Affinage

SP7

Transcription factor Sp7 · UniProt Q8TDD2

Length
431 aa
Mass
45.0 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SP7 (Osterix) is a zinc-finger transcription factor that serves as a master regulator of osteoblast differentiation, osteocyte maturation, cementogenesis, and endochondral ossification. SP7 binds GC-rich (Sp1-type) and AT-rich promoter elements to directly activate osteogenic target genes including Col1a1, MMP13, Satb2, VEGF, Col5a1/a3, SOST, and Osteocrin, and it physically cooperates with NFATc1, Runx2, and DLX5 to achieve synergistic transcriptional activation (PMID:16041384, PMID:22869368, PMID:21828043, PMID:22110141, PMID:34725346, PMID:25158187). SP7 expression is induced downstream of BMP-2 signaling through both Runx2-dependent and Runx2-independent (Dlx5/Msx2-Smad) pathways, and its transcriptional output is modulated by p38 MAPK phosphorylation at S73/S77 (enhancing coactivator recruitment of p300 and Brg1), acetylation by CBP at K307/K312, deacylation by SIRT7 at K368, and ubiquitin-proteasome-mediated turnover at K58/K230 (PMID:18703512, PMID:12963046, PMID:20682789, PMID:27250035, PMID:30026585, PMID:23457570). Beyond osteoblast differentiation, SP7 drives osteocyte dendrite formation through direct transcriptional activation of Osteocrin, and a neomorphic S309W variant that shifts SP7 DNA-binding specificity from AT-rich to GC-consensus motifs produces a skeletal disease phenotype distinct from loss-of-function, demonstrating that SP7's unique AT-rich binding preference is functionally critical (PMID:34725346, PMID:35121733).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2003 High

    Establishing that SP7 expression is controlled by BMP-2 through Dlx5 rather than Runx2 alone resolved how SP7 could be induced in Runx2-null cells and positioned SP7 downstream of a BMP-Dlx5 axis.

    Evidence Antisense Dlx5 knockdown blocked BMP-2-induced Osterix in C2C12 and Runx2-null cells

    PMID:12963046

    Open questions at the time
    • Dlx5 binding site on Osterix promoter not mapped in this study
    • relative contribution of Dlx5 vs. Runx2 pathway in vivo not quantified
  2. 2005 High

    Discovery that NFATc1 physically complexes with SP7 to co-activate Col1a1 established the first identified transcriptional partner that specifies SP7 target gene selectivity.

    Evidence Co-IP and promoter-reporter assays in osteoblasts with FK506 pharmacological validation

    PMID:16041384

    Open questions at the time
    • genome-wide set of NFATc1-Osx co-regulated targets unknown
    • structural basis of NFATc1-Osx interaction not resolved
  3. 2006 High

    Demonstration that Runx2 directly binds the SP7 promoter and activates transcription established SP7 as a direct transcriptional target of Runx2, clarifying the epistatic hierarchy in osteoblast differentiation.

    Evidence EMSA and promoter deletion/mutation reporter assays in C3H10T1/2 and ATDC5 cells

    PMID:16574347

    Open questions at the time
    • chromatin context of Runx2-Osx promoter regulation not examined
    • whether Runx2 is sufficient or only necessary for Osx induction in vivo unclear
  4. 2007 High

    Mapping p38 MAPK phosphorylation of Dlx5 at S34/S217 as the mechanism enhancing Dlx5 transactivation of the Osterix promoter connected BMP-p38 signaling to Osterix induction through a defined phosphorylation cascade.

    Evidence ChIP, EMSA, in vitro kinase assay, and Dlx5 phospho-site mutagenesis with luciferase reporters

    PMID:18056716

    Open questions at the time
    • in vivo phospho-Dlx5 levels at Osterix promoter not measured
    • other kinases targeting Dlx5 not excluded
  5. 2008 High

    Identification of a parallel Runx2-independent pathway (Smad1/Smad4/Msx2) for BMP2-induced Osterix expression explained how Osterix can be activated even in Runx2-deficient contexts.

    Evidence Overexpression of Smad/Msx2 and siRNA knockdown of Msx2 in Runx2-null mesenchymal cells

    PMID:18703512

    Open questions at the time
    • whether Msx2 directly binds the Osx promoter not shown
    • quantitative contribution of each pathway in different skeletal elements unknown
  6. 2010 High

    Mapping p38 MAPK phosphorylation of SP7 itself at S73/S77 and showing that this enhances recruitment of coactivators p300 and Brg1 established a direct post-translational mechanism by which signaling modulates SP7 transcriptional output at target genes.

