Monday, October 12, 2009


Erbb3 is upregulated by LSJL.

Requirement for ErbB2/ErbB signaling in developing cartilage and bone.

"Signaling by the ErbB network generates a diverse array of cellular responses via formation of ErbB dimers activated by distinct ligands that produce distinct signal outputs. Herstatin is a soluble ErbB2 receptor that acts in a dominant negative fashion to inhibit ErbB signaling by binding to endogenous ErbB receptors, preventing functional dimer formation. Here, we examine the effects of Herstatin on limb skeletal element development in transgenic mice, achieved via Prx1 promoter-driven expression in limb cartilage and bone. The limb skeletal elements of Prx1-Herstatin embryos are shortened, and chondrocyte maturation and osteoblast differentiation are delayed. In addition, proliferation by chondrocytes and periosteal cells of Prx1-Herstatin limb skeletal elements is markedly reduced."

"Only ErbB1 and ErbB4 can form functional ligand-activated homodimers, as ErbB3 is kinase-inactive, and ErbB2 lacks a soluble ligand and a ligand binding pocket revealed by the crystal structure of its ectodomain"

"Herstatin blocks tyrosine phosphorylation and activation of ErbB2, ErbB1 and ErbB3 and suppresses expression of ErbB4"

"By day 18.5, the lengths of the limb skeletal elements of Prx1-Herstatin embryos were comparable to littermate wild type controls, indicating that the effects of Herstatin were overcome with time."<-So Erbb inhibition via herstatin may only slow growth rate rather than adult height.

"endogenous ErbB2 is expressed by immature and maturing chondrocytes as well as periosteal bone of developing mouse skeletal elements."

"the functional ErbB requirement blocked by Herstatin expression during endochondral ossification is compensated for over time"

The EGFR network in bone biology and pathology.

"the epidermal growth factor receptor (EGFR) system plays important roles in skeletal biology and pathology. This network, including a family of seven growth factors - the EGFR ligands - and the related tyrosine kinase receptors EGFR (ERBB1){up in LSJL}, ERBB2, ERBB3 and ERBB4, regulates aspects such as proliferation and differentiation of osteoblasts, chondrocytes and osteoclasts, parathyroid hormone-mediated bone formation and cancer metastases in bone."

Egfr knockout results in impaired endochondral ossification.  EGF overexpression results in height loss.  BTC{up in LSJL over 3 fold} overexpression reduces height.

"EGF was shown to be one of the factors required for bone marrow stromal fibroblast colony formation"

"EGF increases IGFI-R expression in growth plate chondrocytes, enhancing IGF-I-stimulated mitotic activity and proteoglycan synthesis; furthermore, systemic treatment of rats and minipigs with EGF reduced circulating levels of IGF-I and modulated the levels of various IGF-binding proteins"

High cortical bone mass phenotype in betacellulin transgenic mice is EGFR dependent.

"Signaling through the epidermal growth factor receptor (EGFR) by ligands such as epidermal growth factor (EGF), transforming growth factor alpha (TGFA), [BTC], and amphiregulin (AREG) has been reported to have effects on skeletal growth. transgenic mice overexpressing BTC ubiquitously under the control of the chicken beta-actin promoter (BTC-tg) exhibited stunted growth and disproportionately sized long bones. In this study, we performed a detailed phenotypic analysis of BTC-tg mice at 3, 6, and 9 wk of age. Osteoblastic cells from transgenic mice showed strong expression of BTC as determined by Western blots and by immunohistochemistry on bone sections. In femurs of male and female BTC-tg mice, we found reduced longitudinal bone growth and a pronounced increase in total volumetric BMD. The increased femoral BMD was mainly caused by augmented endocortical bone apposition and subsequent cortical bone thickening. In contrast, vertebral BMD was reduced in BTC-tg mice of both sexes. An overall similar phenotype was found in 6-mo-old BTC-tg mice. The increase in cortical bone mass in the appendicular skeleton of BTC-tg mice was largely blocked when they were crossed into the Egfr (Wa5) background characterized by a dominant negative EGFR."

"Btc expression was increased ∼1000-fold{much more than 3} in bones from BTC-tg mice. It was reported previously that overexpression of individual EGF ligands can upregulate the expression of other EGF ligands. However, the only statistically significant change in mRNA abundance of EGF ligands in bones from BTC-tg relative to WT mice was a 33% reduction in Egf transcripts"

"nonsignificant trends toward increased expression of Ereg and downregulated expression of Tgfa mRNAs [occurred] in BTC-tg mice"

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