The CD24hi smooth muscle subpopulation is the predominant fraction in uterine fibroids.

Uterine fibroids are the most common gynecological tumors affecting women in their reproductive age. Despite this high incidence the pathogenesis of fibroids is widely unsolved. Whereas formerly only imbalances in hormonal levels were considered to account for tumor development, the identification of genetic changes likely to affect myometrial stem cell reservoirs provided a novel approach to fibroid genesis. Here, we identified a certain subset of cells by the surface marker CD24 with increased abundance in fibroids compared with myometrial tissue. Fibroid cells expressing CD24 shared certain features of immature or progenitor-like cells such as quiescence, reduced expression of smooth muscle differentiation markers and elevated expression of genes involved in the wingless-type (WNT)-pathway such as beta-catenin. In addition, a positive correlation between CD24 and wingless-type family member 4 (WNT4) expression was observed in uterine fibroids with mediator subcomplex 12 gene (MED12) mutations. Our findings suggest that cells highly expressing CD24 represent a type of immature smooth muscle progenitor cells. Their accumulation might be driven by disturbed differentiation processes caused by genetic changes possibly involving MED12 mutations or high mobility group AT-hook (HMGA)2 rearrangements.

Induction of overt menstruation in intact mice.

The complex tissue remodeling process of menstruation is experienced by humans and some primates, whereas most placental mammals, including mice, go through an estrous cycle. How menstruation and the underlying mechanisms evolved is still unknown. Here we demonstrate that the process of menstruation is not just species-specific but also depends on factors which can be induced experimentally. In intact female mice endogenous progesterone levels were raised by the induction of pseudopregnancy. Following an intrauterine oil injection, the decidualization of the endometrium was reliably induced as a prerequisite for menstruation. The natural drop of endogenous progesterone led to spontaneous breakdown of endometrial tissue within an average of 3 days post induction of decidualization. Interestingly, morphological changes such as breakdown and repair of the endometrial layer occurred in parallel in the same uterine horn. Most importantly, endometrial breakdown was accompanied by vaginally visible (overt) bleeding and flushing out of shed tissue comparable to human menstruation. Real-time PCR data clearly showed temporal changes in the expression of multiple factors participating in inflammation, angiogenesis, tissue modulation, proliferation, and apoptosis, as has been described for human menstruating endometrium. In conclusion, human menstruation can be mimicked in terms of extravaginally visible bleeding, tissue remodeling, and gene regulation in naturally non-menstruating species such as intact female mice without the need for an exogenous hormone supply.

Proteasome inhibition: a new anti-inflammatory strategy.

The ubiquitin-proteasome pathway has a central role in the selective degradation of intracellular proteins. Among the key proteins modulated by the proteasome are those involved in the control of inflammatory processes, cell cycle regulation, and gene expression. Consequently proteasome inhibition is a potential treatment option for cancer and inflammatory conditions. Thus far, proof of principle has been obtained from studies in numerous animal models for a variety of human diseases including cancer, reperfusion injury, and inflammatory conditions such as rheumatoid arthritis, asthma, multiple sclerosis, and psoriasis. Two proteasome inhibitors, each representing a unique chemical class, are currently under clinical evaluation. Velcade (PS-341) is currently being evaluated in multiple phase II clinical trials for several solid tumor indications and has just entered a phase III trial for multiple myeloma. PS-519, representing another class of inhibitors, focuses on the inflammatory events following ischemia and reperfusion injury. Since proteasome inhibitors exhibit anti-inflammatory and antiproliferative effects, diseases characterized by both of these processes simultaneously, as is the case in rheumatoid arthritis or psoriasis, might also represent clinical opportunities for such drugs.