Affinage

SP7

Transcription factor Sp7 · UniProt Q8TDD2

Length
431 aa
Mass
45.0 kDa
Annotated
2026-06-10
100 papers in source corpus 43 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SP7/Osterix is an osteoblast-specific C2H2 zinc finger transcription factor of the SP family whose expression is restricted to osteoblast lineage cells and required for osteoblast and osteocyte differentiation (PMID:15474293, PMID:39027344). It is induced downstream of BMP-2 through both Runx2-dependent and Runx2-independent routes: Runx2 directly transactivates the Osx promoter (PMID:16574347), while a parallel Dlx5-mediated arm—itself amplified by p38 MAPK phosphorylation of Dlx5—drives Osx independently of Runx2 (PMID:12963046, PMID:18056716), with Smad1/Smad4/Msx2 providing an additional Runx2-independent input (PMID:18703512). Unlike canonical SP proteins, the SP7 zinc finger has reduced GC-box affinity and instead is recruited to AT-rich osteoblast enhancers via interaction with Dlx5, defining a non-canonical co-factor mode of DNA engagement (PMID:27134141); the disease relevance of this specificity is shown by a de novo neomorphic SP7 p.S309W variant that switches binding from AT-rich to GC-consensus sites and produces an aberrant osteogenic program and a distinct skeletal phenotype in knock-in mice (PMID:35121733). SP7 also physically interacts with Runx2 and synergistically activates phenotype-restricted target genes, a cooperation requiring adjacent SP1/Runx2 sites and MAPK-dependent phosphorylation of both factors (PMID:25122769, PMID:25158187). Through these mechanisms SP7 directly activates a broad osteogenic transcriptional program—including Satb2, VEGF, MMP13, SOST, fibromodulin, bone sialoprotein, type V and type I collagens, and Osteocrin—and in osteocytes drives dendrite/process formation, with Osteocrin acting as a direct target that rescues dendrite defects (PMID:21828043, PMID:22110141, PMID:23185634, PMID:34725346, PMID:39027344). SP7 transcriptional output is tuned by extensive post-translational control: stimulatory phosphorylation by p38 MAPK (Ser-73/77, enhancing p300/Brg1 recruitment), ERK, and Akt (PMID:20682789, PMID:21777568, PMID:22056560), acetylation by CBP at K307/K312 reversed by HDAC4 (PMID:27250035), SIRT7-mediated deacylation at K368 (PMID:30026585), and ubiquitin-proteasome-mediated degradation at K58/K230 (PMID:23457570); it is repressed by physical interaction with p53, which blocks both its DNA binding and its Dlx5 co-factor activity (PMID:28777372). SP7 expression is itself governed by epigenetic switching of its promoter—silencing via DNMT/HDAC/Setdb1/Ezh repressor complexes and activation via Tet1/Tet2 demethylation and SWI/SNF remodeling—and by positive autoregulation through an SP7-selective promoter element (PMID:28784721, PMID:23682129, PMID:22396760).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2003 High

    Established that BMP-2 induction of Osterix proceeds through Dlx5 independently of Runx2, revealing a branched upstream signaling logic for osteoblast commitment.

    Evidence Dlx5 antisense knockdown, Runx2-null cells, and Runx2 overexpression with BMP-2 treatment and RT-PCR

    PMID:12963046

    Open questions at the time
    • Did not map the Dlx5 element on the Osx promoter
    • Did not exclude additional parallel inputs
  2. 2006 High

    Showed Runx2 directly binds and transactivates the Osx promoter, defining a Runx2-dependent arm of Osx induction alongside the Dlx5 route.

    Evidence Luciferase promoter-reporter assays, deletion/mutation analysis, EMSA, and 5' RACE

    PMID:16574347

    Open questions at the time
    • In vitro promoter assays only
    • Relative contribution of Runx2 vs Dlx5 arms in vivo not quantified
  3. 2007 High

    Identified the Dlx5 homeodomain element on the Osx promoter and showed p38 phosphorylation of Dlx5 amplifies its transactivation, connecting BMP signaling to Osx induction mechanistically.

    Evidence Promoter-reporter assays, ChIP, kinase assays, and Dlx5 mutagenesis

    PMID:18056716

    Open questions at the time
    • Focused on Dlx5 regulation rather than Osx protein function
    • Did not address Osx auto-feedback
  4. 2008 High

    Defined a Smad1/Smad4/Msx2-mediated Runx2-independent route for BMP2-driven Osx, expanding the upstream network beyond Dlx5.

    Evidence Smad/Msx2 overexpression, Msx2 siRNA in Runx2-null cells, RT-PCR, and microarray

    PMID:18703512

    Open questions at the time
    • Direct Smad/Msx2 binding sites on Osx promoter not mapped
    • Crosstalk with Dlx5 arm unresolved
  5. 2010 High

    Demonstrated that p38 phosphorylation of Osterix at Ser-73/77 promotes coactivator recruitment, establishing PTM-controlled assembly of the transcriptional machinery at target promoters.

    Evidence Kinase assays, mutagenesis, ChIP, Co-IP with p300/Brg1, and reporter assays

    PMID:20682789

    Open questions at the time
    • GC-box binding model later refined by non-canonical AT-rich mode
    • Single lab
  6. 2014 High

    Established that Osx and Runx2 physically interact and cooperatively activate osteogenic genes in a MAPK-phosphorylation-dependent manner, unifying the two upstream factors as a transcriptional complex.

    Evidence Co-IP, domain mapping, promoter-reporter assays, MAPK inhibition, and ChIP across two studies

    PMID:25122769 PMID:25158187

    Open questions at the time
    • Stoichiometry and structure of the Osx-Runx2 complex unknown
    • Genome-wide co-occupancy not mapped
  7. 2016 High

    Resolved the central paradox of SP7's atypical DNA binding: its zinc finger has reduced GC-box affinity and engages AT-rich osteoblast enhancers via Dlx5, redefining SP7 as a Dlx-recruited co-factor.

