Wednesday, January 18, 2012

BMP vs. TGF-Beta chondrogenesis

Gene expression profile of multipotent mesenchymal stromal cells: Identification of pathways common to TGFbeta3/BMP2-induced chondrogenesis.

Human stem cells were used.

"The genes belonging to class 1 correspond to genes barely but continuously expressed during chondrogenesis and involved in chondrocyte proliferation and cell cycle regulation. This class is characterized by the expression of Notch3, insulinlike growth factor binding protein 1 (IGFBP1), interleukin 1 receptor-like 1 (IL1RL1), Wingless 5a (Wnt5a), endothelial growth factor-related protein (PGF), preprourokinase/urokinase-type plasminogen activator receptor (PLAU/PLAUR), matrilin 2 (MATN2), laminin alpha 2 (LAMA2), phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1)"<-LSJL upregulates IL1RL1 and MATN2.

"The second class corresponds to 17 factors that are up-regulated within the first 3 days of chondrogenesis and then downregulated at the end of chondrogenesis. This class includes the 5 integrin (ITGA5), as well as tissue factor pathway inhibitor-2 (TFPI2), regulator of G-protein signaling 2, (RGS2), B-cell lymphoma 6 (BCL6), spermidinespermine N1-acetyltransferase (SAT1), N-myc downstream regulated (NDRG1), nuclear factor, interleukin 3 regulated (NFIL3){downregulated by LSJL}, adipose differentiation-related protein (ADFP), Max-interacting protein 1 (MXI1){downregulated by LSJL}, hypoxia-inducible protein 2 (HIG2) and B-cell translocation gene 1 (BTG1). These genes are implicated in cell attachment and apoptosis prevention."

"Class 3 consists of 15 genes that are expressed in the late phase of chondrogenesis. These genes included factors involved in osteogenesis inhibition: Dickkopf 1 (Dkk1), apolipoprotein E and D (APOE/APOD){APOD is upregulated in LSJL}, serine proteinase inhibitor (SERPINF1), tissue inhibitor of metalloproteinase 4 (TIMP4), and nidogen (enactin, NID)."<-LSJL decreases Dkk expression.

"Classes 4 and 5 are characterized by genes that are either downregulated (class 4) or upregulated (class 5) as soon as day 1 of chondral differentiation, among which are connective tissue growth factor (CTGF), cysteine-rich angiogenic inducer 61 (CYR61), and homolog of chicken slug zing-finger protein (SLUG)."

Both TGF-Beta3 and BMP-2 had low effect on Class 1 genes.  

Shared pathways between TGF-Beta3 and BMP-2: Wnt5a, CHI3L1, VEGF, PLAUR, PGAR, ITGalpha5,  NID2, DPT{Upregulated by LSJL}, DKK1, SPARCL1.

"Phase 1. Cell attachment and apoptosis induction. This phase is characterized by the transitory upregulation of the class 2 genes whose function is associated with transcription regulation, cell attachment (ITGA5, TFPI2), and hypoxia (HIG2). The regulation of transcription factors as BCL6, BTG1, NFIL3{Upregulated by LSJL}, MXI1{Downregulated by LSJL} suggest a pro-apoptotic effect at this early stage. In parallel, CTGF and CYR61{upregulated by LSJL}, belonging to the class 4 of genes that are involved in skeletal tissue development, are down-regulated during this phase." 

"Phase 2. Differentiation induced by Wnt, Notch, and IGF signaling. This phase is characterized by the class 1 genes that are expressed during the whole period of differentiation and are members of Wnt/ catenin signaling, IGF signaling (as IGFBP, Foxo3A), and Notch signaling regulating cellular growth and cell death (SGK, Notch3)."

"Phase 3. Wnt signaling inhibition and hypertrophy. At the late stage of chondral differentiation, among upregulated genes belonging to class 3 we identified genes associated with hypertrophy, including TIMP4 and SERPINF1 or involved in lipid metabolism, indicating the formation of adipocytes inside the pellet culture. We also identified DKK1, a strong Wnt inhibitor recently shown to play a major role in the prevention of osteogenesis."

sFrp1 is also upregulated during chondrogenesis.

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