March 15, 2008

The following brief was provided to the APDA from Dr. Nestor Gonzalez-Cadavid  from the UCLA Department of Urology, in the Urology Research Laboratory at LABioMed Harbor/UCLA (URL)

Recent Research Findings

Investigators from the UCLA Department of Urology, in the Urology Research Laboratory at LABioMed Harbor/UCLA (URL) is studying the molecular and cellular mechanisms underlying the development of the Peyronie's disease plaque in the penis. This occurs by a process named "fibrosis" (an excessive deposition of collagen fibers) in a penile tissue, the tunica albuginea. The URL group is interested in Peyronie's disease not just because of its burden on the quality of life of patients and their partners, but also because it is an excellent model for fibrotic conditions in other tissues.

These investigations have shown in experimental rat models and cell cultures that a blood clotting protein, possibly released after a minitrauma to the penile tissue leads to the release of a cascade of fibrotic factors. These are fibrin, TGF beta, PAI-1, and oxidative agents that cause considerable collagen deposition, in part through the persistence of cells named myofibroblasts. These cells are important for normal wound healing but disappear after the process is completed. In contrast, myofibroblasts accumulate in the Peyronie's plaque, confirming the prevalent view that it is in fact a sort of scar tissue. It was also found that stem cells able to form other cells are present in the normal tunica albuginea. They may become activated in Peyronie's disease by some of the fibrotic factors to form more myofibroblasts and even bone tissue (that is found in some plaques).

An important finding of the URL laboratory is that the injured penile tissue tries to defend itself from the progressive fibrosis by several mechanisms. One is by increasing an enzyme that makes nitric oxide, named inducible nitric oxide synthase (iNOS). Nitric oxide in turn increases another compound named cGMP. Low levels of both agents during short periods act as mediators of penile erection during sexual stimulation or at sleep. However, when levels are maintained higher for long period they act as antifibrotic agents by inhibiting the formation of myofibroblasts and the accumulation of collagen. Obviously, the growth of the plaque would depend on the balance between fibrotic and antifibrotic factors in the tissue.

The discovery of one of the endogenous antifibrotic mechanisms in Peyronie's disease led to the demonstration in the rat model that continuous long-term administration of drugs that increase cGMP, or iNOS given by gene therapy, not only prevented the development of the plaque but even reduced it partially once it was formed. Similar effects were obtained in this model by counteracting another member of the TGF beta family, named myostatin, these are potential therapeutic approaches, but they need confirmation and extensive experimentation in several animal models before translating them to the clinic.