    Evidence ChIP-seq, transgenic enhancer assays, domain mapping, and sequence comparison

    PMID:27134141

    Open questions at the time
    • Structural basis of the Dlx5-zinc finger interface not solved
    • Direct vs indirect enhancer occupancy distinction incomplete
  8. 2018 High

    Identified SIRT7-mediated deacylation at K368 as a post-translational activator of Osx, linking a sirtuin to bone formation in vivo.

    Evidence Co-IP, in vitro deacylation assay, K368 mutagenesis, and germline/osteoblast-specific Sirt7 knockout mice

    PMID:30026585

    Open questions at the time
    • Acyl group identity at K368 not fully defined
    • Interplay with other Osx PTMs not mapped
  9. 2021 High

    Established SP7's role in osteocyte dendrite formation and identified Osteocrin as a direct, rescuing target, extending SP7 function beyond osteoblast commitment into osteocyte maturation.

    Evidence Conditional knockout mice, ChIP-seq, single-cell RNA-seq, Osteocrin rescue, and human variant analysis

    PMID:34725346

    Open questions at the time
    • Full set of dendrite-relevant SP7 targets not enumerated
    • Mechanism by which Osteocrin shapes dendrites unresolved
  10. 2022 High

    A neomorphic SP7 p.S309W variant that converts DNA-binding specificity from AT-rich to GC-consensus directly demonstrated that SP7's atypical specificity is functionally essential and disease-relevant.

    Evidence Biochemical DNA-binding analysis, knock-in mouse model, and expression profiling

    PMID:35121733

    Open questions at the time
    • Structural mechanism of the specificity switch not solved
    • Spectrum of clinical SP7 variants not catalogued here
  11. 2024 High

    Comprehensive osteoblast-specific knockout defined SP7's dual role in suppressing immature osteoblast proliferation while driving maturation, Col1a1 expression, and osteocyte process formation.

    Evidence Two conditional/hypomorphic mouse models, micro-CT, histomorphometry, BrdU, and gain-of-function in primary osteoblasts

    PMID:39027344

    Open questions at the time
    • Direct targets mediating proliferation arrest not identified
    • Mechanism of increased osteoclast/cortical porosity downstream unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many post-translational modifications, p53 repression, and epigenetic promoter switches are integrated dynamically to set SP7 activity thresholds during osteoblast-to-osteocyte transition remains unresolved.
  • No structural model of the SP7-Dlx5-Runx2 enhancer complex
  • Hierarchy and crosstalk among PTMs not established
  • Quantitative model linking SP7 dosage to lineage stage lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 5
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1266738 Developmental Biology 4 R-HSA-4839726 Chromatin organization 3
Partners
CBPDLX3DLX5NO66RUNX2SIRT7TP53

