Letters in 2011

By immunizing mice with a small synthetic metal-baring complex mimicking the active site of matrix metalloproteinases (MMPs), the authors have generated antibodies that bind and inhibit activated MMP2 and MMP9 in a manner analogous to the mechanism of action of tissue inhibitors of metalloproteinases. Targeting the active conformation of these MMPs is therapeutically effective in mouse models of inflammatory bowel disease.

Huntington's disease is a neurodegenerative disease caused by the accumulation of mutant HTT protein. Now, two groups led by Dimitri Krainc and Wenzhen Duan report that mutant HTT binds and inactivates the deacetylase enzyme SIRT1 and that SIRT1 overexpression is protective in Huntington's disease mouse models.

Huntington's disease is a neurodegenerative disease caused by the accumulation of mutant htt protein. Now, two groups led by Dimitri Krainc and Wenzhen Duan report that mutant htt binds and inactivates the deacetylase enzyme SIRT1 and that SIRT1 overexpression is protective in Huntington's disease mouse models.

A major issue in the clinic is excessive, or hypertrophic, scarring of the skin after injury. Geoffrey Gurtner and his colleagues have now shown that mechanical forces during such injury upregulates focal adhesion kinase (FAK), which in turn leads to the release of a cytokine that promotes inflammation and fibrosis. They also show that genetic deletion of FAK or its pharmacological inhibition results in minimal scarring in a mouse model.

Wound healing involves a transient regeneration of tissue, but, if this process continues unabated, pathology occurs in the form of fibrosis, which can prevent normal organ function and even death. Derek Mann and his colleagues have found that serotonin-responsive profibrogenic hepatic stellate cells inhibit the growth of neighboring liver cells during the termination phase of liver injury. They also found that inhibiting serotonin signaling during established disease improved liver fibrosis in various mouse models of liver injury.

Timothy syndrome is a neurodevelopmental disease that includes autism-like features. Using iPS-derived neurons from individuals with Timothy syndrome, Ricardo Dolmetsch and his colleagues identify changes in cortical neuron fate and neurotransmitter expression that may begin to explain the neural mechanisms that underlie this disorder.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons. Now, Valentin Gribkoff and his colleagues show some preliminary evidence that the drug dexpramipexole may have clinical activity in a small placebo-controlled trial in patients with ALS.

This report identifies oncogenic fusions in individuals with breast cancer involving the genes encoding NOTCH and MAST, recurring in approximately 5–7% of studied cases. The fusions show growth-promoting properties that suggest that they may represent targetable events in a subset of people with breast cancer.

Although maturation of dendritic cells can drive autoimmune responses in mice, it remains unclear whether intrinsic factors hold dendritic cells in a resting state. Pamela Ohashi and her colleagues identify a repressive mechanism requiring expression of nuclear factor-κB1 in dendritic cells. Loss of nuclear factor-κB1 results in CD8⁺ T cell activation, TNF-α production and autoimmune diabetes in mice.

Raf kinase activity is deregulated in cancers and is thought to promote tumor growth by inducing proliferation signaling through MEK/Erk. This report identifies a new role for c-Raf independent of MEK/Erk and relying on phosphorylation of Ser338. Phospho–C-Raf interacts with the mitotic kinases Aurora-A and Plk1, activating the latter to promote mitotic progression and increase cell division, and this pathway is a crucial mediator for the protumorigenic effect of c-Raf in vivo.

b-AP15 is a novel inhibitor of proteasome activity, with a different mechanism of action than the available and widely used proteasome inhibitors such as bortezomib. b-AP15 inhibits the deubiquitinating activity of the regulatory subunit of the proteasome, necessary for protein degradation, and induces cytotoxicity impairing tumor growth in mouse models. The compound may represent an alternative therapeutic approach with a broader spectrum of applicability than current proteasome inhibitors.

Osteoarthritis, the breakdown of cartilage in synovial joints, has long been viewed as the result of 'wear and tear', but this report shows that dysregulation of the complement system has an active role in the pathogenesis of this disease.

Ovarian tumors preferentially metastasize to the omentum, a peritoneal fat layer. This report proposes that the reasons for this predilection stem from the growth advantage conferred by adipocytes on ovarian cancer cells. Adipocytes seem to promote homing of cancer cells through adipokine secretion, and direct contact of the two cell types promotes metabolic changes that result in lipid transfer from adipocytes to tumor cells. Environmental-driven metabolic adaptations could be exploited to target omental metastasis.

Jan Brosens and his colleagues have found that deregulation of a single kinase—SGK1, a kinase involved in fluid balance—in two distinct cellular compartments of the endometrium is linked to two different forms of reproductive failure in humans. Using gain- and loss-of-function approaches in mice, the group confirmed the importance of these expression changes in such pathologies.

The authors find that cell-intrinsic activation of Hedgehog signaling without genetic alterations is a contributing feature to the progression and chemotherapy resistance of small-cell lung carcinoma, and that Hedgehog inhibition can prevent lung cancer growth and recurrence.

Calcineurin inhibitors, such as tacrolimus, are widely used immunosuppressive agents, but they can cause hypertension. In studies of tacrolimus-treated mice, the authors show that hypertension is due to activation of the sodium chloride transporter NCC in the kidney, causing sodium retention. They found that NCC activation also occurred in kidney transplant recipients receiving tacrolimus. The authors suggest that thiazide diuretics, which are NCC inhibitors, might counteract the hypertensive effects of this class of immunosuppressants.

Loss of mismatch repair (MMR) genes is associated with poor cancer prognosis and has been reported to occur through genetic alterations that directly affect the expression of MMR genes such as MSH2. This report identifies a subset of leukemia patients with reduced levels of MSH2 protein but without alterations in the MSH2 gene, and it identifies concurrent deletions in regulators of MSH2 stability as potential contributors to the MSH2 deficiency and associated drug resistance in this and other cancers.

Staphylococcus aureus produces pore-forming toxins, such as α-hemolysin, that damage epithelial cell layers, causing disease. In this issue, Inoshima et al. report that the cellular receptor for α-hemolysin—the metalloprotease ADAM10—is essential for lethal pneumonia caused by S. aureus infection in mice. The authors suggest that the combined effect of α-hemolysin on pore formation and in activating ADAM10 cleavage of the adherens junction protein E-cadherin disrupts the barrier function of the lung epithelium.

Tamas Horvath and his colleagues show that in states of obesity activation of the transcription factor PPAR-γ in POMC neurons occurs, resulting in an increase in peroxisome proliferation. This cellular event leads to reduced ROS levels in these cells, decreased neuronal firing and increased food intake. They also show that central pharmacological inhibition of PPAR-γ reverses these effects, suggesting a possible way to combat obesity.

Vaccines that protect nonhuman primates from lethal Ebola virus infection have been developed, but their protective mechanisms have not been clearly delineated. Nancy Sullivan et al. now report that the protective efficacy of a recombinant Ad5-based Ebola virus vaccine relies primarily on CD8⁺ T cells rather than on antibodies. The findings suggest that clinical development of T cell–based vaccines against Ebola virus is warranted.