    Evidence In vitro p38 kinase assay, site-directed mutagenesis, ChIP for p300/Brg1 at fibromodulin and BSP promoters

    PMID:20682789

    Open questions at the time
    • whether other kinases phosphorylate these sites in vivo
    • structural basis of phospho-dependent coactivator recruitment unknown
  7. 2011 High

    Identification of Satb2 and VEGF as direct SP7 transcriptional targets (via GC-rich promoter binding confirmed by ChIP and EMSA) expanded the SP7 regulon beyond structural matrix genes to include angiogenic and chromatin-remodeling factors.

    Evidence ChIP, EMSA, promoter mutagenesis, and Osx-null calvarial cells for Satb2; conditional KO mice with decreased VEGF for VEGF

    PMID:21828043 PMID:22110141

    Open questions at the time
    • full genome-wide direct target repertoire not yet defined at this stage
    • whether VEGF regulation is osteoblast-stage-specific unknown
  8. 2012 High

    Demonstration that SP7 cooperates with Runx2 to induce MMP13, and that Osx-null mice arrest at hypertrophic chondrocyte stage, established SP7 as essential for endochondral ossification beyond intramembranous bone formation.

    Evidence Co-IP of Osx-Runx2, global and conditional Osx KO mice, MMP13 rescue experiment

    PMID:22869368 PMID:23185634

    Open questions at the time
    • specific DNA element architecture mediating Osx-Runx2 cooperation at MMP13 not fully resolved
    • whether other MMPs are similarly co-regulated unknown
  9. 2013 High

    Identification of K58 and K230 as ubiquitination sites controlling SP7 proteasomal degradation revealed how SP7 protein levels are dynamically regulated; stabilizing mutations enhanced osteoblast differentiation.

    Evidence Proteasome inhibitor treatment, ubiquitination Co-IP, K-to-R mutagenesis, protein stability assays

    PMID:23457570

    Open questions at the time
    • E3 ubiquitin ligase responsible not identified
    • relationship between ubiquitination and acetylation at nearby sites unexplored
  10. 2014 High

    Showing that SP7 governs the chromatin landscape at target genes (Bsp) — controlling H3K4me3, H3K36me3, activator/repressor occupancy — established SP7 as a chromatin state organizer, not merely a conventional transcription factor.

    Evidence ChIP for multiple histone marks and chromatin regulators (Wdr5, c-Myc, NO66, HP1) in Osx-null vs. WT calvarial cells, NO66 demethylase activity assay

    PMID:24115157

    Open questions at the time
    • whether SP7 directly recruits or excludes these chromatin regulators versus indirect effects
    • genome-wide chromatin changes in Osx-null cells not surveyed
  11. 2016 High

    Mapping CBP-mediated acetylation at K307/K312 and HDAC4-mediated deacetylation as regulators of SP7 stability and DNA-binding defined a second post-translational switch (in addition to phosphorylation) controlling SP7 activity.

    Evidence Co-IP, site-directed mutagenesis of K307/K312, HDAC inhibitor treatment, osteogenic differentiation assays in C2C12

    PMID:27250035

    Open questions at the time
    • interplay between acetylation at K307/K312 and ubiquitination at K58/K230 not studied
    • in vivo significance of these acetylation events not tested in mice
  12. 2016 High

    Discovery that p53 physically interacts with SP7 to block its DNA binding and disrupt the DLX5-Osx complex explained how p53 restrains osteogenesis and provided a mechanism linking tumor suppression to skeletal development.

    Evidence Reciprocal Co-IP, EMSA, ChIP, experiments in p53-null and Runx2-null cells, conformational p53 mutant analysis

    PMID:28777372

    Open questions at the time
    • whether this mechanism operates in osteosarcoma pathogenesis in vivo
    • structural details of the p53-Osx interface unknown
  13. 2018 High

    Identification of SIRT7-mediated deacylation of SP7 at K368 as a mechanism enhancing transactivation, with Sirt7-KO mice showing osteopenia, connected NAD-dependent sirtuin signaling to SP7 functional regulation in vivo.

    Evidence Germline and osteoblast-specific Sirt7 KO mice, deacylation assays, K368 mutagenesis, bone histomorphometry

    PMID:30026585

    Open questions at the time
    • identity of the acyl modification (acetyl vs. other acyl groups) at K368 not fully characterized
    • relative importance of SIRT7 vs. SIRT1 at K368 in different osteoblast stages
  14. 2021 High

    Genome-wide SP7 binding analysis revealed osteocyte dendrite formation as a key SP7-dependent process, with Osteocrin identified as a direct target that rescues dendrite defects, fundamentally expanding SP7's role from osteoblast differentiation to osteocyte morphogenesis.

    Evidence SP7 ChIP-seq, conditional Sp7 KO, scRNA-seq, Osteocrin transgenic rescue, human SP7(R316C) patient analysis

    PMID:34725346

    Open questions at the time
    • how SP7 target gene repertoire shifts between osteoblast and osteocyte stages
    • signaling pathways connecting Osteocrin to dendrite extension unknown
  15. 2022 High

    A neomorphic S309W variant showed that SP7 uniquely among SP-family members prefers AT-rich motifs, and switching this to GC-consensus produces a distinct skeletal disease, establishing DNA-binding specificity — not just binding per se — as critical to SP7 function.