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 BMP-2-induced Osterix (Osx) expression is mediated by Dlx5 but is independent of Runx2; antisense blocking of Dlx5 completely abrogated BMP-2-induced Osx expression, while Runx2 overexpression in myogenic C2C12 cells did not induce Osx, and Osx was still induced by BMP-2 in Runx2-null cells. Antisense knockdown of Dlx5, Runx2-null cells, BMP-2 treatment, RT-PCR Biochemical and biophysical research communications High 12963046
2006 Runx2 directly transactivates the Osterix (Osx) promoter by binding to a Runx-responsive element in the proximal promoter region; mutation of this element abrogated Runx2-mediated transactivation. Promoter-reporter (luciferase) assays, deletion/mutation analysis, EMSA (Runx2 binding to Osx promoter DNA), 5' RACE Gene High 16574347
2007 BMP-2 induces Osterix expression through Dlx5, which binds a homeodomain sequence in the proximal Osterix promoter; p38 MAPK phosphorylates Dlx5 at Ser-34 and Ser-217, increasing its transactivation potential and thereby driving Osterix expression. Promoter-reporter assays, ChIP, Dlx5 overexpression/knockdown, in vitro and in vivo kinase assays, site-directed mutagenesis The Journal of biological chemistry High 18056716
2008 BMP2 regulates Osterix expression via two mechanisms: a Runx2-dependent pathway and a Runx2-independent pathway mediated by Smad1/Smad4 and Msx2; Smad6 (inhibitory Smad) suppresses BMP2-induced Osterix in Runx2-null cells, and knockdown of Msx2 inhibits BMP2-induced Osterix in Runx2-null mesenchymal cells. Overexpression of Smad1/Smad4/Smad6/Msx2, siRNA knockdown of Msx2, Runx2-null cells, RT-PCR, microarray The Journal of biological chemistry High 18703512
2010 Osterix is phosphorylated by p38 MAPK at Ser-73 and Ser-77; phosphorylation at these sites enhances Osterix's ability to recruit the coactivators p300 and Brg1 (SWI/SNF) to the fibromodulin and bone sialoprotein promoters, increasing transcriptional activity. Osterix binds GC-rich (Sp1 consensus) sequences in these promoters. In vitro and in vivo p38 kinase assays, site-directed mutagenesis, ChIP, Co-IP (protein-protein interaction with p300 and Brg1), promoter-reporter assays The Journal of biological chemistry High 20682789
2014 Osterix (Osx) and Runx2 physically interact and cooperatively induce osteogenic target genes (Col1a1, Fmod, Ibsp); this cooperation requires adjacent Sp1 and Runx2 DNA binding sites in target promoters and protein-protein interaction between Osx and Runx2. Phosphorylation of both proteins by p38 and ERK MAPKs at known sites is required for their physical interaction and cooperative transcriptional activity; mutation or inhibition of these phosphorylation sites disrupts complex formation. Co-IP, promoter-reporter assays, MAPK inhibition, mutagenesis of phosphorylation sites, ChIP The Journal of biological chemistry High 25122769
2016 Sp7/Osterix acts non-canonically: its zinc finger domain has reduced affinity for GC-box sequences (typical Sp family target) due to amino acid differences, and instead Sp7 engages osteoblast enhancers at AT-rich motifs through interaction with Dlx5. ChIP-seq identified a large set of predicted osteoblast enhancers; Dlx5 binding maps to the Sp7 zinc finger domain, supporting a model of Dlx-recruited Sp7 to AT-rich regulatory elements. ChIP-seq, transgenic mouse enhancer assays, cell culture reporter assays, domain mapping, amino acid sequence comparison Developmental cell High 27134141
2018 SIRT7 deacylates Osterix (OSX) at lysine K368 in its C-terminal region, promoting OSX N-terminal transactivation activity. SIRT7 physically interacts with OSX. SIRT7-mediated deacylation of K368 also facilitates SIRT1-mediated depropionylation of OSX, further increasing transactivation activity. Germline and osteoblast-specific Sirt7 knockout mice show severe osteopenia with decreased bone formation. Co-IP, site-directed mutagenesis (K368), in vitro deacylation assay, Sirt7 knockout mice (germline and osteoblast-specific), bone histomorphometry Nature communications High 30026585
2021 Sp7 drives osteocyte dendrite formation; deletion of Sp7 in osteoblasts/osteocytes causes defects in osteocyte dendrites. ChIP-seq and profiling of Sp7 target genes identified Osteocrin as a direct Sp7 target gene that promotes osteocyte dendrite formation and rescues dendrite defects in Sp7-deficient mice. Single-cell RNA-seq showed defects in osteocyte maturation without Sp7. Humans with SP7-R316C mutation show defective osteocyte morphology. Conditional Sp7 knockout mice, ChIP-seq, single-cell RNA-seq, rescue experiments with Osteocrin, histology, human genetic variant analysis Nature communications High 34725346
2011 Osterix (Osx) directly binds the Satb2 promoter at two GC-rich regions and transcriptionally activates Satb2 expression; Satb2 is downstream of Osx during bone formation. In Osx-null calvaria Satb2 is down-regulated; siRNA-mediated inhibition of Satb2 significantly inhibits Osx-induced osteoblast marker gene expression. Gel shift assay (EMSA), ChIP, promoter-reporter/deletion/point-mutation assays, siRNA knockdown, stable Osx-overexpressing cells (Tet-off system), qRT-PCR The Journal of biological chemistry High 21828043
