren's Disease (DD) and Peyronie's Disease (PD). All normal body processes are regulated and balanced by genetically controlled feedback loops: genes are upregulated (turned on) or downregulated (turned off) to maintain balance. DD and PD are the end effects of a broken feedback loop: an on switch is stuck in the on position, an off switch is stuck off, or both. One way to study up and down regulation is to use reverse transcriptase. Here's how it works. Genes are different molecules strung together into huge DNA molecules. When a gene is upregulated (turned on), it makes RNA molecules, which are like small, mirror images of itself. RNA carries orders from the boss DNA to control the rest of the cell. Reverse transcriptase is a laboratory technique which reverses this process, making DNA mirror images of RNA taken from living cells to find what genes the RNA came from - what genes are upregulated. In this study "Comparison of gene expression profiles between Peyronie’s disease and Dupuytren’s contracture" (full text: http://www.dupuytrenfoundation.org/DupPDFs/2004_Qian_1570.pdf), this technique was used to identify upregulated and downregulated genes in Peyronie's, Dupuytren's and normal tissues. The result? Yes, DD and PD appear to be genetically related. The list of identified genes and their actions is reviewed in the article. More pieces of the puzzle, more steps closer to a cure.

RNA, Growth Factors and Dupuytren's

Sorting out the genetic basis of Dupuytren's is not simply a matter of finding out which genes are involved. The goal is to understand the biochemistry of exactly what these specific genes do to either start or fail to stop the process of Dupuytren's. Cell biology is always a domino like set of events with many steps. The DNA molecules in a cell's genes act as a template to make messenger RNA (mRNA), which travels from the cell's nucleus to its protein manufacturing factories (ribosomes), where the mRNA then acts as a template to string amino acids together to make proteins. Our bodies use some proteins, like collagen, as structural building material; other proteins, called cytokines, are used as currency of communication between cells, directing cells what to do. In this study, "Abnormal growth factor and cytokine expression in Dupuytren's contracture" (full text: http://www.dupuytrenfoundation.org/DupPDFs/1993_Baird_1442.pdf), researchers analyzed the cytokines produced by mRNA in Dupuytren's tissue, and found abnormal activity of interleukin-1a, interleukin-1ß, transforming growth factor ß and basic fibroblast growth factor. This approach, linking genes with proteins, brings us a step closer to solving the puzzle of a cure.

Genes, enzymes and Dupuytren's: the alphabet name game.

A proteinase is an enzyme which breaks down proteins. Metalloproteinases (MPs) are proteinases with a molecular structure and function involves a metal atom, usually zinc. Matrix Metalloproteinases (MMPs) are MPs which act outside of cells, in the tissue matrix. Human collagenases are MMPs which break down different types of collagen. Membrane-type MMPs (MT-MMPs) are MMPs which are attached to cell membranes and protrude into the extracellular matrix. ADAMTS (A Disintegrin And Metalloproteinase with Thrombospondin Motifs) are another subgroup of MMPs. ADAMTs cut off or shed portions of proteins which protrude out of the cell wall, and are classified as sheddases (I am not making this up). TIMPs (Tissue inhibitors of Metalloproteinases) block the action of MMPs. This lecture handout outlines investigation of which genes relating to MMPs and ADAMTs are activated in osteoarthritis and Dupuytren's disease (full text: http://www.dupuytrenfoundation.org/DupPDFs/2007_Clark.pdf). In active Dupuytren's disease, five genes were involved: MMP13, which codes for collagenase 3 (breaks down type II collagen (in cartilage), and to a lesser extent types I and III collagen (in Dupuytren's cords); MMP14 codes for MMP-14, a MT-MMP collagenase which activates collagenase 3 and is activated by poor circulation; ADAMTS5, which codes for aggrecanase, an ADAMTS which breaks down cartilage; ADAMTS14, which is linked to procollagen processing; ADAMTS16, which codes for an enzyme whose function is unknown. More information on this is available here: (full text: http://www.dupuytrenfoundation.org/DupPDFs/2008_Murphy.pdf). Dupuytren's is somehow related to the way that all of these genes interact. Here's a simple question based on all of this: if Dupuytren's is related to not enough collagenase function, and zinc is needed for collagenase to function, and EDTA is an additive put in soda pop because it removes metals such as zinc, could drinking too much of your favorite carbonated beverage raise your risk for Dupuytren's?

Dupuytren's Genes

The hunt is on for the genetic basis of Dupuytren's. A interesting analysis of the chromosome patterns found in Dupuytren's tissue found a variety of genetic abnormalities and the unexpected finding that these variations were not found in the skin but were seen in areas of palmar fascia not usually involved with Dupuytren's. (full text: http://www.dupuytrenfoundation.org/DupPDFs/1988_Wurster-Hill_1091.pdf). Twenty years after this report, the hunt is still on with more sophisticated equipment, identification of involved genes closer but still elusive: http://dupuytrenfoundation.blogspot.com/2009/11/gene-expression-in-dupuytrens.html. Still, so many questions: is it determined by one or several genes? If, as widely believed, the trait is a dominant gene, why is Dupuytren's more common in people with blue eyes, the result of a recessive gene? Does the genetic effect only involve the palmar fascia or all fascia? Dupuytren's skips generations and often appears with no family history: is it a common spontaneous mutation, and if so, is it more common in those born to older parents? Some day, these questions will be answered. With persistence, some day, there will be a cure.

The Dupuytren Symposium is coming!

As tomorrow's deadline for abstract submission nears, internet connections are heating up at command central for the 2010 International Symposium on Dupuytren's Disease. The symposium syllabus looks very exciting, with some amazing new reports. Session topics have solidified as: The Myofibroblast; Genetics and Demographics; Disease Concepts; Collagen and Collagenase; Surgical Treatments; Energy Based Treatments; Manual Therapies; The Future. The Saturday evening dinner presentation will be on the life of Dupuytren. Overall, everything is shaping up well, so get ready. Stragglers, submit your abstracts! Otherwise, register to attend - space will be limited! http://www.DupuytrenSymposium.com

To understand Dupuytren's, first understand women.

Is Dupuytren's a tumor - an independent growth, or is it a reaction of normal tissues to a stimulus? Is a woman one person or several people sharing the same body? This paper answers both questions. Every female human has two X chromosomes, one from each parent, but in any individual cell, only one X chromosome is active, the other permanently inactivated. One X chromosome rules half of a woman's cells, the other rules the other half, and these cells are evenly mixed throughout her body. Now, true neoplastic tumors are clones: one cell reproduces over and over, and so in females all cells of a tumor will have the same active X chromosome. In contrast, reactive tumors are many adjacent cells responding to a common stimulus, and will have a normal mix of active X chromosomes. This fact was used to show that Dupuytren's nodules are not true tumors, not bad cells, but a reaction of normal cells to some stimulus. What is it? http://www.dupuytrenfoundation.org/DupPDFs/2006_Wang_1040.pdf

Dupuytren's Foundation and Scripps Research

The Dupuytren's Foundation http://www.dupuytrenfoundation.org has officially partnered with Scripps research to establish a DNA bank of tissues affected by Dupuytren's disease. This will be available to researchers interested in studying Dupuytren DNA. So far, 20 samples have been collected. If the gene is identified, progress toward acure will be greatly streamlined. Very exciting. Interested in donating your DNA to the cause? Contact The Hand Center http://www.handcenter.org 561-746-7686