    Evidence Human patient study, S309W knock-in mouse, DNA-binding specificity assays, transcriptomic profiling

    PMID:35121733

    Open questions at the time
    • structural basis for SP7's AT-rich preference vs. other SP factors unknown
    • full set of AT-rich-dependent vs. GC-rich-dependent targets not delineated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The E3 ubiquitin ligase(s) targeting SP7 for proteasomal degradation remain unidentified, the structural basis for SP7's unique AT-rich DNA-binding preference is unresolved, and a comprehensive understanding of how multiple post-translational modifications (phosphorylation, acetylation, deacylation, ubiquitination) are coordinated on SP7 during osteoblast-to-osteocyte transition is lacking.
  • E3 ligase for SP7 ubiquitination unidentified
  • no crystal/cryo-EM structure of SP7 zinc-finger domain bound to AT-rich DNA
  • integrated PTM crosstalk model not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 6
Localization
GO:0005634 nucleus 4
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 4
Partners
CBPDLX3DLX5HDAC4NFATC1RUNX2SIRT7TP53

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 NFATc1 forms a physical complex with Osterix that binds DNA, and this interaction is required for Osterix-dependent activation of the Col1a1 promoter; overexpression of NFATc1 stimulates Osterix-dependent Col1a1 transcription but not Runx2-dependent osteocalcin promoter activation. Co-immunoprecipitation, promoter-reporter assays, overexpression in osteoblasts, FK506 pharmacological inhibition Nature medicine High 16041384
2008 BMP2 induces Osterix expression through two parallel pathways: a Runx2-dependent pathway and a Runx2-independent pathway mediated by Smad1/Smad4 and the homeobox transcription factor Msx2; Msx2 knockdown blocks BMP2-induced Osterix in Runx2-null cells. Overexpression of Smad1/Smad4/Msx2, siRNA knockdown of Msx2, BMP2 treatment of Runx2-deficient mesenchymal cells, Smad6 inhibitory overexpression, microarray The Journal of biological chemistry High 18703512
2003 BMP-2-induced Osterix expression is mediated by Dlx5 rather than Runx2; antisense knockdown of Dlx5 abrogates BMP-2-induced Osterix expression, and Runx2 overexpression alone does not induce Osterix in myogenic C2C12 cells. Antisense oligonucleotide knockdown of Dlx5, Runx2 overexpression in C2C12 cells, cycloheximide experiments, BMP-2 treatment of Runx2-null cells Biochemical and biophysical research communications High 12963046
2006 Runx2 directly binds a Runx2 responsive element in the Osterix promoter and transcriptionally activates Osterix expression; mutation of this element abolishes Runx2-mediated transactivation. Promoter deletion and mutation analysis, luciferase reporter assay, EMSA, transient transfection in C3H10T1/2 and ATDC5 cells Gene High 16574347
2007 BMP-2 induces Dlx5 expression, which then directly binds a homeodomain sequence in the Osterix promoter to activate transcription; p38 MAPK phosphorylates Dlx5 at Ser-34 and Ser-217, enhancing its transactivation potential and thus Osterix expression. ChIP, EMSA, Dlx5 overexpression/knockdown, p38 in vitro kinase assay, site-directed mutagenesis of Dlx5 phosphorylation sites, luciferase reporter assay The Journal of biological chemistry High 18056716
2010 p38 MAPK phosphorylates Osterix at Ser-73 and Ser-77 in vitro and in vivo; phosphorylation at these sites enhances Osterix recruitment of the coactivators p300 and Brg1 to the promoters of target genes fibromodulin and bone sialoprotein. Osterix binds to Sp1 (GC-rich GGGCGG) sequences on target gene promoters. In vitro p38 kinase assay, site-directed mutagenesis, ChIP, Co-immunoprecipitation of p300/Brg1, EMSA, promoter-reporter assays The Journal of biological chemistry High 20682789
2012 Osterix physically interacts with Runx2, and this complex cooperatively induces MMP13 expression to regulate cartilage matrix calcification during endochondral ossification; Osterix-deficient mice arrest at the hypertrophic stage of endochondral ossification and show defective MMP13 expression and matrix vesicle formation. Co-immunoprecipitation, conditional and global Osx knockout mice, microarray, rescue experiment with MMP13 introduction, limb bud cell assays The Journal of biological chemistry High 22869368
2012 Osterix directly activates MMP13 gene transcription by binding a GC-rich element in the proximal 80 bp of the MMP13 promoter; endogenous Osterix associates with the native MMP13 promoter in primary osteoblasts in vivo. Promoter deletion and point mutation analysis, luciferase reporter assay, EMSA (gel shift), ChIP, siRNA knockdown and stable overexpression PloS one High 23185634