2011 Osterix (Osx) directly binds to and transcriptionally activates the VEGF promoter via two GC-rich regions; endogenous Osx associates with the native VEGF promoter in primary osteoblasts (ChIP). VEGF is down-regulated in Osx-null calvarial cells and in Osx conditional knockout mice tibiae. Gel shift assay, ChIP, promoter-reporter/deletion/point-mutation assays, siRNA knockdown, Tet-off overexpression, Osx-null and conditional KO mice, immunohistochemistry The Journal of biological chemistry High 22110141
2012 MMP13 is a direct transcriptional target of Osterix (Osx) in osteoblasts; Osx binds a GC-rich region in the proximal 80 bp of the MMP13 promoter (EMSA and ChIP), and endogenous Osx is associated with the native MMP13 promoter in primary osteoblasts. MMP13 expression is dramatically reduced in Osx-null calvaria. Gel shift assay (EMSA), ChIP, promoter-reporter/deletion/point-mutation assays, siRNA knockdown, stable Osx-overexpressing cells, Osx-null mice PloS one High 23185634
2011 Akt phosphorylates Osterix and increases its protein stability, osteogenic activity, and transcriptional activity. BMP-2 increases Osterix protein levels in an Akt-dependent manner. Kinase assay, overexpression of constitutively active Akt, luciferase reporter assays, protein stability assays, BMP-2 treatment with Akt inhibitors Biochemical and biophysical research communications Medium 21777568
2011 Erk1/2 regulates Osterix protein levels and transcriptional activity; constitutively active MEK increases Osterix mRNA, protein, and transcriptional activity and stabilizes Osterix protein, while MEK inhibitor (U0126) suppresses Osterix protein levels and transcriptional activity. Constitutively active MEK overexpression, MEK inhibitor U0126, luciferase reporter assays, protein stability assays Biochemical and biophysical research communications Medium 22056560
2013 Osterix is subject to ubiquitin-proteasome-mediated degradation; K58 and K230 are ubiquitination sites identified by Co-IP and protein stability assays. Mutation of K58 and K230 (K58R/K230R) promoted osteoblast differentiation markers and enhanced osteogenic differentiation in C2C12 cells. Co-IP (ubiquitination), proteasome inhibitor treatment, site-directed mutagenesis of lysine residues, luciferase reporter assays, osteogenic differentiation assays PloS one Medium 23457570
2016 Osterix is acetylated by CBP at K307 and K312; HDAC4 deacetylates Osterix. CBP-Osx interaction and co-localization were confirmed. Acetylation of Osx at K307/K312 enhances protein stability, DNA binding ability, and transcriptional activity, and is required for osteogenic differentiation of C2C12 cells. Co-IP, immunofluorescence colocalization, HDAC inhibitor treatment, site-directed mutagenesis (K307A/K312A), reporter assays, osteogenic differentiation assays Oncotarget Medium 27250035
2013 CaMKII interacts with Osterix (Co-IP), increases Osterix protein levels, and enhances its transcriptional activity; CaMKII inhibitor KN-93 decreases Osterix protein levels, and siRNA knockdown of CaMKII decreases Osterix protein and transcriptional activity. Co-IP, CaMKII inhibitor (KN-93), siRNA knockdown, reporter assays Biochemical and biophysical research communications Medium 23402759
2017 p53 physically interacts with Osterix (Osx/SP7) through a region adjacent to the OSX zinc fingers and the DNA-binding domain of p53; this interaction represses OSX transcriptional activity and inhibits OSX binding to GC-rich responsive Sp1 sites in osteogenic target gene promoters (IBSP, COL1A1). p53 also sequesters OSX from interacting with DLX5, blocking OSX co-factor activity at homeodomain-containing promoters. Co-IP (overexpressed and endogenous proteins), domain mapping, reporter assays, ChIP, conformational mutant analysis Cell death and differentiation High 28777372
2014 Runx2 (via its runt homology domain, RHD) physically interacts with Sp7/Osterix; co-expression of Runx2 and Sp7 synergistically activates the osteocalcin and FGF3 promoters (up to 130-fold), demonstrating cooperative transcriptional activation of cell-phenotype-restricted genes. Co-immunoprecipitation (endogenous proteins), domain mapping, promoter-reporter assays in epithelial and mesenchymal cells Connective tissue research High 25158187
2014 NO66 (a histone demethylase) interacts with Osterix and acts as a negative regulator of Osterix target genes. In Osx-null calvarial cells, the transcriptional repressors HP1 and NO66 occupancy at the Bsp gene is increased, while markers of active chromatin (H3K4me3, H3K36me3, H3ac) are reduced. Osx is required for active chromatin architecture at its target genes, and NO66 interacts with DNMT1A, HDAC1A, and HP1 to form repressor complexes; HP1 stimulates NO66 demethylase activity for H3K4me3 and H3K36me3. ChIP (multiple histone marks and transcriptional regulators), bisulfite sequencing (CpG methylation), Osx-null calvarial cells, Co-IP (NO66 with DNMT1A/HDAC1A/HP1) Journal of bone and mineral research High 24115157
2017 Sp7 gene silencing in undifferentiated mesenchymal cells is mediated by DNMT1/3-, HDAC1/2/4-, Setdb1/Suv39h1-, and Ezh1/2-containing repressor complexes; Sp7 gene activation during osteoblast differentiation involves Tet1/Tet2-mediated DNA demethylation and SWI/SNF-mediated chromatin remodeling. Inhibition of DNA methylation triggers histone modification changes and chromatin remodeling leading to Sp7 gene expression; Tet1/Tet2 silencing prevents Sp7 expression and impairs recruitment of COMPASS, Jmjd2a/Jmjd3, and SWI/SNF complexes to the Sp7 promoter. ChIP, siRNA knockdown (DNMT, HDAC, Tet1/2, SWI/SNF components), bisulfite sequencing, pharmacologic inhibitors Molecular and cellular biology High 28784721
