Microrna-455 in cartilage and skeletal development

microRNAs (miRNAs) are a family of short endogenous non-coding RNAs with a sequence length of 19 to 23 nucleotides, functioning as post-transcriptional regulators of gene expression. During skeletal development, several miRNAs have been identified as important regulators of osteochondral genes. For example, miR-455 is located in an intron of the COL27A1 gene and has been implicated in cartilage physiology and pathology. The aim of this research was to define a role for miR-455-3p in cartilage and skeletal development, identifying regulatory function and novel mRNA targets. The expression of miR-455-3p increases during chondrogenesis, and overexpression of miR-455-3p prior to differentiation results in a downregulation of chondrogenic marker genes. This suggests that although miR-455-3p is required during chondrogenesis, an upregulation of miR-455-3p results in a dysregulation of the differentiation process. Analysis of RNA-seq data from miR-455 null mouse articular cartilage and SW1353 cells inhibiting miR-455-3p supports this finding, demonstrating that differentially expressed genes in response to reduced miR-455 expression were associated with skeletal system development. Overexpression of miR-455-3p in the developing chick limb bud also inhibits limb development. Microinjection of miR-455-3p into the limb bud of chick embryos resulted in a smaller limb bud size and delayed development phenotype. RNA-seq data revealed that differentially expressed genes were involved in mitochondrial dysfunction and a disruption to the cell cycle. The majority of these genes are not miR-455-3p predicted targets, however, they have a common promotor sequence for CREB1 suggesting regulation by the transcription factor. In the chick limb bud, CREB1 is downregulated by miR-455-3p and further analysis identified CREB1 as a direct target of miR-455-3p. To conclude, this research indicates that miR-455-3p has a role in chondrogenesis, regulating the expression of CREB1, and possibly influencing chondrocyte proliferation. Within skeletal development, the impact of miR-455-3p demonstrates a significant regulatory mechanism to explore further

The function of microRNAs in cartilage and osteoarthritis

MicroRNAs are small double-stranded RNAs, which negatively regulate gene expression and have been shown to have key roles in both chondrocyte development and cartilage homeostasis with age. Deletion of all microRNAs in chondrocytes leads to skeletal growth defects in mice, whilst deletion of specific mi croRNAs, e.g. miR-140, leads to premature articular cartilage degradation and increased susceptibility to posttraumatic osteoarthritis. Studies comparing microRNA expression in normal human articular cartilage compared to osteoarthritic cartilage show differential expression, but varying sample groups make interpretation difficult. MicroRNAs have been proposed as circulating biomarkers of osteoarthritis, but again, this differs amongst patient cohorts. Many micro- RNAs have been shown to have roles in chondrocyte phenotype via signaling pathways, apoptosis, autophagy and senescence. Modulating microRNAs in the joint has been shown to reduce osteoarthritis in animal models and translating this to man as a novel therapeutic strategy will be key

Psychedelics Promote Structural and Functional Neural Plasticity.

Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders

Psychedelics Promote Structural and Functional Neural Plasticity.

Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders

Psychedelics Promote Structural and Functional Neural Plasticity.

Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders