The Secret Life of Myofibroblasts: Dr. Boris Hinz reveals all!

Boris Hinz PhD, University of Toronto, Ontario, CA presents "Fundamental aspects of myofibroblast contraction." and explains how the process is both simple and complex. How do these little cells do such big things? More importantly, what steps in the process go wrong to result in Dupuytren's and what can be done to safely and simply correct this? Watch the video and see: http://www.youtube.com/user/DupuytrenFoundation#p/u/0/fvmRS3OiWic

Funding for these and other Miami Dupuytren Symposium videos at http://dupuytrensymposium.com/program.html, is provided by the Dupuytren Foundation. Support the Dupuytren Foundation with an online donation: http://CureDup.com.

Stretching, Myofibroblasts and Dupuytren's

How, and why, does Dupuytren's disease actually contract? What is the physical mechanism? What provokes it? There is a genetic risk, but genes don't provide the entire script, otherwise Dupuytren's contractures should be symmetric, the same problem developing at the same time in the same way in both hands, but that's not what happens: usually, contractures in one hand are different in time and space than the other hand. Why? One explanation is that Dupuytren's is both biological and mechanical, and that physical forces somewhat influence the process. One way to study the big picture is to look at the little picture: what happens inside Dupuytren cells in response to physical forces? This is an active and exciting area of research. Myofibroblasts are the contracting cells producing Dupuytren's and other fibrotic contractures. Myofibroblasts respond to stretching by first relaxing and then pulling against the line of pull. This process is the subject of ongoing studies. In "Stretch-activated force-shedding, force recovery, and cytoskeletal remodeling in contractile fibroblasts" (full text: http://www.dupuytrenfoundation.org/DupPDFs/2008_Nekouzadeh.pdf), researchers used a laboratory model to demonstrate fibroblast reactions to stretch. Stretching cells initially tears the scaffolding inside cells, which is made of the protein actin. This releases tension, but also provokes the cells to pull back in two phases. The first phase starts within seconds ("Rapid Active Response"), the second after a few minutes ("Gradual Active Response"). These responses show the cell repairing the torn proteins. Other responses follow, modifying the collagen matrix outside the cells. The result? The more you pull, the more Dupuytren's pulls back. This is the type of data we need to move past what would seem to make sense, but is probably exactly wrong (pulling and stretching your fingers back to keep them from contracting) to an effective treatment, a cure.

Metalloproteinases and Dupuytren's

A better understanding of the biology of metalloproteinases may lead to new treatment options for Dupuytren's. Metalloproteinases (MMPS) are a group of enzymes in our bodies which break down certain proteins, including collagen. MMPS are blocked by tissue inhibitors of metalloproteinases (TIMPS). MMPS and TIMPS balance each other: imbalances have been implicated in conditions of excess collagen, as seen in Dupuytren's, or inadequate collagen leading to rotator cuff tears. The article "Metalloproteinases and their inhibitors—diagnostic and therapeutic opportunities in orthopedics" (full text: http://www.dupuytrenfoundation.org/DupPDFs/2009_Pasternak.pdf) is a clearly written and thorough review of the topic and its implications for Dupuytren's and other conditions. MMPs are involved in the biology of inflammation and wound healing, which overlaps the cell biology of Dupuytren's. The authors note "In view of the strong hereditary component and a predilection for men in Dupuytren’s disease, it is interesting to note that TIMP-1 is located on the X-chromosome." It may not be that a man's Y chromosome puts him at special risk, but that a woman's X chromosome offers her special protection. In addition to involvement with Dupuytren's, MMPs and TIMPs appear to play key roles in unrelated disorders including arthritis, degenerative disk disease, tendinitis, fracture healing and other conditions. Inroads made in understanding their role in Dupuytren's are likely to benefit people suffering from other conditions - an added incentive to work for a cure.

Dupuytren's and other fibroses

Dupuytren's is a fibrotic disease, a fibrosis - one of many. Fibrosis, as a word, sounds exotic, but it is really just the medical name for scar. Although injuries come in many forms and can involve any structure, our bodies have a limited repertoire for reacting to injuries. The universal poultice our body's healing process puts into areas of injury is collagen. A scar is mostly collagen. When a broken bone heals, the body first glues the break together with collagen; calcium crystals form in this glue, eventually turning it into bone. Collagen is stuff we are made of: anything solid or mechanically important in our bodies, even bone, is mostly made of collagen. Collagen needed for us to live; collagen is good, but in the right place and in the right amount. Fibroses show that even for collagen, there can be too much of a good thing. If collagen is like the bricks making up the house in which our cells live, fibrosis is like adding extra bricks inside the house: too many bricks and the house stops being livable. Fibrosis may affect a specific location, as in Dupuytren's, or may diffusely involve an entire organ, as in pulmonary fibrosis. Why do fibroses occur? This is the question we need to investigate on the quest to find a cure for Dupuytren's. Drugs play a part in certain fibroses. In "Drug-Induced Localized Systemic Scleroses" (full text: http://www.dupuytrenfoundation.org/DupPDFs/1981_Graham_1601.pdf), the role of drugs and fibroses, including Dupuytren's, is explored.