2022 A de novo neomorphic missense variant in SP7 (p.S309W) alters the DNA-binding specificity of SP7 from AT-rich motifs (normal Sp7 target, distinct from other SP family members) to GC-consensus sequences (typical of other SP proteins), producing an aberrant gene expression profile including increased Col1a1 and endogenous Sp7 but decreased expression of genes involved in matrix mineralization. Corresponding knock-in mice recapitulate a complex skeletal phenotype distinct from Sp7-null mice. Structural/biochemical analysis of DNA binding specificity, knock-in mouse model, gene expression profiling, histomorphometry Nature communications High 35121733
2012 miR-93 directly targets Sp7 by binding to the coding sequence (CDS) region of Sp7 mRNA, reducing Sp7 protein without affecting its mRNA level. Sp7 binds to the promoter of miR-93 (confirmed by EMSA, ChIP, and promoter-luciferase assay) and represses miR-93 transcription, forming a regulatory feedback loop that controls osteoblast mineralization. Luciferase reporter assay (CDS targeting), EMSA, ChIP, miRNA overexpression/knockdown, Western blot Journal of bone and mineral research High 22467200
2013 miR-322 promotes osteoblast differentiation partly by targeting Tob2, which normally binds and mediates degradation of Osx mRNA; miR-322 suppresses Tob2, thereby stabilizing Osx mRNA and increasing Osterix expression. miRNA gain/loss-of-function, luciferase reporter assay (Tob2 3'-UTR), qRT-PCR, osteogenic differentiation assays The Journal of biological chemistry Medium 23564456
2010 Sp7/Osterix directly upregulates mouse Col5a1 (pro-α1(V) collagen) gene expression in osteoblastic cells via an Sp1 binding site in the proximal promoter; overexpression increases Col5a1 promoter activity and endogenous mRNA, siRNA knockdown decreases both, and mutation of the Sp1 site abrogates the effect. Promoter-reporter assays, siRNA knockdown, overexpression, mutation analysis Matrix biology Medium 20888414
2010 Sp7/Osterix upregulates Col5a3 (pro-α3(V) collagen) gene expression in osteoblastic cells via an Sp1 binding site in the core promoter; ChIP confirmed Sp7/Osterix interaction with the Col5a3 promoter in vivo. Promoter-reporter assays, siRNA knockdown, overexpression, ChIP Biochemical and biophysical research communications Medium 20206127
2014 Sp7/Osterix induces Col1a2 (pro-α2(I) collagen) gene expression via a GC-rich sequence in the proximal promoter; overexpression and siRNA knockdown confirm this, and the GC-rich sequence is specifically required in osteoblastic cells. Promoter-reporter assays, mutagenesis, siRNA knockdown, overexpression, osteoblast differentiation model Biochemical and biophysical research communications Medium 25172663
2016 Osterix (Osx) and RUNX2 cooperatively activate SOST (sclerostin) expression in human osteoblasts by binding to specific SP-protein family and AML1 consensus sequences near the SOST transcription start site; ChIP confirmed OSX and RUNX2 binding to the SOST promoter. ChIP, promoter-reporter assays, overexpression of OSX and RUNX2 Calcified tissue international Medium 27154028
2015 Osterix (Osx) upregulates DKK1 expression in cementoblasts, thereby downregulating canonical Wnt/β-catenin signaling (reduced β-catenin nuclear translocation and TCF1 levels); Osx conditional knockout (cKO) mice show reduced DKK1 and increased β-catenin, consistent with in vitro data. Overexpression of Osx in cementoblast cell line, cKO mice (Osx loxP × 2.3Col1-Cre), Western blot, rescue experiments with DKK1, LiCl/Wnt3a treatments International journal of biological sciences Medium 25678852
2006 TNF-α inhibits Osterix (Osx) transcription via MEK1/ERK1 signaling (not JNK, p38, or NFκB); MEK/ERK inhibitors abrogate TNF inhibition of Osx mRNA and promoter activity. Two independent Osx promoters (upstream of Osx1 and Osx2 start sites) are both inhibited by TNF. Promoter-reporter assays, deletion/mutation analysis, pharmacological inhibitors, EMSA (nuclear protein binding), mRNA stability assay The Journal of biological chemistry Medium 16410254
2006 p38 MAPK positively regulates Osterix expression at both mRNA and protein levels; inhibition of p38 down-regulates Osx in osteoblasts, and this inhibitory effect is significantly relieved in osteoblasts overexpressing Osx. In p53-/- osteoblasts (with sustained Osx expression), p38 inhibition has minimal effect on differentiation. p38 inhibitor treatment, Osx overexpression, p53-/- osteoblasts, differentiation assays Endocrinology Medium 17185377
2007 Runx3 directly binds to the Osterix promoter at a Runx-responsive element at -713 to -707 bp (site 3, AGTGGTT) and negatively regulates Osterix expression in dental pulp cells; mutation of site 3 abrogates Runx3-mediated down-regulation. Promoter-reporter assays with mutation analysis, EMSA, ChIP in dental pulp cells The Biochemical journal High 17352693
2009 Parathyroid hormone (PTH) inhibits Osterix mRNA and protein expression in osteoblasts via stimulation of cAMP/PKA signaling (mimicked by forskolin/8-bromo-cAMP/caGsα), mapping to two promoter regions flanking the Osx1 start site (-304/-119 and -71/+91); inhibition did not require new protein synthesis and did not involve mRNA stability changes. PTH treatment, cAMP analogues, dominant-negative constructs, promoter-reporter assays with deletion mapping, mRNA stability assays Journal of molecular endocrinology Medium 19505977
