LSJL alters Wif-1 expression. On the pathway diagram WIF-1 is highlighted and since WIF-1 is the only protein associated with that node. LSJL likely alters WIF-1 in some fashion. LSJL also alters either SFRP1, 2, 4, or 5.
Wif-1 is expressed at cartilage-mesenchyme interfaces and impedes Wnt3a-mediated inhibition of chondrogenesis.
"Wnt factors are involved in the regulation of all steps of cartilage development. The activity of Wnt factors is generally regulated at the extracellular level by factors like the Dkk family, sFRPs, Cerberus and Wnt inhibitory factor 1 (Wif-1). Wif-1 is highly expressed at cartilage-mesenchyme interfaces of the early developing skeleton. In fetal and postnatal skeletal development, Wif-1 is expressed in a sharply restricted zone in the upper hyaline layer of epiphyseal and articular cartilage and in trabecular bone. Wif-1 [has specific binding] to Wnt3a, Wnt4, Wnt5a, Wnt7a, Wnt9a and Wnt11. Wif-1 [blocks] Wnt3a-mediated activation of the canonical Wnt signalling pathway. Wif-1 impaired growth of mesenchymal precursor cells and neutralised Wnt3a-mediated inhibition of chondrogenesis in micromass cultures of embryonic chick limb-bud cells."
So we may want to counteract Wif-1 if it is upregulated by LSJL. LSJL upregulates Wnt2 expression.
"Wnt3a and Wnt7a are expressed in nonchondrogenic limb tissue and, similarly to Wnt1, prevent chondrogenesis in micromass culture "
"Wnt5a and Wnt5b support formation of cartilage nodules in micromass cultures"<-LSJL upregulates Fzd2 and Fzd3 which can serve as frizzled receptors.
"Secreted antagonists of Wnt signalling, such as Dkk1 and sFRP1, have been identified as important factors that control the activity of Wnt proteins in skeletal development"<-LSJL alters Dkk expression.
"Dkk1-deficient mice exhibit abnormalities in skeletal development such as duplication and fusion of limb digits"
"Targeted mutation of the gene encoding secreted frizzled-related protein 1 (Sfrp1) in the mouse leads to a rather mild skeletal phenotype characterised by enhanced endochondral ossification. Chondrogenesis of murine embryonic fibroblasts isolated from Sfrp1-deficient mice is also accelerated"<-so Sfrp1 may be a way to grow taller.
"Wif-1 expression in the mesenchyme surrounding cartilage elements forming in the limb during early embryogenesis"
"WIF1 [is] a gene that was strongly downregulated in chondrocytes after their retinoic acid-induced dedifferentiation."
"Wif1 mRNA was absent from the growth plate"<-maybe Wif1 is a senescence related mechanism and restoring Wif1 can inhibit growth plate senescence.
The Wnt antagonist Wif-1 interacts with CTGF and inhibits CTGF activity.
"Wnt inhibitory factor 1 (Wif-1) is a secreted antagonist of Wnt signalling. [Wif-1] is expressed predominantly in superficial layers of epiphyseal cartilage but also in bone and tendon. Wif-1 is capable of binding to several cartilage-related Wnt ligands and interferes with Wnt3a-dependent Wnt signalling in chondrogenic cells. Wif-1 physically binds to connective tissue growth factor (CTGF/CCN2) in vitro, predominantly by interaction with the C-terminal cysteine knot domain of CTGF. In vivo such an interaction appears also likely since the expression patterns of these two secreted proteins overlap in peripheral zones of epiphyseal cartilage. In chondrocytes CTGF has been shown to induce the expression of cartilage matrix genes such as aggrecan (Acan) and collagen2a1 (Col2a1). Wif-1 is capable to interfere with CTGF-dependent induction of Acan and Col2a1 gene expression in primary murine chondrocytes. CTGF does not interfere with Wif-1-dependent inhibition of Wnt signalling."
" Wif-1 is predominantly expressed in the peripheral chondrocyte layers of epiphyseal and articular cartilage. It is capable to interfere with Wnt3a-mediated signalling in chondrogenic cells; for example, it releases Wnt3a-dependent blockade of chondrogenesis"<-But target deletion of Wif-1 does not cause modultion of skeletal phenotypes.
"CTGF [enhances] expression of aggrecan (Acan) mRNA in chondrocytes"
"CTGF expression in peripheral layers of epiphyseal and articular cartilage may play a role in stabilising the cartilage surface."
"CTGF does not affect canonical Wnt signalling in HEK293T cells or 4C3 chondrocytes."
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