Amyotrophic lateral sclerosis (ALS) is an incurable degenerative disorder of motoneurons. We recently reported that reduced expression of Vegfa causes ALS-like motoneuron degeneration in Vegfa(delta/delta) mice. In a meta-analysis of over 900 individuals from Sweden and over 1,000 individuals from Belgium and England, we now report that subjects homozygous with respect to the haplotypes -2,578A/-1,154A/-634G or -2,578A/-1,154G/-634G in the VEGF promoter/leader sequence had a 1.8 times greater risk of ALS (P = 0.00004). These 'at-risk' haplotypes lowered circulating VEGF levels in vivo and reduced VEGF gene transcription, IRES-mediated VEGF expression and translation of a novel large-VEGF isoform (L-VEGF) in vivo. Moreover, SOD1(G93A) mice crossbred with Vegfa(delta/delta) mice died earlier due to more severe motoneuron degeneration. Vegfa(delta/delta) mice were unusually susceptible to persistent paralysis after spinal cord ischemia, and treatment with Vegfa protected mice against ischemic motoneuron death. These findings indicate that VEGF is a modifier of motoneuron degeneration in human ALS and unveil a therapeutic potential of Vegfa for stressed motoneurons in mice.

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Vascular endothelial growth factor (VEGF), a major mediator of vascular permeability and angiogenesis, may play a pivotal role in mediating the development and progression of diabetic retinopathy. In the present study, we examined the genetic variations of the VEGF gene to assess its possible relation to diabetic retinopathy in type 2 diabetic patients. Among seven common polymorphisms in the promoter region, 5-untranslated region (UTR) and 3UTR of the VEGF gene, genotype distribution of the C(؊634)G polymorphism differed significantly (P ‫؍‬ 0.011) between patients with (n ‫؍‬ 150) and without (n ‫؍‬ 118) retinopathy, and the C allele was significantly increased in patients with retinopathy compared with those without retinopathy (P ‫؍‬ 0.0037). The odds ratio (OR) for the CC genotype of C(؊634)G to the GG genotype was 3.20 (95% CI 1.45-7.05, P ‫؍‬ 0.0046). The ؊634C allele was significantly increased in patients with nonproliferative diabetic retinopathy (non-PDR) (P ‫؍‬ 0.0026) and was insignificantly increased in patients with proliferative diabetic retinopathy (PDR) (P ‫؍‬ 0.081) compared with patients without retinopathy, although frequencies of the allele did not differ significantly between the non-PDR and PDR groups. Logistic regression analysis revealed that the C(؊634)G polymorphism was strongly associated with an increased risk of retinopathy (P ‫؍‬ 0.0018). Furthermore, VEGF serum levels were significantly higher in healthy subjects with the CC genotype of the C(؊634)G polymorphism than in those with the other genotypes. These data suggest that the C(؊634)G polymorphism in the 5UTR of the VEGF gene is a novel genetic risk factor for diabetic retinopathy.

The receptor activator of NF-B ligand (RANKL) induces various osteoclast-specific marker genes during osteoclast differentiation mediated by mitogen-activated protein (MAP) kinase cascades. However, the results of transcriptional programming of an osteoclastspecific cathepsin K gene are inconclusive. Here we report the regulatory mechanisms of RANKL-induced cathepsin K gene expression during osteoclastogenesis in a p38 MAP kinase-dependent manner. The reporter gene analysis with sequential 5-deletion constructs of the cathepsin K gene promoter indicates that limited sets of the transcription factors such as NFATc1, PU.1, and microphthalmia transcription factor indeed enhance synergistically the gene expression when overexpressed in RAW264 cells. In addition, the activation of p38 MAP kinase is required for the maximum enhancement of the gene expression. RANKL-induced NFATc1 forms a complex with PU.1 in nuclei of osteoclasts following the nuclear accumulation of NFATc1 phosphorylated by the activated p38 MAP kinase. These results suggest that the RANKL-induced cathepsin K gene expression is cooperatively regulated by the combination of the transcription factors and p38 MAP kinase in a gradual manner.

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