Wednesday, February 18, 2009


TAK1 regulates LMP1 regulation by TGF-Beta.  TAK1 activates MKK3/6.

TAK1 regulates cartilage and joint development via the MAPK and BMP signaling pathways.

"TGF-beta activated kinase 1 (TAK1) is a MAP3K activated by TGF-beta, BMP, and other mitogen-activated protein kinase (MAPK) signaling components. [We delete] Tak1 in chondrocytes (Col2Cre;Tak1(f/f)) and the developing limb mesenchyme (Prx1Cre;Tak1(f/f)). Deletion of Tak1 in chondrocytes resulted in novel embryonic developmental cartilage defects including decreased chondrocyte proliferation, reduced proliferating chondrocyte survival, delayed onset of hypertrophy, reduced Mmp13 expression, and a failure to maintain interzone cells of the elbow joint, which were not observed previously in another Col2Cre;Tak1(f/f) model. Deletion of Tak1 in limb mesenchyme resulted in widespread joint fusions likely owing to the differentiation of interzone cells to the chondrocyte lineage. Loss of Tak1 results in impaired activation of the downstream MAPK target p38, as well as diminished activation of the BMP/SMAD signaling pathway."

"Mouse models lacking the TGF-β type II receptor in chondrocytes (Col2Cre;Tgfbr2f/f) exhibit defects in the postnatal regulation of chondrocyte maturation primarily within the axial skeleton. Deletion of Tgfbr2 in early limb mesenchyme (Prx1Cre;Tgfbr2f/f) resulted in delayed cartilage formation, reduced chondrocyte proliferation, and malformation of joints within the digits."

"Mice lacking BMP receptors 1a and 1b within cartilage (Col2Cre;Bmpr1af/f, Bmpr1b+/−, and Col2Cre;Bmpr1a f/f;Bmpr1b−/−) or lacking canonical BMP targets Smads 1 and 5 within cartilage (Col2Cre;Smad1f/f;Smad5f/f) have reduced chondrocyte proliferation, delayed onset of chondrocyte maturation, reduced proliferating chondrocyte survival, and delayed progression of terminal maturation. Conditional deletion of the BMP ligands, BMP-2 and BMP-4, using the Prx1Cre transgene (Prx1Cre;Bmp2f/f;Bmp4f/f) resulted in shorter and thinner limbs, delayed differentiation and marrow cavity formation, disorganized clearance of hypertrophic chondrocytes, joint fusion of the stylopod and zeugopod elements with little effect on the autopod, and incomplete bone formation. Conventional deletion of another BMP family member, Gdf5, also demonstrated effects on the limb skeleton, resulting in decreased limb length and various joint fusions/abnormalities."

" transgenic mice overexpressing constitutively active MKK6 in chondrocytes are dwarfed, have decreased chondrocyte proliferation, delayed onset of hypertrophic differentiation during embryonic development, and a shortened zone of hypertrophic chondrocytes."

"Treatment of sternal chondrocytes with TAK1 inhibitor TI-2 (LLZ1640-2, 3 µM) resulted in decreased Smad 1/5/8 and p38 phosphorylation"

"loss of Tak1 via Cre-mediated deletion decreased BMP-2-induced phosphorylation of Smads 1/5/8"

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