Further analysis also showed the presence of binding sites for other transcrip tion factors linked to WNT signaling such as Oct 1, EP300, Gata and AP 1. Among the down regulated pathways and processes, effects on the cell cycle and partially overlapping p53 signaling were most striking. Down regulation of different cyclins and cyclin kinases as well selleckchem as many other positive regulators of the cell cycle suggest inhibi tion of mitosis and cell proliferation. Ribcage chondro cytes derived from Frzb mice proliferated significantly less than those derived from the wild type mice in vitro after one week, corroborating the effect of FRZB on chondrocyte proliferation. Discussion Our transcriptome analysis of the bone cartilage biome chanical unit of Frzb and wild type mice provides evi dence for tight regulation of WNT signaling, shifts in ECM component synthesis and alterations in cell prolif eration and differentiation.

Inhibitors,Modulators,Libraries FRZB is a secreted WNT antagonist, originally identified from a chondrogenic extract Inhibitors,Modulators,Libraries of bovine articular cartilage and misexpres sion of FRZB in the chick limb inhibits chondrocyte hypertrophy. Polymorphisms in the human FRZB gene have been associated with OA, although this link has been debated recently. Here, absence of Frzb in the articular cartilage and subchondral bone induces a subtle increase in WNT sig naling evident by up regulation of several WNT target genes as demonstrated by pathway analysis and by com parison with a user compiled list of WNT target genes.

Absence of Frzb also results in the up regulation of other SFRP family members and different WNT modu Inhibitors,Modulators,Libraries lators, suggesting that compensatory mechanisms exist in order to tightly control WNT signaling in these tis sues. We previously demonstrated that Frzb mice show increased articular cartilage damage in different induced models of OA, although we did not see signs of spontaneous accelerated OA development in one year old mice. This contrasts with more direct and radical changes in the WNT canonical cascade as both tissue specific gain and loss of function of b catenin, result in premature OA. FRZB can modulate both canonical and non canonical Inhibitors,Modulators,Libraries WNT signaling. New insights into the differential activa tion of these pathways in articular chondrocytes may help to further explain why deletion of a single antago nist induces only subtle changes as compared to the dramatic effects of b catenin modulation.

Distinct SFRPs do not bind different WNTs with similar affinities and their effect may depend on the cell type and interactions with other pathways. Nalesso et al. demonstrated Inhibitors,Modulators,Libraries that low amounts of WNT ligand can activate non canonical signaling whereas higher amounts activate the b catenin mediated www.selleckchem.com/products/MG132.html pathway. Moreover, inhibition of either pathway can de repress the alternative one.