Type beta transforming growth factor controls the adipogenic differentiation of 3T3 fibroblasts.

Ignotz, Ronald A.; Massagué, Joan

doi:10.1073/pnas.82.24.8530

Cited by 335 publications

(192 citation statements)

References 26 publications

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“…Stimulatory and inhibitory effects of TGF-p on proliferation and differentiation in cell lines have been reported recently (36)(37)(38)(39)(40). Our results and those of others (15,16) suggest that bone may also be an important target tissue for TGF-p. TGF-p stimulates DNA synthesis in fetal rat calvaria cultures and increases alkaline phosphatase activity, a marker for the osteoblastic phenotype, in the osteoblastic osteosarcoma cell line ROS 17/2.8 (17).…”

Section: Discussionsupporting

confidence: 75%

Modulation of type beta transforming growth factor activity in bone cultures by osteotropic hormones.

Pfeilschifter¹,

Mundy²

1987

Proc. Natl. Acad. Sci. U.S.A.

394

149

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Type (3 transforming growth factor (TGF-fi) activity was found in conditioned medium harvested from fetal rat and neonatal mouse calvariae by using the anchorageindependent growth of normal rat kidney fibroblasts as an indicator system. Calvariae incubated with parathyroid hormone, 1,25-dihydroxyvitamin D3, and interleukin 1, all factors that stimulate bone resorption, showed a concentration-dependent increase in TGF-,3 activity in the culture medium. Increases in TGF-fi activity persisted undiminished for 48 hr after removal of these factors. The increases in TGF-fi activity from the resorbing bone cultures were relatively greater than the increases in bone resorption. Calcitonin inhibition of bone resorption correlated with a decrease in TGF-fi activity. Thus, agents that modulate bone resorption also affect TGF-fi activity in the bone culture medium. Changes in local concentrations of TGF-f3 activity by osteotropic hormones may be important in the regulation of normal bone remodeling.Transforming growth factors (TGFs) are operationally defined by their ability to induce anchorage-independent growth of cells in soft agar (1-3). By using normal rat kidney (NRK) fibroblasts as indicator cells, two distinct classes of TGFs have been identified. Type a TGF (TGF-a) is a structural analog of epidermal growth factor (EGF) and binds to the EGF receptor (4, 5). TGF-a induces the formation of small colonies of NRK cells in soft agar. Type (3 TGF (TGF-/3) does not bind to the EGF receptor and differs from TGF-a in molecular composition. TGF-,6 alone does not induce anchorage-independent growth of NRK cells but potentiates the effects of TGF-a or EGF on colony formation (6, 7). Unlike TGF-a, which has been demonstrated so far only in neoplastic and embryonic tissues (8, 9), TGF-/3 has also been detected in many normal nonneoplastic adult tissues (6, 10, 11).Recently, it has been realized that bone is a rich source of MATERIALS AND METHODSOrgan Culture of Bone. Calvariae (frontal and parietal bones) from 21-day fetal rats or 4-day-old mice were dissected aseptically and cultured on steel grids at the interface between 1 ml of medium and air in 12-well plastic culture dishes (Coming, Medfield, MA). The bones were maintained in BGJ medium (Irvine Scientific, Santa Ana, CA) containing either 5% heat-inactivated fetal bovine serum (GIBCO) or 1 mg of bovine serum albumin (Sigma) per ml. A 24-hr preincubation in control medium preceded all experiments. The calvariae were then incubated in fresh medium containing bone resorbing factors or corresponding control medium. After 48 hr of incubation with the calvariae, this medium was collected, and 45Ca release and TGF-P activity in the medium were determined as described below.In a second set of experiments the calvariae were incubated for 48 hr in medium containing bone resorbing factors or corresponding control medium, then rinsed extensively in phosphate-buffered saline, and cultured for another 4-24 hr in control medium to free them from the presence of the bone resorbin...

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Section: Discussionsupporting

confidence: 75%

Modulation of type beta transforming growth factor activity in bone cultures by osteotropic hormones.

Pfeilschifter¹,

Mundy²

1987

Proc. Natl. Acad. Sci. U.S.A.