2011 Osterix directly activates Satb2 promoter transcription by binding GC-rich elements in the proximal 130 bp; endogenous Osterix associates with the native Satb2 promoter in osteoblasts in vivo, and Satb2 siRNA inhibits Osx-induced osteoblast marker gene expression. qRT-PCR in Osx-null calvaria, Tet-Off overexpression system, siRNA, promoter deletion/point mutation analysis, EMSA, ChIP The Journal of biological chemistry High 21828043
2011 Osterix directly activates VEGF gene transcription by binding two GC-rich elements in the proximal 140 bp of the VEGF promoter; endogenous Osterix associates with the native VEGF promoter in primary osteoblasts, and conditional Osx knockout mice show decreased VEGF protein in bone. qRT-PCR in Osx-null calvarial cells, Tet-Off stable overexpression, siRNA, promoter deletion/point mutation analysis, EMSA, ChIP, immunohistochemistry in conditional KO mice The Journal of biological chemistry High 22110141
2018 SIRT7 deacylates Osterix at lysine K368 in its C-terminal region, promoting N-terminal transactivation activity; SIRT7-mediated deacylation of K368 also facilitates subsequent depropionylation by SIRT1. Germline and osteoblast-specific Sirt7 knockout mice show severe osteopenia with decreased bone formation. Germline and conditional (osteoblast-specific) Sirt7 knockout mice, Co-immunoprecipitation, site-directed mutagenesis of K368, deacylation assays, bone histomorphometry Nature communications High 30026585
2016 A de novo p53 missense variant abrogates osteogenesis; p53 physically interacts with Osterix through a region adjacent to the Osx zinc fingers and the p53 DNA-binding domain, repressing OSX transcriptional activity and preventing OSX binding to GC-rich sites on osteogenic promoters (IBSP, COL1A1). p53 also sequesters Osx from DLX5, blocking the DLX5–Osx co-activation of homeodomain-containing promoters. Co-immunoprecipitation of overexpressed and endogenous proteins, promoter-reporter assays, EMSA, ChIP, p53-null and Runx2-null cell experiments, conformational p53 mutant Cell death and differentiation High 28777372
2022 A neomorphic SP7 variant (S309W) alters DNA-binding specificity from AT-rich motifs (unique to SP7 among SP family members) to GC-consensus sequences typical of other SP proteins, producing an aberrant gene expression profile including increased Col1a1 and Sp7, but decreased genes involved in matrix mineralization. Mice with the corresponding variant show a complex skeletal phenotype distinct from Sp7-null mice. Human patient study, knock-in mouse model with corresponding variant, bone histomorphometry, transcriptomic profiling, DNA-binding specificity assays Nature communications High 35121733
2021 SP7 drives osteocyte dendrite formation and osteocytogenesis; deletion of Sp7 in osteoblasts/osteocytes causes defects in osteocyte dendrites. Osteocrin is identified as a direct SP7 target gene that promotes dendrite formation and rescues dendrite defects in Sp7-deficient mice. A SP7(R316C) mutation in humans causes defective osteocyte morphology. Conditional Sp7 knockout, SP7 ChIP-seq (target gene/binding site profiling), single-cell RNA-sequencing, transgenic rescue with Osteocrin, human patient analysis Nature communications High 34725346
2013 Osterix is ubiquitinated at lysine residues K58 and K230, and this ubiquitin-proteasome-mediated degradation regulates Osterix stability; K58R and K230R point mutations enhance Osterix stability and promote osteoblast differentiation markers in C2C12 cells. Proteasome inhibitor (MG-132, lactacystin) treatment, Co-IP ubiquitination assay, site-directed mutagenesis, protein stability assays, luciferase reporter assay PloS one High 23457570
2016 Osterix is acetylated by CBP (and less efficiently p300) at K307 and K312; HDAC4 mediates deacetylation of Osterix. Acetylation at these sites enhances Osterix stability, DNA-binding ability, and transcriptional activity, and is required for osteogenic differentiation of C2C12 cells. HDAC inhibitor treatment, Co-immunoprecipitation, immunofluorescence co-localization, site-directed mutagenesis of K307/K312, transcriptional reporter assays, osteogenic differentiation assays Oncotarget High 27250035
2014 Runx2 physically interacts with Sp7 through the Runx homology domain (RHD) of Runx2; the two proteins synergistically (not additively) activate osteocalcin and FGF3 promoters in both epithelial and mesenchymal cells, indicating functional cooperation requiring physical interaction. Co-immunoprecipitation of endogenous proteins, domain-deletion analysis of Runx2, promoter-reporter synergy assays in multiple cell lines Connective tissue research High 25158187
2014 Osterix controls the chromatin state at its target gene Bsp: in Osx-null calvarial cells, occupancy of transcriptional activators (Wdr5, c-Myc, H2A.Z) is markedly decreased and H3K4me3, H3K36me3, and H3ac marks are reduced at Bsp, while the repressor NO66 (a histone demethylase) and HP1 occupancy increases. HP1 stimulates NO66 demethylase activity toward H3K4me3 and H3K36me3. NO66 interacts with DNMT1A and HDAC1A. ChIP in Osx-null vs. wild-type calvarial cells, Co-IP (NO66 interactions), bisulfite sequencing of Bsp promoter CpG methylation, NO66 demethylase activity assay Journal of bone and mineral research High 24115157
