Publications

Bone remodelling, the mechanism by which vertebrates regulate bone mass, comprises two phases, namely resorption by osteoclasts and formation by osteoblasts; osteoblasts are multifunctional cells also controlling osteoclast differentiation. Sympathetic signalling via beta2-adrenergic receptors (Adrb2) present on osteoblasts controls bone formation downstream of leptin. Here we show, by analysing Adrb2-deficient mice, that the sympathetic nervous system favours bone resorption by increasing expression in osteoblast progenitor cells of the osteoclast differentiation factor Rankl. This sympathetic function requires phosphorylation (by protein kinase A) of ATF4, a cell-specific CREB-related transcription factor essential for osteoblast differentiation and function. That bone resorption cannot increase in gonadectomized Adrb2-deficient mice highlights the biological importance of this regulation, but also contrasts sharply with the increase in bone resorption characterizing another hypogonadic mouse with low sympathetic tone, the ob/ob mouse. This discrepancy is explained, in part, by the fact that CART ('cocaine amphetamine regulated transcript'), a neuropeptide whose expression is controlled by leptin and nearly abolished in ob/ob mice, inhibits bone resorption by modulating Rankl expression. Our study establishes that leptin-regulated neural pathways control both aspects of bone remodelling, and demonstrates that integrity of sympathetic signalling is necessary for the increase in bone resorption caused by gonadal failure.

OBJECTIVES

To examine the relationship between patent foramen ovale (PFO) or atrial septal defect (ASD) with the incidence of migraine headache (MHA) and assess whether closure of the interatrial shunt in patients with MHA would result in improvement of MHA.

BACKGROUND

Migraine headache is present in 12% of adults and has been associated with interatrial communications. This study examined the relationship between PFO or ASD with the incidence of MHA and assessed whether closure of the interatrial shunt in patients with MHA would result in improvement of MHA.

METHODS

A sample of 89 (66 PFO/23 ASD) adult patients underwent transcatheter closure of an interatrial communication using the CardioSEAL (n = 22), Amplatzer PFO (n = 43), or the Amplatzer ASD (n = 24) device.

RESULTS

Before the procedure, MHA was present in 42% of patients (45% of patients with PFO and 30% of patients with ASD). At three months after the procedure, MHA disappeared completely in 75% of patients with MHA and aura and in 31% of patients with MHA without aura. Of the remaining patients, 40% had significant improvement (>or=2 grades by the Migraine Disability Assessment Questionnaire) of MHA.

CONCLUSIONS

Transcatheter closure of PFO or ASD results in complete resolution of MHA in 60% of patients (75% of patients with migraine and aura) and improvement in symptoms in 40% of the remaining patients. Interatrial communications may play a role in the etiology of MHA either through paradoxic embolism or humoral factors that escape degradation in bypassing the pulmonary circulation. A randomized trial is needed to determine whether transcatheter closure of interatrial shunts is an effective treatment for MHA.

Although the functions of granzyme A (GzmA) and GzmB are well-defined, a number of orphan granzymes of unknown function are also expressed in cytotoxic lymphocytes. Previously, we showed that a targeted loss-of-function mutation for GzmB was associated with reduced expression of several downstream orphan granzyme genes in the lymphokine-activated killer cell compartment. To determine whether this was caused by the retained phosphoglycerate kinase I gene promoter (PGK-neo) cassette in the GzmB gene, we retargeted the GzmB gene with a LoxP-flanked PGK-neo cassette, then removed the cassette in embryonic stem cells by transiently expressing Cre recombinase. Mice homozygous for the GzmB null mutation containing the PGK-neo cassette (GzmB-/-/+PGK-neo) displayed reduced expression of the closely linked GzmC and F genes in their MLR-derived CTLs and lymphokine-activated killer cells; removal of the PGK-neo cassette (GzmB-/-/DeltaPGK-neo) restored the expression of both genes. Cytotoxic lymphocytes derived from mice with the retained PGK-neo cassette (GzmB-/-/+PGK-neo) had a more severe cytotoxic defect than those deficient for GzmB only (GzmB-/-/DeltaPGK-neo). Similarly, GzmB-/-/+PGK-neo mice displayed a defect in the allogeneic clearance of P815 tumor cells, whereas GzmB-/-/DeltaPGK-neo mice did not. These results suggest that the retained PGK-neo cassette in the GzmB gene causes a knockdown of GzmC and F expression, and also suggest that these granzymes are relevant for the function of cytotoxic lymphocytes in vitro and in vivo.