BMP2 commitment to the osteogenic lineage involves activation of Runx2 by DLX3 and a homeodomain transcriptional network
BMP2 commitment to the osteogenic lineage involves activation of Runx2 by DLX3 and a homeodomain transcriptional network
Several homeodomain (HD) proteins are critical for skeletal patterning and respond directly to BMP2 as an early step in bone formation. RUNX2, the earliest transcription factor proven essential for commitment to osteoblastogenesis, is also expressed in response to BMP2. However, there is a gap in our knowledge of the regulatory cascade from BMP2 signaling to the onset of osteogenesis. Here we show that BMP2 induces DLX3, a homeodomain protein that activates Runx2 gene transcription. Small interfering RNA knockdown studies in osteoblasts validate that DLX3 is a potent regulator of Runx2. Furthermore in Runx2 null cells, DLX3 forced expression suffices to induce transcription of Runx2, osteocalcin, and alkaline phosphatase genes, thus defining DLX3 as an osteogenic regulator independent of RUNX2. Our studies further show regulation of the Runx2 gene by several homeodomain proteins: MSX2 and CDP/cut repress whereas DLX3 and DLX5 activate endogenous Runx2 expression and promoter activity in non-osseous cells and osteoblasts. These HD proteins exhibit distinct temporal expression profiles during osteoblast differentiation as well as selective association with Runx2 chromatin that is related to Runx2 transcriptional activity and recruitment of RNA polymerase II. Runx2 promoter mutagenesis shows that multiple HD elements control expression of Runx2 in relation to the stages of osteoblast maturation. Our studies establish mechanisms for commitment to the osteogenic lineage directly through BMP2 induction of HD proteins DLX3 and DLX5 that activate Runx2, thus delineating a transcriptional regulatory pathway mediating osteoblast differentiation. We propose that the three homeodomain proteins MSX2, DLX3, and DLX5 provide a key series of molecular switches that regulate expression of Runx2 throughout bone formation.
40515-40526
Hassan, MQ
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Tare, R.S.
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Mandeville, M
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Morasso, MI
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Javed, A
7e603cdc-911c-4e67-bff4-fb489173fe8c
van Wijnen, AJ
f9847494-a48e-4c6d-9d08-9c6e08a0c89d
Stein, JL
1d9ff9f2-7287-4d6a-a9e8-7f7a9eab407b
Stein, GS
6cad2a10-a844-4d92-bbaa-25db6b5d1113
Lian, JB
59174079-d7ce-40f2-90b8-3e2262c043dc
23 October 2006
Hassan, MQ
ddf2994d-5399-4966-b120-09e3f55cf9df
Tare, R.S.
587c9db4-e409-4e7c-a02a-677547ab724a
Mandeville, M
0b30a651-7c74-444d-9fff-43aec1c02d75
Morasso, MI
b8919f04-252e-4bd0-aada-ebf28b6d4a75
Javed, A
7e603cdc-911c-4e67-bff4-fb489173fe8c
van Wijnen, AJ
f9847494-a48e-4c6d-9d08-9c6e08a0c89d
Stein, JL
1d9ff9f2-7287-4d6a-a9e8-7f7a9eab407b
Stein, GS
6cad2a10-a844-4d92-bbaa-25db6b5d1113
Lian, JB
59174079-d7ce-40f2-90b8-3e2262c043dc
Hassan, MQ, Tare, R.S., Mandeville, M, Morasso, MI, Javed, A, van Wijnen, AJ, Stein, JL, Stein, GS and Lian, JB
(2006)
BMP2 commitment to the osteogenic lineage involves activation of Runx2 by DLX3 and a homeodomain transcriptional network.
The Journal of Biological Chemistry, 281 (52), .
(doi:10.1074/jbc.M604508200).
Abstract
Several homeodomain (HD) proteins are critical for skeletal patterning and respond directly to BMP2 as an early step in bone formation. RUNX2, the earliest transcription factor proven essential for commitment to osteoblastogenesis, is also expressed in response to BMP2. However, there is a gap in our knowledge of the regulatory cascade from BMP2 signaling to the onset of osteogenesis. Here we show that BMP2 induces DLX3, a homeodomain protein that activates Runx2 gene transcription. Small interfering RNA knockdown studies in osteoblasts validate that DLX3 is a potent regulator of Runx2. Furthermore in Runx2 null cells, DLX3 forced expression suffices to induce transcription of Runx2, osteocalcin, and alkaline phosphatase genes, thus defining DLX3 as an osteogenic regulator independent of RUNX2. Our studies further show regulation of the Runx2 gene by several homeodomain proteins: MSX2 and CDP/cut repress whereas DLX3 and DLX5 activate endogenous Runx2 expression and promoter activity in non-osseous cells and osteoblasts. These HD proteins exhibit distinct temporal expression profiles during osteoblast differentiation as well as selective association with Runx2 chromatin that is related to Runx2 transcriptional activity and recruitment of RNA polymerase II. Runx2 promoter mutagenesis shows that multiple HD elements control expression of Runx2 in relation to the stages of osteoblast maturation. Our studies establish mechanisms for commitment to the osteogenic lineage directly through BMP2 induction of HD proteins DLX3 and DLX5 that activate Runx2, thus delineating a transcriptional regulatory pathway mediating osteoblast differentiation. We propose that the three homeodomain proteins MSX2, DLX3, and DLX5 provide a key series of molecular switches that regulate expression of Runx2 throughout bone formation.
More information
Published date: 23 October 2006
Organisations:
Human Development & Health
Identifiers
Local EPrints ID: 200007
URI: http://eprints.soton.ac.uk/id/eprint/200007
ISSN: 0021-9258
PURE UUID: 2e572afc-6dd5-4062-9fbc-39f0594f696a
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Date deposited: 27 Oct 2011 10:41
Last modified: 15 Mar 2024 03:20
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Author:
MQ Hassan
Author:
M Mandeville
Author:
MI Morasso
Author:
A Javed
Author:
AJ van Wijnen
Author:
JL Stein
Author:
GS Stein
Author:
JB Lian
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