2015 Osterix (c-Src substrate): c-Src kinase physically interacts with and phosphorylates Osterix, increasing Osterix protein stability and transcriptional activity; siRNA knockdown or pharmacological inhibition of c-Src reduces Osterix protein levels and transcriptional activity. Co-immunoprecipitation, in vitro phosphorylation assay, siRNA knockdown, Src inhibitor (SU6656), transcriptional reporter assays Molecular and cellular endocrinology Medium 25802190
2013 CaMKII interacts with Osterix and increases its protein levels and transcriptional activity; siRNA-mediated knockdown of CaMKII decreases Osterix protein levels and transcriptional activity. Co-immunoprecipitation, CaMKII inhibitor (KN-93), siRNA knockdown, transcriptional reporter assay Biochemical and biophysical research communications Medium 23402759
2012 miR-93 directly targets the coding sequence (CDS) region of Sp7 mRNA to suppress Sp7 protein without affecting mRNA levels; conversely, Sp7 binds the miR-93 promoter to repress miR-93 transcription, forming a feedback loop regulating osteoblast mineralization. Luciferase reporter assay (CDS targeting), EMSA, ChIP on miR-93 promoter, overexpression/inhibition experiments in primary osteoblasts Journal of bone and mineral research High 22467200
2015 Osterix upregulates DKK1 expression in cementoblasts, thereby reducing β-catenin protein levels and nuclear translocation to suppress canonical Wnt signaling; this mechanism controls cementoblast proliferation and differentiation, confirmed in Osx conditional KO mice showing reduced DKK1 and increased β-catenin. Osx overexpression in cementoblast cell line, qRT-PCR, Western blot for β-catenin, LiCl/Wnt3a Wnt activation, conditional Osx KO mice (2.3 Col1-Cre) International journal of biological sciences Medium 25678852
2010 Sp7/Osterix activates the mouse pro-α1(V) collagen gene (Col5a1) in osteoblastic cells by binding a Sp1-binding site in the proximal promoter; overexpression increases and siRNA knockdown decreases Col5a1 promoter activity and endogenous mRNA levels in osteoblastic but not non-osteoblastic cells. Promoter mutation analysis, Osx overexpression, siRNA knockdown, osteoblast differentiation model Matrix biology Medium 20888414
2010 Sp7/Osterix activates the mouse pro-α3(V) collagen gene (Col5a3) in osteoblastic cells by binding to a Sp1 site in its core promoter, as confirmed by ChIP assay. Osx overexpression, siRNA knockdown, promoter-reporter assay, ChIP, osteoblast differentiation model Biochemical and biophysical research communications Medium 20206127
2007 Runx3 directly binds to the Osterix promoter at a Runx responsive element at -713 to -707 bp and negatively regulates Osterix expression in dental pulp cells; mutation of this site abrogates Runx3-mediated repression. Promoter mutation analysis, luciferase reporter assay, EMSA, ChIP in dental pulp cells The Biochemical journal High 17352693
2006 p38 MAPK positively regulates Osterix expression and osteoblast differentiation: pharmacological inhibition of p38 reduces Osterix protein and mRNA, but has minimal effect on osteoblasts with sustained Osterix overexpression; Osx overexpression rescues the differentiation block caused by p38 inhibition. p38 inhibitor treatment, dominant-negative p38, Osx overexpression rescue, p53-/- osteoblasts (which overexpress Osx), RT-PCR, protein analysis Endocrinology Medium 17185377
2017 In odontoblasts, Dlx3 and Osx physically interact (Co-IP), and both bind independently to the Dspp promoter (Dlx3 at two sites, Osx at one site identified by EMSA and ChIP); Osx is a downstream target of Dlx3 and both activate Dspp transcription, mediating BMP-2-regulated Dspp expression. Co-immunoprecipitation, ChIP, EMSA, luciferase reporter with promoter deletions and site-directed mutagenesis, BMP-2 treatment in vivo and in vitro Scientific reports High 28883412
2016 Osterix regulates Lef1 expression and Tcf/Lef-binding activity in canonical Wnt signaling during cementogenesis; constitutively active β-catenin upregulates Osx expression by directly binding the Osx promoter, and ablation of Osx prevents β-catenin-induced excessive cementum formation. Transgenic mice with constitutively active β-catenin and conditional Osx ablation, retroviral transduction, promoter binding analysis, in vivo cementum phenotyping Scientific reports Medium 28811640
2013 Osterix promotes expression of ZBTB16 in human mesenchymal stromal cells by directly binding GC-rich Sp1 sequences in the ZBTB16 promoter, as shown by ChIP; ZBTB16 acts as a downstream transcriptional regulator of Osx required for osteoblastogenesis. Next-generation sequencing transcriptome analysis, siRNA knockdown of Osx and ZBTB16, ChIP of Osx at ZBTB16 promoter Journal of cellular biochemistry Medium 27335174
