Bone diseases such as otosclerosis (conductive hearing loss) and osteoporosis (low bone mineral density) can result from the abnormal expression of genes that regulate cartilage and bone development. The forkhead box transcription factor FOXL1 has been identified as the causative gene in a family with autosomal dominant otosclerosis and has been reported as a candidate gene in GWAS meta-analyses for osteoporosis. This potentially indicates a novel role for foxl1 in chondrogenesis, osteogenesis, and bone remodelling. We created a foxl1 mutant zebrafish strain as a model for otosclerosis and osteoporosis and examined jaw bones that are homologous to the mammalian middle ear bones, and mineralization of the axial skeleton. We demonstrate that foxl1 regulates the expression of collagen genes such as collagen type 1 alpha 1a and collagen type 11 alpha 2, and results in a delay in jawbone mineralization, while the axial skeleton remains unchanged. foxl1 may also act with other forkhead genes such as foxc1a, as loss of foxl1 in a foxc1a mutant background increases the severity of jaw calcification phenotypes when compared to each mutant alone. Our zebrafish model demonstrates atypical cartilage formation and mineralization in the zebrafish craniofacial skeleton in foxl1 mutants and demonstrates that aberrant collagen expression may underlie the development of otosclerosis.
Background: Cannabis has demonstrated anticonvulsant properties, and cannabis-based medicines are approved to treat pediatric patients with severe pediatric epilepsies that are particularly refractive to approved anti-epileptic drugs (AEDs). About thirty percent of epileptic patients do not have satisfactory seizure management with AEDs and could potentially benefit from cannabis-based intervention. Here we report the use of single and combined cannabinoids to treat Pentylenetetrazol (PTZ) induced convulsions in a zebrafish model, their effect on gene expression, and a simple assay for assessing their uptake in zebrafish tissues. These data provide novel insights as to the potential of treating epilepsy with cannabinoids. Methods: Zebrafish larvae were treated with cannabinoids and their seizures measured through an optimized behaviour tracking method. Cannabinoid uptake was measured with a novel HPLC-UV method. Gene expression changes were assessed using quantitative PCR (qPCR), and chemical inhibitors of potential cannabinoid receptors were used to block activity. Results: Treatment with cannabinol (CBN), cannabichromene (CBC) and cannabigerol (CBG) decreased seizure intensity at lower doses than CBD when accounting for the amount of cannabinoid recovered from exposed larvae. Δ9-tetrahydrocannabinol (Δ9-THC), Δ8-tetrahydrocannabinol (Δ8-THC) were effective at higher doses. Synergistic effects were observed between CBD and other cannabinoids such as Δ9-THC, Δ8-THC, and CBG. The reduction of PTZ induced seizures via CBD is partially mediated by the G-protein coupled receptor GPR55, as pharmacological inhibition of the receptor reduced the therapeutic action of CBD. Changes in expression of endocannabinoid system (napepld, gde1, faah, ptgs2a) and neural (fosab, pyya) genes in response to phytocannabinoid treatment were observed and highlight novel mechanisms of phytocannabinoid action. Conclusions: CBD can be combined with additional cannabinoids for optimal reduction of seizure activity and requires the activity of GPR55. Changes in fosab regulation of gene expression and endocannabinoid signalling may influence the anticonvulsant effects of cannabis, however further investigation is required.
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