2013 Osterix autoregulates its own promoter by binding to a tandem repeat sequence in the Osx2 promoter region that selectively binds OSX but not other Sp factors (Sp1, Sp3, Klf10). PTH inhibits this autoregulation partly through suppression of p38 MAPK; constitutively active MKK6 (p38 activator) blocks PTH inhibition of OSX. Promoter-reporter assays, point-mutation analysis of binding sites, p38 inhibitors, constitutively active MKK6 expression Journal of molecular endocrinology Medium 23682129
2012 SP7 overexpression in mature osteoblasts (using 2.3 kb Col1a1 promoter) causes osteopenia, reduces osteocyte process numbers, reduces expression of Col1a1, Spp1, Ibsp, and Bglap2, and inhibits bone mineralization at late stages. SP7 positively autoregulates its own promoter (confirmed by ChIP showing endogenous SP7 binding the proximal Sp7 promoter). Transgenic mice (2.3 kb Col1a1-Sp7), adenoviral shRNA/overexpression in primary osteoblasts, BrdU incorporation, ChIP, double-transgenic (Sp7/Runx2) analysis PloS one High 22396760
2017 In odontoblasts, BMP-2 activates Dspp gene transcription via a Dlx3/Osx signaling pathway; Osx is a downstream target of Dlx3, and both Dlx3 and Osx activate the Dspp promoter. Protein-protein interaction between Dlx3 and Osx in odontoblasts was detected by Co-IP; two Dlx3 and one Osx binding sites on the Dspp promoter were confirmed by EMSA and ChIP. Co-IP, EMSA, ChIP, promoter-reporter/mutagenesis assays, luciferase assays, in vitro and in vivo BMP-2 treatment Scientific reports High 28883412
2016 TIEG1/KLF10 directly binds to and activates the Osterix promoter (confirmed by ChIP); TIEG1 is required for TGFβ- and BMP2-induced Osterix expression in osteoblasts. Loss of TIEG1 decreases Osterix mRNA, and restoration of TIEG1 in knockout osteoblasts rescues Osterix expression. ChIP, transfection reporter assays, siRNA knockdown, TIEG1 KO osteoblasts, domain mapping (zinc finger domain required) Biochemical and biophysical research communications Medium 26801561
2019 Conditional deletion of Osterix (Osx) in chondrocytes (Col2-Cre-ERT2) impairs secondary ossification in the tibial epiphysis, reducing trabecular bone mass, trabecular number, and expression of MMP13, COL10, ALP, and BSP; Osx overexpression in ATDC5 chondrocytes increases Col10, Mmp13, Alp, and Bsp expression, supporting a role for chondrocyte Osx in regulating genes involved in hypertrophy and osteoblast transdifferentiation. Conditional knockout mice (Osx fl/fl; Col2-Cre-ERT2), tamoxifen induction, µCT, histology, IHC, overexpression in ATDC5 cells Bone research High 31646014
2019 Sp7 directly regulates dlx2b and bglap expression in zebrafish through Sp7-binding sites on their promoters (confirmed by cell transfection reporter assays); loss of sp7 by CRISPR/Cas9 knockout reduces dlx2b and bglap expression and causes defects in bone mineralization and tooth development. CRISPR/Cas9 knockout in zebrafish, qRT-PCR, cell transfection promoter assays Journal of biosciences Medium 31894108
2017 Melatonin inhibits ubiquitin-proteasome-mediated degradation of Osterix, thereby stabilizing its expression and increasing Osterix transcriptional activity on the osteogenic promoter. Melatonin-induced Osterix phosphorylation and transcriptional activity are blocked by PKA inhibitor H89 and PKC inhibitor Go6976. Proteasome inhibitor treatment, ubiquitination assays, PKA/PKC inhibitors, reporter assays, osteogenic differentiation assays Scientific reports Medium 28720849
2004 The human SP7 gene encodes a 431 amino acid C2H2 zinc finger transcription factor of the SP family with three consecutive C2H2 zinc finger repeats; two alternatively spliced isoforms exist. SP7 maps to chromosome 12q13.13. SP7 mRNA is restricted to osteoblast-derived cell lines in vitro and is expressed specifically in osteoblasts in vivo (confirmed by in situ hybridization on human embryonic tissues). cDNA cloning, Northern blot, in situ hybridization, FISH (chromosomal mapping), sequence analysis Gene Medium 15474293
2024 Osteoblast-specific deletion of Sp7 (using 2.3-kb Col1a1-EGFP-Cre) reveals that Sp7 inhibits proliferation of immature osteoblasts, induces osteoblast maturation and Col1a1 expression, and is required for osteocyte process formation; Sp7 overexpression directly induces Col1a1 expression. Loss of Sp7 in osteoblasts causes reduced osteocyte canaliculi, increased TUNEL-positive lacunae, increased osteoclasts, and cortical porosity. Conditional knockout mice (Sp7 fl/fl; 2.3kb-Col1a1-EGFP-Cre), hypomorphic Sp7 mice, micro-CT, histomorphometry, BrdU incorporation, RT-PCR, primary osteoblast cultures, Sp7 overexpression Journal of orthopaedic translation High 39027344
2021 SIRT7 forms a complex with RBM6 that downregulates H3K18 acetylation at the OSX promoter, inhibiting OSX isoform 1 and 2 expression and osteogenic differentiation of MSCs. lncRNA PLXDC2-OT associates with the SIRT7/RBM6 complex, diminishing its binding and deacetylation activity at the OSX promoter and thereby promoting osteogenesis. Co-IP (SIRT7-RBM6 interaction), ChIP (H3K18Ac at OSX promoter), siRNA knockdown, lncRNA-protein interaction assay, osteogenic differentiation assays in vitro and in vivo Stem cells Medium 33684230

