Monday, July 4, 2011

height by inhibiting asporin?

LSJL upregulates asporin by 3 fold.

Mechanisms for asporin function and regulation in articular cartilage.

"Asporin binds to transforming growth factor-beta (TGF-beta) and inhibits TGF-beta-induced chondrogenesis.  Asporin blocks chondrogenesis and inhibits TGF-beta1-induced expression of matrix genes and the resulting chondrocyte phenotypes. Small interfering RNA-mediated knockdown of asporin increases the expression of cartilage marker genes and TGF-beta1; in turn, TGF-beta1 stimulates asporin expression in articular cartilage cells, suggesting that asporin and TGF-beta1 form a regulatory feedback loop{So asporin upregulation in LSJL is also a sign of TGF-Beta signaling}. Asporin inhibits TGF-beta/Smad signaling upstream of TGF-beta type I receptor activation in vivo by co-localizing with TGF-beta1 on the cell surface and blocking its interaction with the TGF-beta type II receptor."

"Knockdown of asporin significantly increased type II collagen and aggrecan mRNA expression"

"Decorin inhibits TGF-β function"

"Decorin blocks interaction of TGF-β with its cell-surface receptor(s)"

"Decorin inhibits TGF-β-induced expression of plasminogen activator inhibitor-1 via activation of the Ca2+/calmodulin-dependent protein kinase II, which results in phosphorylation of Smad2 at Ser204, an important negative regulatory site."

"Asporin co-localizes with TGF-β in the human articular cartilage extracellular space, inhibiting TGF-β signaling upstream of TβRI"

"Asporin inhibits TGF-β1 binding to TβRII"

"A serum glycoprotein, fetuin, also inhibits TGF-β activity by competing with TGF-β for binding to TβRII"

"[Asporin is a] class I small leucine-rich proteoglycan (SLRP) in human articular chondrocytes.  Interleukin-1β and tumor necrosis factor-α downregulated ASPN, whereas transforming growth factor-β1 (when incubated in a serum-free medium) upregulated it. Similarly to proinflammatory cytokines, chondrocyte dedifferentiation induced by a successive passages of cells was accompanied by a decreased asporin expression, whereas their redifferentiation by three-dimensional culture restored its expression. The transcription factor Sp1 [regulates] ASPN expression. Sp1 ectopic expression increased ASPN mRNA level and promoter activity[thus we want to reduce Sp1]. Sp1 mediated [ASPN's] effect through a region located between -473 and -140 bp upstream of the transcription start site in ASPN gene."

"Asporin [is] also called periodontal ligament–associated protein-1 (PLAP-1)"

"GFβ exerts its positive effect on ASPN only when cells are cultured in the absence or with very weak levels of FCS"

"ASPN is the indirect target of Smad3, and hence, its expression could be influenced by GADD45, a factor that upregulates biglycan upon TGFβ treatment and is a target gene of Smad3"

"ASPN mRNA [is present] in the perichondrium/periosteum of long bones{thus periosteal stimulation may affect height growth and ability to form new growth plates with TGF-Beta}, but [is absent] in articular cartilage and growth plates. ASPN protein expression [is predominantly] in the perichondrium/periosteum. TGF-beta1 induced endogenous ASPN mRNA expression over time in vitro, and this induction was suppressed by the TGF-beta type I receptor kinase inhibitor SB431542. Inhibition of Smad3 significantly reduced TGF-beta1-induced ASPN expression, whereas overexpression of Smad3 augmented the induction. Characterization of the human ASPN promoter region revealed a region from -126 to -82 that is sufficient for full promoter activity; however, TGF-beta1 failed to increase activity through the ASPN promoter."

"TGF-β1 induces ASPN expression through ALK5 activity (TGF-β type I receptor)"

According to Systems analysis of matrix metalloproteinase mRNA expression in skeletal tissues., "[elements with a] stimulatory role [are] cis-acting elements such as AP1, NFY, PEA3, and Sp1 [whereas AP2 has an inhibitory role]".  But they are stimulatory on transcription not necessarily on chondrogenesis.

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