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Modulation of Bone Morphogenetic Protein (BMP) 2 gene expression by Sp1 transcription factors.

ABSTRACT: Changes in Bone Morphogenetic Protein (BMP) 2 gene expression and activity have been linked to many pathological conditions including cancer, osteoarthritis, and birth defects. BMP2 gene polymorphisms have been linked to osteoporosis and osteoarthritis. Sp1 and related proteins are widely expressed regulators of gene expression whose transcription activating abilities vary in different cells and on different genes. We present data indicating that the ratio of Sp1 and Sp3 isoforms varies in cells that express or do not express BMP2. Furthermore, the orientation of Sp1 sites conserved between four orders of mammals influences BMP2 expression. Together our data indicate that the stoichiometry and orientation of Sp1 and Sp3 complexes on the BMP2 promoter influence BMP2 expression.

SUBMITTER: Xu J

PROVIDER: S-EPMC1934513 | biostudies-literature | 2007 May

REPOSITORIES: biostudies-literature

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Modulation of Bone Morphogenetic Protein (BMP) 2 gene expression by Sp1 transcription factors.

Xu Junwang J Rogers Melissa B MB

Gene 20070120 1-2

Changes in Bone Morphogenetic Protein (BMP) 2 gene expression and activity have been linked to many pathological conditions including cancer, osteoarthritis, and birth defects. BMP2 gene polymorphisms have been linked to osteoporosis and osteoarthritis. Sp1 and related proteins are widely expressed regulators of gene expression whose transcription activating abilities vary in different cells and on different genes. We present data indicating that the ratio of Sp1 and Sp3 isoforms varies in cells ...[more]

PMID: 17317039

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Project description:IntroductionSuccessful graft ingrowth following reconstruction of the anterior cruciate ligament is governed by complex biological processes at the tendon-bone interface. The aim of this study was to investigate in an in vitro study the effects of bone morphogenetic protein 7 (BMP-7) on tendon-bone integration.Materials and methodsTo study the biological effects of BMP-7 on the process of tendon-bone-integration, two independent in vitro models were used. The first model involved the mono- and coculture of bovine tendon specimens and primary bovine osteoblasts with and without BMP-7 exposure. The second model comprised the mono- and coculture of primary bovine osteoblasts and fibroblasts. Alkaline phosphatase (ALP), lactate dehydrogenase (LDH), lactate and osteocalcin (OCN) were analyzed by ELISA. Histological analysis and electron microscopy of the tendon specimens were performed.ResultsIn both models, positive effects of BMP-7 on ALP enzyme activity were observed (p<0.001). Additionally, similar results were noted for LDH activity and lactate concentration. BMP-7 stimulation led to a significant increase in OCN expression. Whereas the effects of BMP-7 on tendon monoculture peaked during an early phase of the experiment (p<0.001), the cocultures showed a maximal increase during the later stages (p<0.001). The histological analysis showed a stimulating effect of BMP-7 on extracellular matrix formation. Organized ossification zones and calcium carbonate-like structures were only observed in the BMP-stimulated cell cultures.DiscussionThis study showed the positive effects of BMP-7 on the biological process of tendon-bone integration in vitro. Histological signs of improved mineralization were paralleled by increased rates of osteoblast-specific protein levels in primary bovine osteoblasts and fibroblasts.ConclusionOur findings indicated a role for BMP-7 as an adjuvant therapeutic agent in the treatment of ligamentous injuries, and they emphasized the importance of the transdifferentiation process of tendinous fibroblasts at the tendon-bone interface.

Project description:BackgroundThe capsaicin receptor, transient receptor potential vanilloid type -1 (TRPV1) directs complex roles in signal transduction including the detection of noxious stimuli arising from cellular injury and inflammation. Under pathophysiologic conditions, TRPV1 mRNA and receptor protein expression are elevated in dorsal root ganglion (DRG) neurons for weeks to months and is associated with hyperalgesia. Building on our previous isolation of a promoter system for the rat TRPV1 gene, we investigated the proximal TRPV1 P2-promoter by first identifying candidate Sp1-like transcription factors bound in vivo to the P2-promoter using chromatin immunoprecipitation (ChIP) assay. We then performed deletion analysis of GC-box binding sites, and quantified promoter activity under conditions of Sp1 / Sp4 over-expression versus inhibition/knockdown. mRNA encoding Sp1, Sp4 and TRPV1 were quantified by qRT-PCR under conditions of Sp1/Sp4 over-expression or siRNA mediated knockdown in cultured DRG neurons.ResultsUsing ChIP analysis of DRG tissue, we demonstrated that Sp1 and Sp4 are bound to the candidate GC-box site region within the endogenous TRPV1 P2-promoter. Deletion of GC-box "a" or "a + b" within the P2- promoter resulted in a complete loss of transcriptional activity indicating that GC-box "a" was the critical site for promoter activation. Co-transfection of Sp1 increased P2-promoter activity in cultured DRG neurons whereas mithramycin-a, an inhibitor of Sp1-like function, dose dependently blocked NGF and Sp1-dependent promoter activity in PC12 cells. Co-transfection of siRNA directed against Sp1 or Sp4 decreased promoter activity in DRG neurons and NGF treated PC12 cells. Finally, electroporation of Sp1 or Sp4 cDNA into cultures of DRG neurons directed an increase in Sp1/Sp4 mRNA and importantly an increase in TRPV1 mRNA. Conversely, combined si-RNA directed knockdown of Sp1/Sp4 resulted in a decrease in TRPV1 mRNA.ConclusionBased on these studies, we now propose a model of TRPV1 expression that is dependent on Sp1-like transcription factors with Sp4 playing a predominant role in activating TRPV1 RNA transcription in DRG neurons. Given that increases of TRPV1 expression have been implicated in a wide range of pathophysiologic states including persistent painful conditions, blockade of Sp1-like transcription factors represents a novel direction in therapeutic strategies.

Dataset Information

Modulation of Bone Morphogenetic Protein (BMP) 2 gene expression by Sp1 transcription factors.

Publications

Modulation of Bone Morphogenetic Protein (BMP) 2 gene expression by Sp1 transcription factors.

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