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 BMP2 regulates Osterix through Msx2 and Runx2 during osteoblast differentiation. The Journal of biological chemistry 427 18703512
2003 BMP-2-induced Osterix expression is mediated by Dlx5 but is independent of Runx2. Biochemical and biophysical research communications 331 12963046
2006 Runx2-mediated regulation of the zinc finger Osterix/Sp7 gene. Gene 260 16574347
2005 BMP-2 and insulin-like growth factor-I mediate Osterix (Osx) expression in human mesenchymal stem cells via the MAPK and protein kinase D signaling pathways. The Journal of biological chemistry 259 16000303
2013 Genetic and molecular control of osterix in skeletal formation. Journal of cellular biochemistry 223 23225263
2009 Runx2, osx, and dspp in tooth development. Journal of dental research 223 19783797
2014 Osx-Cre targets multiple cell types besides osteoblast lineage in postnatal mice. PloS one 196 24454809
2007 BMP-2 induces Osterix expression through up-regulation of Dlx5 and its phosphorylation by p38. The Journal of biological chemistry 185 18056716
2010 Transcriptional regulation of bone formation by the osteoblast-specific transcription factor Osx. Journal of orthopaedic surgery and research 155 20550694
2005 Osx transcriptional regulation is mediated by additional pathways to BMP2/Smad signaling. Journal of cellular biochemistry 130 15786511
2006 Transcriptional regulation of the osterix (Osx, Sp7) promoter by tumor necrosis factor identifies disparate effects of mitogen-activated protein kinase and NF kappa B pathways. The Journal of biological chemistry 115 16410254
2014 Mitogen-activated protein kinase (MAPK)-regulated interactions between Osterix and Runx2 are critical for the transcriptional osteogenic program. The Journal of biological chemistry 111 25122769
2010 p38 regulates expression of osteoblast-specific genes by phosphorylation of osterix. The Journal of biological chemistry 109 20682789
2016 Sp7/Osterix Is Restricted to Bone-Forming Vertebrates where It Acts as a Dlx Co-factor in Osteoblast Specification. Developmental cell 103 27134141
2008 Osterix/Sp7 regulates mesenchymal stem cell mediated endochondral ossification. Journal of cellular physiology 97 17579353
2012 miR-93/Sp7 function loop mediates osteoblast mineralization. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 94 22467200
2018 Long noncoding RNA MALAT1 promotes osterix expression to regulate osteogenic differentiation by targeting miRNA-143 in human bone marrow-derived mesenchymal stem cells. Journal of cellular biochemistry 93 29741283
2018 SIRT7 has a critical role in bone formation by regulating lysine acylation of SP7/Osterix. Nature communications 90 30026585
2013 miR-145 and miR-143 regulate odontoblast differentiation through targeting Klf4 and Osx genes in a feedback loop. The Journal of biological chemistry 90 23430263
2021 Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin. Nature communications 89 34725346
2016 Targeted disruption of sp7 and myostatin with CRISPR-Cas9 results in severe bone defects and more muscular cells in common carp. Scientific reports 86 26976234
2015 Scleraxis and osterix antagonistically regulate tensile force-responsive remodeling of the periodontal ligament and alveolar bone. Development (Cambridge, England) 80 25670797
2012 The transcription factor osterix (SP7) regulates BMP6-induced human osteoblast differentiation. Journal of cellular physiology 80 21898406
2006 p38 mitogen-activated protein kinase regulates osteoblast differentiation through osterix. Endocrinology 80 17185377
2014 Osterix-Cre transgene causes craniofacial bone development defect. Calcified tissue international 77 25550101
2012 SP7 inhibits osteoblast differentiation at a late stage in mice. PloS one 77 22396760
2013 MicroRNA-322 (miR-322) and its target protein Tob2 modulate Osterix (Osx) mRNA stability. The Journal of biological chemistry 75 23564456
2011 Osteoblast-specific transcription factor Osterix (Osx) is an upstream regulator of Satb2 during bone formation. The Journal of biological chemistry 74 21828043
2016 Osterix and RUNX2 are Transcriptional Regulators of Sclerostin in Human Bone. Calcified tissue international 73 27154028
2015 Osterix controls cementoblast differentiation through downregulation of Wnt-signaling via enhancing DKK1 expression. International journal of biological sciences 71 25678852
2019 LncRNA ODIR1 inhibits osteogenic differentiation of hUC-MSCs through the FBXO25/H2BK120ub/H3K4me3/OSX axis. Cell death & disease 70 31827076
2016 Osterix/Sp7 limits cranial bone initiation sites and is required for formation of sutures. Developmental biology 68 26992365
2017 Melatonin promotes osteoblast differentiation by regulating Osterix protein stability and expression. Scientific reports 64 28720849
2011 Transcriptional regulation of Vascular Endothelial Growth Factor (VEGF) by osteoblast-specific transcription factor Osterix (Osx) in osteoblasts. The Journal of biological chemistry 63 22110141
2014 Skeletal defects in Osterix-Cre transgenic mice. Transgenic research 62 25139670
2022 Klotho in Osx+-mesenchymal progenitors exerts pro-osteogenic and anti-inflammatory effects during mandibular alveolar bone formation and repair. Signal transduction and targeted therapy 60 35538062
2015 Osterix regulates tooth root formation in a site-specific manner. Journal of dental research 58 25568170
2017 p53 inhibits SP7/Osterix activity in the transcriptional program of osteoblast differentiation. Cell death and differentiation 57 28777372
2015 Different Methylation Patterns of RUNX2, OSX, DLX5 and BSP in Osteoblastic Differentiation of Mesenchymal Stem Cells. Cell journal 55 25870836
2011 Akt phosphorylates and regulates the osteogenic activity of Osterix. Biochemical and biophysical research communications 54 21777568
2004 Molecular cloning, structure, expression, and chromosomal localization of the human Osterix (SP7) gene. Gene 54 15474293
2012 Synergistic inhibition of Wnt pathway by HIF-1α and osteoblast-specific transcription factor osterix (Osx) in osteoblasts. PloS one 53 23300831
2003 Expression of alternatively spliced isoforms of human Sp7 in osteoblast-like cells. BMC genomics 53 14604442
2012 Matrix metalloproteinase 13 (MMP13) is a direct target of osteoblast-specific transcription factor osterix (Osx) in osteoblasts. PloS one 50 23185634
2011 Dexamethasone modulates osteogenesis and adipogenesis with regulation of osterix expression in rat calvaria-derived cells. Journal of cellular physiology 50 20717928
2014 Wnts produced by Osterix-expressing osteolineage cells regulate their proliferation and differentiation. Proceedings of the National Academy of Sciences of the United States of America 47 25422448
2015 Expression of osterix Is Regulated by FGF and Wnt/β-Catenin Signalling during Osteoblast Differentiation. PloS one 46 26689368
2006 Parathyroid hormone regulates osterix and Runx2 mRNA expression predominantly through protein kinase A signaling in osteoblast-like cells. Journal of endocrinological investigation 46 16610234
2024 Regulation of Skeletal Development and Maintenance by Runx2 and Sp7. International journal of molecular sciences 45 39337587
2022 β-Ecdysterone Enhanced Bone Regeneration Through the BMP-2/SMAD/RUNX2/Osterix Signaling Pathway. Frontiers in cell and developmental biology 44 35669516
2019 Mg2+ in β-TCP/Mg-Zn composite enhances the differentiation of human bone marrow stromal cells into osteoblasts through MAPK-regulated Runx2/Osx. Journal of cellular physiology 43 31742679