2009 PTH (1-34) inhibits Osterix mRNA and protein expression in osteoblasts through stimulation of cAMP; this effect is mediated by inhibition of p38 MAPK signaling and maps to two promoter regions (-304/-119 and -71/+91 relative to the Osx1 start site); PTH inhibition occurs without requiring new protein synthesis or altered mRNA stability. PTH/forskolin/cAMP analog treatment, luciferase reporter with Osx promoter deletions, constitutively active Gsα/Gqα, p38 inhibitor, MKK6 overexpression Journal of molecular endocrinology Medium 19505977
2013 Osterix autoregulates its own promoter by binding to tandem repeat sequences that selectively bind Osx but not other Sp factors (Sp1, Sp3, Klf10); mutation of either or both repeats eliminates 90% of promoter activity and partially abrogates PTH-mediated inhibition. Mithramycin A inhibitor, promoter deletion/mutation analysis, transcription factor binding site mutation, luciferase reporter assay Journal of molecular endocrinology Medium 23682129
2003 Human SP7 (Osterix) maps to 12q13.13 and encodes two alternatively spliced isoforms (long 431-aa α and short 413-aa β); expression in humans is largely restricted to osteoblasts and chondrocytes, with the short isoform predominating; the protein contains three Cys2-His2 zinc fingers with 78% identity to Sp1 in the DNA-binding domain. cDNA cloning, RT-PCR in human fetal osteoblasts and osteosarcoma lines, protein isoform characterization by Western blot BMC genomics Medium 14604442
2019 lnc-ob1 upregulates Osterix expression in osteoblasts, likely via inhibition of H3K27me3 methylation at the Osterix locus; osteoblast-specific knock-in enhances bone formation and protects against ovariectomy-induced osteoporosis in mice. Osteoblast-specific knock-in mice, pharmacological lnc-ob1 overexpression, H3K27me3 analysis, bone mass measurement Nature metabolism Medium 32694877
2019 LNCODIR1 inhibits Osterix expression by facilitating proteasomal degradation of FBXO25 (by recruiting CUL3), which reduces H2BK120 mono-ubiquitination and H3K4me3 at the Osterix promoter, thereby closing chromatin and suppressing Osterix transcription. lncRNA knockdown/overexpression, Co-IP (ODIR1-FBXO25-CUL3 complex), ChIP (H2BK120ub, H3K4me3 at Osx promoter), in vitro and in vivo osteogenic differentiation Cell death & disease Medium 31827076
2008 Osterix/Sp7 inhibits chondrocyte differentiation while promoting osteoblast maturation; in chondro/osteoprogenitor cells, gain-of-function of Osx inhibits chondrogenic markers, and PTHrP enhances Osx mRNA in these cells. MLB13MYC Clone 17 chondro/osteoprogenitor cell gain/loss-of-function assays, fracture callus mRNA analysis, PTHrP treatment Journal of cellular physiology Medium 17579353
2018 SP7/Osterix directly binds the SOST promoter to transactivate sclerostin expression; increased SOST methylation in osteoporotic patients impairs SP7, RUNX2, and ERα binding to the SOST promoter as shown by ChIP. ChIP in human bone samples, promoter reporter assay, bisulfite sequencing, AzadC demethylation treatment Biochemistry and cell biology Medium 30257098
2021 SIRT7 forms a complex with RBM6 that recruits SIRT7 to the Osterix promoter to deacetylate H3K18Ac, thereby repressing OSX isoforms 1 and 2 expression; lncRNA PLXDC2-OT disrupts this complex, relieving repression and promoting osteogenic differentiation. Co-IP (SIRT7-RBM6 complex), ChIP (H3K18Ac at Osx promoter), siRNA knockdown, lncRNA overexpression, osteogenic differentiation assays 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 425 18703512
2005 NFAT and Osterix cooperatively regulate bone formation. Nature medicine 368 16041384
2003 BMP-2-induced Osterix expression is mediated by Dlx5 but is independent of Runx2. Biochemical and biophysical research communications 327 12963046
2006 Runx2-mediated regulation of the zinc finger Osterix/Sp7 gene. Gene 260 16574347
2013 Genetic and molecular control of osterix in skeletal formation. Journal of cellular biochemistry 222 23225263
2009 Runx2, osx, and dspp in tooth development. Journal of dental research 220 19783797
2014 Osx-Cre targets multiple cell types besides osteoblast lineage in postnatal mice. PloS one 195 24454809
2007 BMP-2 induces Osterix expression through up-regulation of Dlx5 and its phosphorylation by p38. The Journal of biological chemistry 184 18056716
2010 Transcriptional regulation of bone formation by the osteoblast-specific transcription factor Osx. Journal of orthopaedic surgery and research 155 20550694
2012 Osterix regulates calcification and degradation of chondrogenic matrices through matrix metalloproteinase 13 (MMP13) expression in association with transcription factor Runx2 during endochondral ossification. The Journal of biological chemistry 137 22869368
