Sonic hedgehog increases the commitment of pluripotent mesenchymal cells into the osteoblastic lineage and abolishes adipocytic differentiation

2001 ◽  
Vol 114 (11) ◽  
pp. 2085-2094 ◽  
Author(s):  
Sylviane Spinella-Jaegle ◽  
Georges Rawadi ◽  
Shinji Kawai ◽  
Sylvie Gallea ◽  
Chi Faucheu ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Inverse Relationship ◽  
Mesenchymal Cell ◽  
Bone Morphogenetic Protein 2 ◽  
Short Treatment ◽  
Morphogenetic Protein ◽  
Adipocytic Differentiation ◽  
Hh Signaling ◽  
Transcriptional Output ◽  
Calvaria Cell

The proteins of the hedgehog (Hh) family regulate various aspects of development. Recently, members of this family have been shown to regulate skeletal formation in vertebrates and to control both chondrocyte and osteoblast differentiation. In the present study, we analyzed the effect of Sonic hedgehog (Shh) on the osteoblastic and adipocytic commitment/differentiation. Recombinant N-terminal Shh (N-Shh) significantly increased the percentage of both the pluripotent mesenchymal cell lines C3H10T1/2 and ST2 and calvaria cells responding to bone morphogenetic protein 2 (BMP-2), in terms of osteoblast commitment as assessed by measuring alkaline phosphatase (ALP) activity. This synergistic effect was mediated, at least partly, through the positive modulation of the transcriptional output of BMPs via Smad signaling. Furthermore, N-Shh was found to abolish adipocytic differentiation of C3H10T1/2 cells both in the presence or absence of BMP-2. A short treatment with N-Shh was sufficient to dramatically reduce the levels of the adipocytic-related transcription factors C/EBPα and PPARγ in both C3H10T1/2 and calvaria cell cultures. Given the inverse relationship between marrow adipocytes and osteoblasts with aging, agonists of the Hh signaling pathway might constitute potential drugs for preventing and/or treating osteopenic disorders.

scholarly journals Differential Roles of Smad1 and p38 Kinase in Regulation of Peroxisome Proliferator-activating Receptor γ during Bone Morphogenetic Protein 2-induced Adipogenesis

2003 ◽  
Vol 14 (2) ◽  
pp. 545-555 ◽  
Author(s):  
Kenji Hata ◽  
Riko Nishimura ◽  
Fumiyo Ikeda ◽  
Kenji Yamashita ◽  
Takuma Matsubara ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Transcriptional Activity ◽  
Mesenchymal Cells ◽  
Bone Morphogenetic Protein 2 ◽  
Peroxisome Proliferator ◽  
P38 Kinase ◽  
Morphogenetic Protein ◽  
Adipocytic Differentiation ◽  
Pparγ Expression ◽  
Activating Receptor

Bone morphogenetic protein 2 (BMP2) promotes the differentiation of undifferentiated mesenchymal cells into adipocytes. To investigate the molecular mechanisms that regulate this differentiation process, we studied the relationship between BMP2 signaling and peroxisome proliferator-activating receptor γ (PPARγ) during adipogenesis of mesenchymal cells by using pluripotent mesenchymal cell line C3H10T1/2. In C3H10T1/2 cells, BMP2 induced expression of PPARγ along with adipogenesis. Overexpression of Smad6, a natural antagonist for Smad1, blocked PPARγ expression and adipocytic differentiation induced by BMP2. Overexpression of dominant-negative PPARγ also diminished adipocytic differentiation of C3H10T1/2 cells, suggesting the central role of PPARγ in BMP2-induced adipocytic differentiation. Specific inhibitors for p38 kinase inhibited BMP2-induced adipocytic differentiation and transcriptional activation of PPARγ, whereas overexpression of Smad6 had no effect on transcriptional activity of PPARγ. Furthermore, activation of p38 kinase by overexpression of TAK1 and TAB1, without affecting PPARγ expression, led the up-regulation of transcriptional activity of PPARγ. These results suggest that both Smad and p38 kinase signaling are concomitantly activated and responsible for BMP2-induced adipocytic differentiation by inducing and up-regulating PPARγ, respectively. Thus, BMP2 controls adipocytic differentiation by using two distinct signaling pathways that play differential roles in this process in C3H10T1/2 cells.

scholarly journals Differential Regulation of the Two Principal Runx2/Cbfa1 N-Terminal Isoforms in Response to Bone Morphogenetic Protein-2 during Development of the Osteoblast Phenotype

Endocrinology ◽  
2001 ◽  
Vol 142 (9) ◽  
pp. 4026-4039 ◽  
Author(s):  
Chaitali Banerjee ◽  
Amjad Javed ◽  
Je-Yong Choi ◽  
Jack Green ◽  
Vicki Rosen ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Osteoblast Differentiation ◽  
Mesenchymal Cell ◽  
Cellular Protein ◽  
C2c12 Cells ◽  
Bone Morphogenetic Protein 2 ◽  
Type I ◽  
Type Ii ◽  
Specific Expression ◽  
Morphogenetic Protein