394

149

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“…Increased TGF-β1 mRNA levels are observed in animal and human obesity (Ignotz and Massague 1985;Wahab et al 2005;Secker et al 2008;Wrighton and Feng 2008). One of the downstream mediators of TGF-β1 is the protein connective tissue growth factor (CTGF), also known as CCN2, a heparin binding 36-and 38 kDa cysteine rich protein and a member of the highly conserved CCN early response gene family of peptides (Dixon et al 2001;Li et al 2008).…”

Section: Introductionmentioning

confidence: 99%

CCN2 requires TGF-β signalling to regulate CCAAT/enhancer binding proteins and inhibit fat cell differentiation

Song

McLennan

Tam

et al. 2014

J. Cell Commun. Signal.

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Introduction Fat cell differentiation (FCD) potentiates adipose cell characteristics including lipid storage and insulin sensitivity. In vitro, we have demonstrated that CCN2, also known as connective tissue growth factor (CTGF), inhibits FCD in NIH3T3-L1 cells and in adipocytes isolated from mouse epididymal fat pads. The aim of this study was to determine if the CCN2 effect on FCD is dependent on TGF-β and TGF-β downstream pathway signalling. Methods NIH3T3-L1 cells were differentiated using standard methods with IBMX/Dex/Insulin. FCD at day 10 was confirmed by induced gene markers resistin and adiponectin and by lipid accumulation. Cells were treated at d0 with single dose active rhTGF-β1 (2 ng/mL), rhCCN2 (500 ng/mL) and/ or TGF-β type 1 receptor blocker (SB431542, 5 μM). Early induction of FCD transcription factors: CCAAT/enhancer binding proteins (C/EBPs) and peroxisome proliferatoractivated receptor-γ (PPAR-γ), were also determined. Results In an early time course from 2 h, single doses of rhTGF-β1 or rhCCN2 significantly inhibited by~70 % the induction of C/EBP-β and -δ mRNA, and also nuclear protein levels otherwise seen during FCD, whereas only delayed effects on PPAR-γ, at 48 h, occurred. Furthermore, the CCN2 inhibition of FCD markers adiponectin and resistin and lipid accumulation by Oil red O stain were each prevented by TGF-β receptor blockade. Similar prevention was found using pan-specific anti-TGF-β neutralising antibody. CCN2 and TGF-β treatment each rapidly phosphorylated SMAD-3 signalling in early stages of FCD. Conclusion This work shows novel findings that CCN2 effects on FCD are both TGF-β and TGF-β pathway dependent and are related to early effects on C/EBPs.

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“…Growth factors like EGF and platelet-derived growth factor (6) or cytokines, such as interleukin-11 (7)(8)(9), tumor necrosis factor-␣ (10,11), and transforming growth factor-␤ (11)(12)(13), can inhibit adipogenesis and cause reversal of the adipocyte phenotype. In addition, growth hormone has been shown to inhibit differentiation of primary preadipocytes (6), but it exerts a proadipogenic action on several preadipocyte cell lines, including 3T3-L1 (14 -16).…”

mentioning

confidence: 99%

Insulin-like Growth Factor-1/Insulin Bypasses Pref-1/FA1-mediated Inhibition of Adipocyte Differentiation

Zhang

Nøhr

Jensen

et al. 2003

Journal of Biological Chemistry

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Pref-1 is a highly glycosylated Delta-like transmembrane protein containing six epidermal growth factorlike repeats in the extracellular domain. Pref-1 is abundantly expressed in preadipocytes, but expression is down-regulated during adipocyte differentiation. Forced expression of Pref-1 in 3T3-L1 cells was reported to inhibit adipocyte differentiation. Here we show that efficient and regulated processing of Pref-1 occurs in 3T3-L1 preadipocytes releasing most of the extracellular domain as a 50-kDa heterogeneous protein, previously isolated and characterized as FA1. Unexpectedly, we found that forced expression of the soluble form, FA1, or full-length Pref-1 did not inhibit adipocyte differentiation of 3T3-L1 cells when differentiation was induced by standard treatment with methylisobutylxanthine, dexamethasone, and high concentrations of insulin. However, forced expression of either form of Pref-1/FA1 in 3T3-L1 or 3T3-F442A cells inhibited adipocyte differentiation when insulin or insulin-like growth factor-1 (IGF-1) was omitted from the differentiation mixture. We demonstrate that the level of the mature form of the IGF-1 receptor is reduced and that IGF-1-dependent activation of p42/p44 mitogen-activated protein kinases (MAPKs) is compromised in preadipocytes with forced expression of Pref-1. This is accompanied by suppression of clonal expansion and terminal differentiation. Accordingly, supplementation with insulin or IGF-1 rescued p42/p44 MAPK activation, clonal expansion, and adipocyte differentiation in a dose-dependent manner.

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Type beta transforming growth factor controls the adipogenic differentiation of 3T3 fibroblasts.

Cited by 335 publications

References 26 publications

Modulation of type beta transforming growth factor activity in bone cultures by osteotropic hormones.

Modulation of type beta transforming growth factor activity in bone cultures by osteotropic hormones.

CCN2 requires TGF-β signalling to regulate CCAAT/enhancer binding proteins and inhibit fat cell differentiation

Insulin-like Growth Factor-1/Insulin Bypasses Pref-1/FA1-mediated Inhibition of Adipocyte Differentiation

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