Mechanisms of Disease: new insights into the cellular and molecular pathology of Peyronie's disease.

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Abstract

Peyronie's disease (PD) is characterized by fibrotic plaques in the penile tunica albuginea that cause curvature of the erect penis, and is often accompanied by pain and/or erectile dysfunction. This condition affects up to 9% of men. Treatment is mainly surgical, as pharmacologic therapy has limited efficacy. The pathophysiology of PD is poorly understood, but development of two rat models, extrapolation of what is known about the molecular pathology of other fibrotic conditions, and emphasis on the role of myofibroblasts and adult stem cells are helping to clarify etiology and identify new pharmacologic targets. Recent studies demonstrate a role for oxidative stress and cytokine release-primarily transforming-growth-factor beta1-in development of PD fibrotic plaques. There is evidence indicating that these profibrotic factors interact with antifibrotic defense mechanisms, such as decrease of myofibroblast accumulation, elimination of reactive oxygen species by inducible nitric oxide synthase and neutralization of transforming-growth-factor beta1 by decorin, such that some plaques are in dynamic turnover. Injury to the erect penis is thought to trigger PD by inducing extravasation of fibrin and subsequent synthesis of transforming-growth-factor beta1. Despite the lack of statistical support for a causal association between trauma and PD, it is possible that undetected microtrauma is involved. It is not known whether ossification of PD plaques is linked to fibrosis progression or is a manifestation of an alternative pathway. Both processes seem to be related to activation of fibroblast/myofibroblast differentiation in the tunica albuginea and to osteogenic commitment of stem cells in this tissue.

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Since the original description of circulating fibrocytes in 1994, our knowledge of this unique cell population has grown steadily. While initially described in the context of wound repair, fibrocytes have since been found to participate in granuloma formation, antigen presentation, and various fibrosing disorders. Fibrocytes produce matrix proteins such as vimentin, collagens I and III, and they participate in the remodeling response by secreting matrix metalloproteinases. Fibrocytes also are a rich source of inflammatory cytokines, growth factors, and chemokines that provide important intercellular signals within the context of the local tissue environment. Moreover, fibrocytes express the immunological markers typical of an antigen-presenting cell, and they are fully functional for the presentation of antigen to naïve T cells. Fibrocytes can further differentiate, and they may represent a systemic source of the contractile myofibroblast that appears in many fibrotic lesions. Clinically, there is evidence that patients with hypertrophic scars such as keloids, and those affected by scleroderma and other fibrosing disorders have fibrocytes in their lesions. Recently, a new disease entity called nephrogenic fibrosing dermopathy (NFD) has been described, and the fibrocyte may play an important etiopathogenic role in disease development. Nephrogenic fibrosing dermopathy occurs in patients with renal insufficiency and leads to thickening and hardening of the skin, especially of the extremities. Ongoing research is focusing on the molecular signals that influence fibrocyte migration, proliferation, and function in the context of normal physiology and pathology.