2016 Parathyroid hormone receptor signalling in osterix-expressing mesenchymal progenitors is essential for tooth root formation. Nature communications 116 27068606
2006 Osterix enhances proliferation and osteogenic potential of bone marrow stromal cells. Biochemical and biophysical research communications 114 16466699
2010 p38 regulates expression of osteoblast-specific genes by phosphorylation of osterix. The Journal of biological chemistry 109 20682789
2012 Genetic evidence for the vital function of Osterix in cementogenesis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 102 22246569
2013 Histone demethylase Jmjd3 regulates osteoblast differentiation via transcription factors Runx2 and osterix. The Journal of biological chemistry 97 24106268
2008 Osterix/Sp7 regulates mesenchymal stem cell mediated endochondral ossification. Journal of cellular physiology 96 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
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
2018 SIRT7 has a critical role in bone formation by regulating lysine acylation of SP7/Osterix. Nature communications 89 30026585
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
2021 Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin. Nature communications 85 34725346
2015 Mechanosensitive TRPM7 mediates shear stress and modulates osteogenic differentiation of mesenchymal stromal cells through Osterix pathway. Scientific reports 82 26558702
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 79 17185377
2011 Osteoblast-specific transcription factor Osterix (Osx) is an upstream regulator of Satb2 during bone formation. The Journal of biological chemistry 74 21828043
2007 Osteoblast differentiation in vitro and in vivo promoted by Osterix. Journal of biomedical materials research. Part A 71 17559111
2019 LncRNA ODIR1 inhibits osteogenic differentiation of hUC-MSCs through the FBXO25/H2BK120ub/H3K4me3/OSX axis. Cell death & disease 70 31827076
2015 Osterix controls cementoblast differentiation through downregulation of Wnt-signaling via enhancing DKK1 expression. International journal of biological sciences 70 25678852
2016 Osterix/Sp7 limits cranial bone initiation sites and is required for formation of sutures. Developmental biology 68 26992365
2014 MiR-143 suppresses osteogenic differentiation by targeting Osterix. Molecular and cellular biochemistry 65 24381059
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 58 35538062
2019 The long noncoding RNA lnc-ob1 facilitates bone formation by upregulating Osterix in osteoblasts. Nature metabolism 56 32694877
2017 p53 inhibits SP7/Osterix activity in the transcriptional program of osteoblast differentiation. Cell death and differentiation 56 28777372
2015 Different Methylation Patterns of RUNX2, OSX, DLX5 and BSP in Osteoblastic Differentiation of Mesenchymal Stem Cells. Cell journal 55 25870836
2008 Bone regulatory factors NFATc1 and Osterix in human calcific aortic valves. International journal of cardiology 53 19019468
2003 Expression of alternatively spliced isoforms of human Sp7 in osteoblast-like cells. BMC genomics 53 14604442
2015 Essential role of osterix for tooth root but not crown dentin formation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 51 25349111
2014 NFI-C regulates osteoblast differentiation via control of osterix expression. Stem cells (Dayton, Ohio) 51 24801901
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
2019 VEGFA From Early Osteoblast Lineage Cells (Osterix+) Is Required in Mice for Fracture Healing. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 44 31081125
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
2022 β-Ecdysterone Enhanced Bone Regeneration Through the BMP-2/SMAD/RUNX2/Osterix Signaling Pathway. Frontiers in cell and developmental biology 42 35669516
1989 Identification of DNA regions homologous to nitrogen fixation genes nifE, nifUS and fixABC in Azospirillum brasilense Sp7. Journal of general microbiology 42 2695597
2018 Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment. Bone 41 29382611
2024 Regulation of Skeletal Development and Maintenance by Runx2 and Sp7. International journal of molecular sciences 40 39337587
2016 TGF-β Signaling Regulates Cementum Formation through Osterix Expression. Scientific reports 40 27180803
2013 Characterization of Osterix protein stability and physiological role in osteoblast differentiation. PloS one 39 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 38 24115157
2019 Deficiency of Macf1 in osterix expressing cells decreases bone formation by Bmp2/Smad/Runx2 pathway. Journal of cellular and molecular medicine 37 31709715
2009 Protein palmitoylation regulates osteoblast differentiation through BMP-induced osterix expression. PloS one 37 19125191
2016 Osterix acetylation at K307 and K312 enhances its transcriptional activity and is required for osteoblast differentiation. Oncotarget 36 27250035
