Monday, August 8, 2011


LSJL upregulates Dhh.

Comparative biological responses to human Sonic, Indian, and Desert hedgehog.

"We compared recombinant forms of the N-terminal domains of human Shh, Ihh, and Dhh in a variety of cell-based and tissue explant assays in which their activities could be assessed at a range of concentrations.  The proteins were similar in their affinities for the Hh-binding proteins; Patched (Ptc) and Hedgehog-interacting protein (Hip) {upregulated by LSJL}."

"Ihh has been implicated in modulating chondrogenesis in the appendicular skeleton, and acts as a negative regulator of the differentiation of proliferating chondrocytes"

"The transmembrane protein Patched (Ptc) is required for cellular responsiveness to Hh, and is highly expressed in all cells known to be actively responding to any of the vertebrate Hh proteins. Ptc is a receptor for the Hh protein. In the absence of Hh, Ptc represses the signaling activity of a second transmembrane protein Smoothened (Smo) {up} by indirectly destabilizing Smo. Hh binding to Ptc causes Ptc to be removed from the cell surface, directing it to a distinct subcellular compartment and thereby relieving the repression of Smo signaling. Ptc itself is an important transcriptional target of Hh signaling, activated downstream of Smo. Because of its ability to bind to Hh, the high levels of Ptc induced by Hh have the effect of acting as a sink, binding additional Hh molecules and thus limiting the range of Hh action"

"we also evaluated the ability of the Hh proteins to induce gli-1, ptc, ptc-2, and hip mRNA using RT-PCR assays in C3H10T1/2 cells. Shh, Ihh, and Dhh had the same dose responses for each gene, with Shh being more potent than Ihh with Dhh the weakest."<-none of these three proteins was upregulated in LSJL above threshold.

"Dhh was unable to fully suppress Collagen X expression at any of the protein concentrations tested"<-col10 was upregulated by LSJL which is consistent with this.

"the three Hh proteins have the potential to function similarly"<-Thus LSJL's upregulation of Dhh could substitute for Ihh.

Characterization of two new zebrafish members of the hedgehog family: atypical expression of a zebrafish indian hedgehog gene in skeletal elements of both endochondral and dermal origins.

"We have characterized two new members of the Hedgehog (Hh) family in zebrafish, ihha and dhh, encoding for orthologues of the tetrapod Indian Hedgehog (Ihh) and Desert Hedgehog (Dhh) genes, respectively. Comparison of ihha and Type X collagen (col10a1) expression during skeletal development show that ihha transcripts are located in hypertrophic chondrocytes of cartilaginous elements of the craniofacial and fin endoskeleton. Surprisingly, col10a1 expression was also detected in cells forming intramembranous bones of the head and in flat cells surrounding cartilaginous structures. The expression of col10a1 in both endochondral and intramembranous bones reflects an atypical composition of the extracellular matrix of the zebrafish craniofacial skeleton. In addition, during fin ray regeneration, both ihha and col10a1 are detected in scleroblasts, osteoblast-like cells secreting the matrix of the dermal bone fin ray. The presence of cartilage markers suggests that the dermal fin ray possesses an intermediate phenotype between cartilage and bone{Can we induce this phenotype to increase height?}."

"Overexpression of Ihh causes the formation of shorter and thicker bone due to an inhibition of chondrocyte differentiation whereas mouse null mutants present a reduced chondrocyte proliferation and absence of differentiated osteoblasts"

"PTHrP knock-out mice exhibit skeletal defects induced by an early maturation of chondrocytes leading to premature ossification"

"ihha-expressing cells possess the typical morphology of hypertrophic chondrocytes, since they are much larger than the neighboring cells and are surrounded by a thick acellular material consistent with active extracellular matrix secretion. We did not detect expression of ihha in forming intramembranous bones of the craniofacial region, which is consistent with previous studies that showed that intramembranous bones do form in ihh−/− mouse, although their growth is impaired by the mutation "

"Chondrogenic features appear in intramembranous bones that necessitate a rapid growth such as secondary cartilage, chondroid bone, and fracture healing"<-if chondrogenic features can appear intramembraneous bones than the can definately appear in adult cortical and trabecular bone.

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