Abstract Cbfa1/Runx2 is a transcription factor essential for bone formation and osteoblast differentiation. Two major N-terminal isoforms of Cbfa1, designated type I/p56 (PEBP2aA1, starting with the sequence MRIPV) and type II/p57 (til-1, starting with the sequence MASNS), each regulated by distinct promoters, are known. Here, we show that the type I transcript is constitutively expressed in nonosseous mesenchymal tissues and in osteoblast progenitor cells. Cbfa1 type I isoform expression does not change with the differentiation status of the cells. In contrast, the type II transcript is increased during differentiation of primary osteoblasts and is induced in osteoprogenitors and in premyoblast C2C12 cells in response to bone morphogenetic protein-2. The functional equivalence of the two isoforms in activation and repression of bone-specific genes indicates overlapping functional roles. The presence of the ubiquitous type I isoform in nonosseous cells and before bone morphogenetic protein-2 induced expression of the type II isoform suggests a regulatory role for Cbfa1 type I in early stages of mesenchymal cell development, whereas type II is necessary for osteogenesis and maintenance of the osteoblast phenotype. Our data indicate that Cbfa1 function is regulated by transcription, cellular protein levels, and DNA binding activity during osteoblast differentiation. Taken together, our studies suggest that developmental timing and cell type- specific expression of type I and type II Cbfa isoforms, and not necessarily molecular properties or sequences that reside in the N-terminus of Cbfa1, are the principal determinants of the osteogenic activity of Cbfa1.

scholarly journals Inhibition of Microtubule Assembly in Osteoblasts Stimulates Bone Morphogenetic Protein 2 Expression and Bone Formation through Transcription Factor Gli2

2008 ◽  
Vol 29 (5) ◽  
pp. 1291-1305 ◽  
Author(s):  
Ming Zhao ◽  
Seon-Yle Ko ◽  
Jin-Hua Liu ◽  
Di Chen ◽  
Jianghong Zhang ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Morphogenetic Protein ◽  
Molecular Mechanisms ◽  
Fracture Repair ◽  
Microtubule Assembly ◽  
Bone Morphogenetic Protein 2 ◽  
Microtubule Inhibitors ◽  
Morphogenetic Protein ◽  
Hh Signaling

ABSTRACT Bone morphogenetic protein 2 (BMP-2) is essential for postnatal bone formation and fracture repair. By screening chemical libraries for BMP-2 mimics using a cell-based assay, we identified inhibitors of microtubule assembly as stimulators of BMP-2 transcription. These microtubule inhibitors increased osteoblast differentiation in vitro, stimulated periosteal bone formation when injected locally over murine calvaria, and enhanced trabecular bone formation when administered systemically in vivo. To explore molecular mechanisms mediating these responses, we examined effects of microtubule inhibitors on the hedgehog (Hh) pathway, since this pathway is known to regulate BMP-2 transcription in osteoblasts and microtubules have been shown to be involved in Hh signaling in Drosophila. Here we show that in osteoblasts, inhibition of microtubule assembly increased cytoplasmic levels and transcriptional activity of Gli2, a transcriptional mediator of Hh signaling that we have previously shown to enhance BMP-2 expression in osteoblasts (M. Zhao et al., Mol. Cell. Biol. 26:6197-6208, 2006). Microtubule inhibition blocked β-TrCP-mediated proteasomal processing of Gli2 in osteoblasts. In summary, inhibition of microtubule assembly enhances BMP-2 gene transcription and subsequent bone formation, in part, through inhibiting proteasomal processing of Gli2 and increasing intracellular Gli2 concentrations.

Conservation in hedgehog signaling: induction of a chicken patched homolog by Sonic hedgehog in the developing limb

Development ◽  
1996 ◽  
Vol 122 (4) ◽  
pp. 1225-1233 ◽  
Author(s):  
V. Marigo ◽  
M.P. Scott ◽  
R.L. Johnson ◽  
L.V. Goodrich ◽  
C.J. Tabin
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Limb Bud ◽  
Bone Morphogenetic Protein 2 ◽  
Fibroblast Growth ◽  
Sonic Hedgehog Signaling ◽  
Morphogenetic Protein ◽  
Direct Target

Hedgehog genes have been implicated in inductive signaling during development in a variety of organisms. A key element of the hedgehog signaling system is encoded by the gene patched. In Drosophila hedgehog regulates gene expression by antagonizing the action of patched. In addition, patched is itself a transcriptional target of hedgehog signaling. We have isolated a chicken patched homolog and find it to be strongly expressed adjacent to all tissues where members of the hedgehog family are expressed. As in Drosophila, ectopic expression of Sonic hedgehog leads to ectopic induction of chicken Patched. Based on this regulatory conservation, vertebrate Patched is likely to be directly downstream of Sonic hedgehog signaling. An important role of Sonic hedgehog is the regulation of anterior/posterior pattern in the developing limb bud. Since Patched is directly downstream of the hedgehog signal, the extent of high level Patched expression provides a measure of the distance that Sonic hedgehog diffuses and directly acts. On this basis, we find that Sonic hedgehog directly acts as a signal over only the posterior third of the limb bud. During limb patterning, secondary signals are secreted in both the mesoderm (e.g. Bone Morphogenetic Protein-2) and apical ectodermal ridge (e.g. Fibroblast Growth Factor-4) in response to Sonic hedgehog. Thus knowing which is the direct target tissue is essential for unraveling the molecular patterning of the limb. The expression of Patched provides a strong indication that the mesoderm and not the ectoderm is the direct target of Sonic hedgehog signaling in the limb bud. Finally we demonstrate that induction of Patched requires Sonic hedgehog but, unlike Bone Morphogenetic Protein-2 and Hox genes, does not require Fibroblast Growth Factor as a co-inducer. It is therefore a more direct target of Sonic hedgehog than previously reported patterning genes.

scholarly journals Comparison of bone morphogenetic protein-2 and osteoactivin for mesenchymal cell differentiation: Effects of bolus and continuous administration

2011 ◽  
Vol 226 (11) ◽  
pp. 2943-2952 ◽  
Author(s):  
Oneida A. Arosarena ◽  
Fabiola E. Del Carpio-Cano ◽  
Raul A. Dela Cadena ◽  
Mario C. Rico ◽  
Emeka Nwodim ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Bone Morphogenetic Protein ◽  
Mesenchymal Cell ◽  
Bone Morphogenetic Protein 2 ◽  
Continuous Administration ◽  
Morphogenetic Protein
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