2018 Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment. Bone 42 29382611
2016 TGF-β Signaling Regulates Cementum Formation through Osterix Expression. Scientific reports 41 27180803
2011 Osterix is regulated by Erk1/2 during osteoblast differentiation. Biochemical and biophysical research communications 41 22056560
2013 Characterization of Osterix protein stability and physiological role in osteoblast differentiation. PloS one 40 23457570
2014 Osterix and NO66 histone demethylase control the chromatin of Osterix target genes during osteoblast differentiation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 39 24115157
2019 Deficiency of Macf1 in osterix expressing cells decreases bone formation by Bmp2/Smad/Runx2 pathway. Journal of cellular and molecular medicine 38 31709715
2016 Osterix acetylation at K307 and K312 enhances its transcriptional activity and is required for osteoblast differentiation. Oncotarget 37 27250035
2009 Protein palmitoylation regulates osteoblast differentiation through BMP-induced osterix expression. PloS one 37 19125191
2015 Ucma, a direct transcriptional target of Runx2 and Osterix, promotes osteoblast differentiation and nodule formation. Osteoarthritis and cartilage 36 25865393
2019 CCN3 Facilitates Runx2 and Osterix Expression by Inhibiting miR-608 through PI3K/Akt Signaling in Osteoblasts. International journal of molecular sciences 34 31284378
2013 Calmodulin-dependent kinase II regulates osteoblast differentiation through regulation of Osterix. Biochemical and biophysical research communications 34 23402759
2017 Tet-Mediated DNA Demethylation Is Required for SWI/SNF-Dependent Chromatin Remodeling and Histone-Modifying Activities That Trigger Expression of the Sp7 Osteoblast Master Gene during Mesenchymal Lineage Commitment. Molecular and cellular biology 33 28784721
2016 Role of Osterix and MicroRNAs in Bone Formation and Tooth Development. Medical science monitor : international medical journal of experimental and clinical research 32 27543160
2022 A neomorphic variant in SP7 alters sequence specificity and causes a high-turnover bone disorder. Nature communications 31 35121733
2012 Molecular mechanisms of osteoblast-specific transcription factor Osterix effect on bone formation. Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences 30 23073571
2022 Sp7 Action in the Skeleton: Its Mode of Action, Functions, and Relevance to Skeletal Diseases. International journal of molecular sciences 29 35628456
2019 Conditional disruption of the osterix gene in chondrocytes during early postnatal growth impairs secondary ossification in the mouse tibial epiphysis. Bone research 29 31646014
2017 A Reciprocal Interaction between β-Catenin and Osterix in Cementogenesis. Scientific reports 29 28811640
2010 Sp7/Osterix is involved in the up-regulation of the mouse pro-α1(V) collagen gene (Col5a1) in osteoblastic cells. Matrix biology : journal of the International Society for Matrix Biology 29 20888414
2015 Identification of novel osteogenic compounds by an ex-vivo sp7:luciferase zebrafish scale assay. Bone 28 25600250
2012 Osterix is required for Sonic hedgehog-induced osteoblastic MC3T3-E1 cell differentiation. Cell biochemistry and biophysics 28 22648388
2018 MiR-96 regulates bone metabolism by targeting osterix. Clinical and experimental pharmacology & physiology 27 29288578
2017 Epigenetic Signatures at the RUNX2-P1 and Sp7 Gene Promoters Control Osteogenic Lineage Commitment of Umbilical Cord-Derived Mesenchymal Stem Cells. Journal of cellular physiology 27 27689934
2017 BMP-2 induced Dspp transcription is mediated by Dlx3/Osx signaling pathway in odontoblasts. Scientific reports 27 28883412
2014 Sp7 and Runx2 molecular complex synergistically regulate expression of target genes. Connective tissue research 27 25158187
1998 Identification and isolation of the indole-3-pyruvate decarboxylase gene from Azospirillum brasilense Sp7: sequencing and functional analysis of the gene locus. Current microbiology 27 9608743
2014 Osterix/Sp7 regulates biomineralization of otoliths and bone in medaka (Oryzias latipes). Matrix biology : journal of the International Society for Matrix Biology 26 24407212
2019 Sp7/osterix positively regulates dlx2b and bglap to affect tooth development and bone mineralization in zebrafish larvae. Journal of biosciences 25 31894108
2010 Polymethylmethacrylate particles impair osteoprogenitor viability and expression of osteogenic transcription factors Runx2, osterix, and Dlx5. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 25 20014320
2010 Sp7/Osterix up-regulates the mouse pro-alpha3(V) collagen gene (Col5a3) during the osteoblast differentiation. Biochemical and biophysical research communications 25 20206127
2010 Dynamic expression of Runx2, Osterix and AJ18 in the femoral head of steroid-induced osteonecrosis in rats. Orthopaedic surgery 25 22009963
2016 Site-specific function and regulation of Osterix in tooth root formation. International endodontic journal 24 26599722
2017 Zinc finger transcription factor Sp7/Osterix acts on bone formation and regulates col10a1a expression in zebrafish. Science bulletin 23 36659402
2023 SP7: from Bone Development to Skeletal Disease. Current osteoporosis reports 22 36881265
2020 miR‑27a‑3p negatively regulates osteogenic differentiation of MC3T3‑E1 preosteoblasts by targeting osterix. Molecular medicine reports 22 32705283
2010 The effects of Sp7/Osterix gene silencing in the chondroprogenitor cell line, ATDC5. Biochemical and biophysical research communications 22 21075078
2009 Regulation of osterix (Osx, Sp7) and the Osx promoter by parathyroid hormone in osteoblasts. Journal of molecular endocrinology 22 19505977
2021 LncRNA, PLXDC2-OT promoted the osteogenesis potentials of MSCs by inhibiting the deacetylation function of RBM6/SIRT7 complex and OSX specific isoform. Stem cells (Dayton, Ohio) 21 33684230
2019 miR‑124 regulates the osteogenic differentiation of bone marrow‑derived mesenchymal stem cells by targeting Sp7. Molecular medicine reports 21 30896834
2017 Pseudoshikonin I enhances osteoblast differentiation by stimulating Runx2 and Osterix. Journal of cellular biochemistry 21 28657691
2014 Sp7/Osterix induces the mouse pro-α2(I) collagen gene (Col1a2) expression via the proximal promoter in osteoblastic cells. Biochemical and biophysical research communications 21 25172663
2013 Regulation of the osterix (Osx, Sp7) promoter by osterix and its inhibition by parathyroid hormone. Journal of molecular endocrinology 21 23682129
2024 Roles of Sp7 in osteoblasts for the proliferation, differentiation, and osteocyte process formation. Journal of orthopaedic translation 20 39027344
2022 Dominant osteogenesis imperfecta with low bone turnover caused by a heterozygous SP7 variant. Bone 20 35367406
2022 Identification of kaempferol as an OSX upregulator by network pharmacology-based analysis of qianggu Capsule for osteoporosis. Frontiers in pharmacology 20 36210811
2018 Osterix promotes the migration and angiogenesis of breast cancer by upregulation of S100A4 expression. Journal of cellular and molecular medicine 20 30450809
2016 TIEG1 enhances Osterix expression and mediates its induction by TGFβ and BMP2 in osteoblasts. Biochemical and biophysical research communications 20 26801561
2014 The effects of osterix on the proliferation and odontoblastic differentiation of human dental papilla cells. Journal of endodontics 20 25258338
2007 Runx3 negatively regulates Osterix expression in dental pulp cells. The Biochemical journal 20 17352693

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