Friday, January 9, 2009


LSJL downregulates Dicer1.

Dicer-dependent pathways regulate chondrocyte proliferation and differentiation.

"Dicer, an essential component for biogenesis of miRNAs, is essential for normal skeletal development. Dicer-null growth plates show a progressive reduction in the proliferating pool of chondrocytes, leading to severe skeletal growth defects and premature death of mice. The reduction of proliferating chondrocytes in Dicer-null growth plates is caused by two distinct mechanisms: decreased chondrocyte proliferation and accelerated differentiation into postmitotic hypertrophic chondrocytes. These defects appear to be caused by mechanisms downstream or independent of the Ihh-PTHrP signaling pathway, a pivotal signaling system that regulates chondrocyte proliferation and differentiation. Microarray analysis of Dicer-null chondrocytes showed limited expression changes in miRNA-target genes, suggesting that, in the majority of cases, chondrocytic miRNAs do not directly regulate target RNA abundance.Dicer-dependent pathway [regulates] chondrocyte proliferation and differentiation during skeletal development"

"primiRNAs are cleaved into small-hairpin premiRNAs by the microprocessor complex containing Drosha and DGCR8. premiRNAs are exported into the cytoplasm, where the RNase III, Dicer, removes the loop region of the hairpin."

Lack of dicer downregulates miR-30c and let-7b.

"At E18.5, the hypertrophic region, indicated by Col10a1 expression, was expanded, whereas the Mmp13 expression domain of the cartilage was not expanded in Col2-Cre:Dicerfl/fl mice. Because Mmp13 is expressed only by terminally differentiated hypertrophic chondrocytes in the growth plate, these observations suggest that the expansion of the hypertrophic region was caused by an acceleration of hypertrophic differentiation of proliferating chondrocytes rather than a reduction in cartilage resorption by bone cells, which would cause an increase in terminally differentiated hypertrophic chondrocytes. Expansion of the hypertrophic region can also occur as a consequence of stimulation of chondrocyte differentiation at earlier steps"

"We did find up-regulation of Hmga2 mRNA in Dicer-deficient chondrocytes."<-HMGA2 is upregulated by LSJL.  Tamoxifen inhibits dicer.  Dicer inhibition also upregulated COL10A1 and PTH-R.

Gene comparison of LSJL to gene info given in Table3 to be done.

Table4 provides a very interesting list of miRNA binding sites in chondrocytes.

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