Wnt Signaling Increases Dermal Fibroblast Proliferation
Pachydermoperiostosis is characterized by pachydermia (skin thickening), digital clubbing, and periostosis of long bones. Kabashima et al (Am J Pathol 2010, 176:721–732) hypothesized that Wnt signaling was involved in the development of pachydermia. They found that DKK1, a Wnt-signaling antagonist, was expressed at lower levels in pachydermoperiostosis than in control dermal fibroblasts, whereas the Wnt-signaling molecule β-catenin was expressed at higher levels. In addition, expression of DKK1 inhibited dermal fibroblast proliferation, and DKK1 inhibition increased skin thickening in mouse ears. Therefore, enhanced Wnt signaling may contribute to pachydermia by increasing levels of dermal fibroblast proliferation.
Wnt/β-Catenin in Hepatic Pathology
The Wnt/β-catenin signaling pathway is involved in liver development, regeneration, and hepatocarcinogenesis; however, its role in noncancerous hepatic pathology has not been well characterized. To determine the effects of β-catenin deficiency on hepatic steatosis and injury, Behari et al (Am J Pathol 2010, 176:744–753) fed a steatogenic methionine– and choline–deficient diet to both wild-type and β-catenin–deficient mice. They found that β-catenin–deficient mice developed higher levels of steatosis and fibrosis as well as accumulated higher hepatic cholesterol levels than wild-type mice. Furthermore, β-catenin–deficient mice had higher hepatic bile acid and serum bilirubin levels despite lower expression of bile acid synthesis enzymes, suggesting defects in bile export. These findings suggest that β-catenin signaling plays a key role in hepatic bile acid and cholesterol homeostasis as well as in protecting against metabolic stress.
Chronic Morphine Use Delays Wound Healing
Chronic morphine users and opioid abusers have inadequate wound closure and increased susceptibility to infection. Martin et al (Am J Pathol 2010, 176:786–799) explored wound healing in a mouse model of chronic morphine use/abuse. In the presence of inflammation, chronic morphine exposure resulted in a marked decrease in wound closure, compromised wound integrity, and increased bacterial sepsis. Altered expression of keratinocyte-derived cytokine and monocyte chemotactic protein-1 led to decreased recruitment of both neutrophils and macrophages to the wound site. Wound-site angiogenesis and myofibroblast recruitment were also suppressed in these animals. These data suggest that the immunosuppression attributable to morphine treatment delays innate immune cell recruitment, leading to lack of bacterial clearance and delayed wound closure.
Breast Epithelial Stroma Can Control Proto-Oncogene Function
The stromal extracellular matrix microenvironment may contribute to both breast homeostasis and tumorigenesis. To determine how stromal extracellular matrix remodeling affects proto-oncogene expression in breast epithelia, Taraseviciute et al (Am J Pathol 2010, 176:827–838) developed a computational model to quantify changes in a three-dimensional culture of human mammary epithelial cells. They found that tenascin-C, a stromal glycoprotein whose expression correlates with disease severity, promoted epithelial cell proliferation and luminal filling, similar to the results of c-met overexpression. Indeed, tenascin-C increased c-met expression, and blocking c-met function inhibited tenascin-C–induced luminal filling. Taken together, these results indicate a role for stromal changes in regulating proto-oncogene function.
Islet Amyloid Polypeptide (IAPP) Oligomers Toxic in Diabetes
The loss of β cells in type 2 diabetes mellitus (T2DM) is associated with the accumulation of IAPP amyloids; however, the toxic form of IAPP may be intracellular oligomers rather than extracellular amyloid fibrils. Gurlo et al (Am J Pathol 2010, 176:861–869) explored the role of IAPP amyloids in T2DM pathology. They discovered that IAPP oligomers formed intracellularly and disrupted the membranes at all steps of the secretory pathway in β cells. These oligomers were also found in β cells in human patients with T2DM. Moreover, IAPP oligomers disrupted mitochondrial membrane function when adjacent to mitochondria. Secretory and mitochondrial membrane disruption attributable to IAPP oligomers may therefore contribute to cellular dysfunction and apoptosis in T2DM.