2019 CCN3 Facilitates Runx2 and Osterix Expression by Inhibiting miR-608 through PI3K/Akt Signaling in Osteoblasts. International journal of molecular sciences 34 31284378
2015 Ucma, a direct transcriptional target of Runx2 and Osterix, promotes osteoblast differentiation and nodule formation. Osteoarthritis and cartilage 34 25865393
2016 ZBTB16 as a Downstream Target Gene of Osterix Regulates Osteoblastogenesis of Human Multipotent Mesenchymal Stromal Cells. Journal of cellular biochemistry 33 27335174
2013 Calmodulin-dependent kinase II regulates osteoblast differentiation through regulation of Osterix. Biochemical and biophysical research communications 33 23402759
2022 A neomorphic variant in SP7 alters sequence specificity and causes a high-turnover bone disorder. Nature communications 31 35121733
2016 Role of Osterix and MicroRNAs in Bone Formation and Tooth Development. Medical science monitor : international medical journal of experimental and clinical research 31 27543160
2009 T-box 3 negatively regulates osteoblast differentiation by inhibiting expression of osterix and runx2. Journal of cellular biochemistry 31 19115250
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
2015 Intermittent Stretching and Osteogenic Differentiation of Bone Marrow Derived Mesenchymal Stem Cells via the p38MAPK-Osterix Signaling Pathway. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 29 26112248
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 29 23073571
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
2016 A vertebrate-specific and essential role for osterix in osteogenesis revealed by gene knockout in the teleost medaka. Development (Cambridge, England) 28 27993982
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
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
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
2021 The Glucocorticoid Receptor in Osterix-Expressing Cells Regulates Bone Mass, Bone Marrow Adipose Tissue, and Systemic Metabolism in Female Mice During Aging. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 24 34747055
2016 Site-specific function and regulation of Osterix in tooth root formation. International endodontic journal 24 26599722
2015 Src enhances osteogenic differentiation through phosphorylation of Osterix. Molecular and cellular endocrinology 23 25802190
2020 miR‑27a‑3p negatively regulates osteogenic differentiation of MC3T3‑E1 preosteoblasts by targeting osterix. Molecular medicine reports 22 32705283
2013 An immunohistochemistry study of Sox9, Runx2, and Osterix expression in the mandibular cartilages of newborn mouse. BioMed research international 22 23762831
2009 Regulation of osterix (Osx, Sp7) and the Osx promoter by parathyroid hormone in osteoblasts. Journal of molecular endocrinology 22 19505977
2023 SP7: from Bone Development to Skeletal Disease. Current osteoporosis reports 21 36881265
2019 miR‑124 regulates the osteogenic differentiation of bone marrow‑derived mesenchymal stem cells by targeting Sp7. Molecular medicine reports 21 30896834
2019 MicroRNA-638 inhibits human aortic valve interstitial cell calcification by targeting Sp7. Journal of cellular and molecular medicine 21 31140727
2017 Pseudoshikonin I enhances osteoblast differentiation by stimulating Runx2 and Osterix. Journal of cellular biochemistry 21 28657691
2022 Identification of kaempferol as an OSX upregulator by network pharmacology-based analysis of qianggu Capsule for osteoporosis. Frontiers in pharmacology 20 36210811
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) 20 33684230
2018 miR-485-5p promotes osteoporosis via targeting Osterix. European review for medical and pharmacological sciences 20 30070309
2015 Selective regulation of Mmp13 by 1,25(OH)2D3, PTH, and Osterix through distal enhancers. The Journal of steroid biochemistry and molecular biology 20 26348136
2015 β-catenin signaling induces the osteoblastogenic differentiation of human pre-osteoblastic and bone marrow stromal cells mainly through the upregulation of osterix expression. International journal of molecular medicine 20 26496941
2014 The effects of osterix on the proliferation and odontoblastic differentiation of human dental papilla cells. Journal of endodontics 20 25258338
2013 Regulation of the osterix (Osx, Sp7) promoter by osterix and its inhibition by parathyroid hormone. Journal of molecular endocrinology 20 23682129
2007 Runx3 negatively regulates Osterix expression in dental pulp cells. The Biochemical journal 20 17352693
2018 Methylation of bone SOST impairs SP7, RUNX2, and ERα transactivation in patients with postmenopausal osteoporosis. Biochemistry and cell biology = Biochimie et biologie cellulaire 19 30257098
2018 Osterix promotes the migration and angiogenesis of breast cancer by upregulation of S100A4 expression. Journal of cellular and molecular medicine 19 30450809