Letters in 2009

Orexin, a neuropeptide best known for its role in arousal and its absence in people with narcolepsy, is also involved in the pathophysiology of panic anxiety disorder.

Deficiency of the transcription factor HNF-1β results in kidney cyst formation. Marco Pontoglio and his colleagues now show that HNF-1β normally remains bound to condensed chromatin during mitosis to facilitate the rapid expression of key genes involved in cell quiescence post-mitosis. In the absence of HNF-1β, these genes fail to express, and the kidney epithelial cells continue to proliferate, resulting in cysts.

Idiopathic pulmonary fibrosis, or lung scarring, is known, at least in part, to be driven by TGF-β signaling. Shuh Narumiya and colleagues now find that prostaglandin F_2α receptor also has a key role in this disease, independently of TGF-β signaling, and that its genetic deletion ameliorates disease progression in a mouse model.

In a new report, Benjamin Alman and his colleagues find that the morphogenic pathway activated by Hedgehog signaling is a key mediator of osteoarthritis, a condition that is marked by irreversible degeneration of the joints and with no current treatment. They also found that blockade of Hedgehog signaling prevented osteoarthritis in a mouse model, suggesting this pathway as a possible target to treat this devastating disease.

Viral gene expression can be regulated by chromatin methylation and demethylation. Thomas Kristie and his colleagues have identified a histone demethylase that is required to remove repressive methylation from the immediate early promoters of two α-herpesviruses. Monoamine oxidase inhibitors, which block this demethylase, prevented lytic replication and reactivation from latency.

Extracellular histones released in response to inflammatory challenge contribute to organ failure and death during sepsis. Histone-specific antibodies and activated protein C had beneficial effects in animal models of sepsis, pointing to extracellular histones as therapeutics targets for sepsis and other inflammatory conditions (pages 1245–1246).

Hepatic insulin resistance is often associated with mitochondrial dysfunction, leading to defects in cellular activity. Morris White and his colleagues have now found that continued activity of the transcription factor Foxo1, which is normally inhibited by insulin signaling, is at the crux of this dysfunction, and, when it is genetically deleted, proper mitochondrial function in two models of insulin resistance is restored.

A role for cell senescence and p53 in the development of insulin resistance (or prediabetes) has been obscure. Issei Komuro and colleagues now show that premature cell senescence occurs in the adipose tissue of obese mice and humans and that genetic deficiency of p53 is sufficient to prevent insulin resistance in mouse models of obesity, suggesting a new target to treat diabetes.

Dysregulation of osteoclasts, the cells that chew up bone, can lead to severe bone loss. Although many positive regulators of the differentiation of this cell type have been identified, few negative regulators have. Now, Masamichi Takami and colleagues have identified IRF-8 as an inhibitor of osteoclast formation and explore its role in disease.

These two studies show that primary cilia can either mediate or suppress tumorigenesis in models of basal cell carcinoma and medulloblastoma, respectively, depending on the nature of the initial oncogenic event (pages 994–996) and (pages 1055–1061).

The mechanisms that lead to idiopathic pulmonary fibrosis, or lung scarring, is not clear. Victor Thannickal and his colleagues have now provided further insight by showing that induction of NOX4, an enzyme that creates reactive oxygen species, is required for the progression of the disease. Their findings suggest NOX4 as a potential target to treat this common ailment that currently has no proven treatment options.

These two studies show that primary cilia can either mediate or suppress tumorigenesis in models of basal cell carcinoma and medulloblastoma, respectively, depending on the nature of the initial oncogenic event (pages 994–996) and (pages 1062–1065).

The degenerative joint disease osteoarthritis is known to involve the activation of the protease ADAMTS-5. Now, Frank Echtermeyer and his colleagues have shown that the transmembrane proteoglycan syndecan-4 is responsible for this activation. They also show that genetic deletion of syndecan-4, or inhibition with a blocking antibody, reduces disease progression in a mouse model.

Inflammatory cells invade the brain after stroke, but their role in disease has been unclear. Now, Akihiko Yoshimura and colleagues report that a particular population of T cells that express the inflammatory cytokine IL-17 plays a key role in stroke progression: depletion of these cells—even as late as 1 day after stroke—can alleviate brain injury in mice pages 844–846).

Mast cells, which are involved in inflammation and wound healing, have now been shown to have a role in obesity and diabetes in a new report by Guo-Ping Shi and his colleagues. They go on to show that pharmacological inhibition of mast cell function is sufficient to reduce these metabolic disturbances in mice, suggesting a new therapeutic avenue in the clinic for these disorders.

Women seem to progress to AIDS more rapidly than men after HIV-1 infection. Marcus Altfeld and his colleagues show that, after adjusting for viral load, HIV-1–infected women have higher levels of immune activation, and the authors provide a potential mechanism to account for this difference between the sexes.

Modulating the entry of inflammatory T cells into the brain could be one way to treat the autoimmune disease multiple sclerosis. Now, Frauke Zipp and colleagues demonstrate that activation of kinin receptor B1 can block autoimmune T cell migration into the brain and can therefore inhibit experimental autoimmune encephalomyelitis in mice.

Enterovirus 71 (EV71) causes hand, foot and mouth disease, a mild infectious disease that can, however, occasionally lead to severe neurological impairments. These two studies, by Nishimura et al. and Yamayoshi et al., independently identify two different receptors for EV71—P-selectin glycoprotein ligand-1 ((PSGL-1) and scavenger receptor class B, member 2 (SCARB2) (pages 728–729) and (pages 794–797).

Enterovirus 71 (EV71) causes hand, foot and mouth disease, a mild infectious disease that can, however, occasionally lead to severe neurological impairments. These two studies, by Nishimura et al. and Yamayoshi et al., independently identify two different receptors for EV71—P-selectin glycoprotein ligand-1 ((PSGL-1) and scavenger receptor class B, member 2 (SCARB2) (pages 728–729) and (pages 798–801).