DDR2

LSJL downregulates DDR2 by 0.382 fold.

Discoidin Domain Receptor 2 (DDR2) regulates proliferation of endochondral cells in mice.

"Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase. DDR2 regulates cell proliferation, cell adhesion, migration, and extracellular matrix remodeling. The decrement of endogenous DDR2 represses osteoblastic marker gene expression and osteogenic differentiation in murine preosteoblastic cells. We inhibited Ddr2 expression via the inhibitory effect of miRNA on Ddr2 mRNA (miDdr2) and analyzed the cellular proliferation and differentiation in the prechondrocyte ATDC5 cell lines. To investigate DDR2's molecular role in endochondral cellular proliferation in vivo, we also produced transgenic mice in which the expression of truncated, kinase dead (KD) DDR2 protein is induced, and evaluated the DDR2 function in cellular proliferation in chondrocytes. Although the miDdr2-transfected ATDC5 cell lines retained normal differentiation ability, DDR2 reduction finally promoted cellular proliferation in proportion to the decreasing ratio of Ddr2 expression[Since LSJL downregulates DDR2 it's also likely that LSJL promotes cellular proliferation which was observed], and it also promoted earlier differentiation to cartilage cells by insulin induction. The layer of hypertrophic chondrocytes in KD Ddr2 transgenic mice was not significantly thicker than that of normal littermates, but the layer of proliferative chondrocytes in KD-Ddr2 transgenic mice was significantly thicker than that of normal littermates[This was confirmed in the lengthening of mouse hindlimbs with joint loading study]."

"DDR2 binds to and is activated by collagen I, II, III, V, and X{all upregulated by LSJL}, with the notable exception of basement membrane collagen IV"

"a recessive, loss-of-function allele for Ddr2 (designated Ddr2slie/slie) that causes dwarfism and infertility. DDR2 null allele mice exhibit dwarfing with a shortening of the long bones and a reduction in body weight, which caused by a reduced proliferation rate of chondrocytes"

"We compared the time course of cell proliferation determined by the growth curve for 4 d in transfected ATDC5 cells, and found significantly greater numbers of miDdr2-transfected[Knock Down] cells than mock cells"

"the relative ratio of miDdr2cell lines to mock cells decreased in Runx2 as the ratio of Ddr2 suppression decreased"

"the decrease in DDR2 leads to cellular proliferation due to the direct signal reduction of DDR2, not to the loss of function of endochondralcells in miDdr2-transfected ATDC5 cells."

"DDR2 activates Runx2 through p38 MAPK to promote osteoblast differentiation"

"reduced expression of DDR2 may lead to the subsequent downregulation of Runx2 in miDdr2-transfected ATDC5 cells in proportion to the expression reduction level of Ddr2."

"the reduction of DDR2 expression is systemic in Ddr2 knockout mice and spontaneous mutant mice, and dwarfism also can be provoked by reasons other than only the decrease in the ability of chondrocyte cellular proliferation."<-in LSJL the reduction in DDR2 is specific to the tissues of the bone.  DDR2 deletion affects the pituitary gland and that may be where DDR2 knockout reduces height.

"Body size and skeleton length of KD-Ddr2 overexpressed mice were not significantly different compared with the littermates. On the other hand, the layer of hypertrophic chondrocytes in KD-Ddr2 transgenic mice was not significantly thicker than that of normal littermates, but the layer of proliferative chondrocytes in KD-Ddr2 transgenic mice was significantly thicker than that of normal littermates."