Fibroblasts expressing Sonic hedgehog induce osteoblast differentiation and ectopic bone formation

Kinto, Naoki; Iwamoto, Masahiro; Enomoto‐Iwamoto, Motomi; Noji, Sumihare; Ohuchi, Hideyo; Yoshioka, Hidefumi; Kataoka, Hiroko; Wada, Yasuhiro; Gao, Yuhao; Takahashi, Hideaki; Yoshiki, Shusaku; Yamaguchi, Akira

doi:10.1016/s0014-5793(97)00014-8

Cited by 118 publications

(80 citation statements)

References 25 publications

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“…Third, mouse embryos made deficient in Ndst2 or Ndst3 function did not show delayed ossification (not shown). Lastly, Ndst1 is the predominant Ndst expressed in multipotent C3H10T1/2 mouse mesenchymal precursor cells, which, under the induction of Hhs, differentiate into AP-producing osteoblasts (Kinto et al, 1997). The importance of Ndst1 in Hh-induced C3H10T1/2 differentiation was shown by siRNAi, and the general importance of HS in that system was confirmed by chlorate treatment or addition of heparin, which resulted in undersulfated cell surface HS (Safaiyan et al, 1999) or competing Hh binding sites in the medium, respectively, resulting in reduced availability of soluble Hh to cell surface HS.…”

Section: Discussionmentioning

confidence: 99%

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Heparan sulfate Ndst1 gene function variably regulates multiple signaling pathways during mouse development

Pallerla

Pan

Zhang

et al. 2006

Developmental Dynamics

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Disruption of heparan sulfate (HS) synthesis in vertebrate development causes malformations that are composites of those caused by mutations of multiple HS binding growth factors and morphogens. We previously reported severe developmental defects of the forebrain and the skull in mutant mice bearing a targeted disruption of the heparan sulfate-generating enzyme GlcNAc N-deacetylase/GlcN Nsulfotransferase 1 (Ndst1). Here, we further characterize the molecular mechanisms leading to frontonasal dysplasia in Ndst1 mutant embryos and describe additional malformations, including impaired spinal and cranial neural tube fusion and skeletal abnormalities. Of the numerous proteins that bind HS, we show that impaired fibroblast growth factor, Hedgehog, and Wnt function may contribute to some of these phenotypes. Our findings, therefore, suggest that defects in HS synthesis may contribute to multifactor types of congenital developmental defects in humans, including neural tube defects. Developmental Dynamics 236: 556 -563, 2007.

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Section: Discussionmentioning

confidence: 99%

“…3g; Kinto et al, 1997). C3H10T1/2 cells can serve as a model for early stages of endochondral bone formation, in which alkaline phosphatase-expressing osteoblastic cells derived from the periosteum establish and calcify an osteoid matrix.…”

Section: Defects Of the Skeleton And Reduced Expression Of The Osteogmentioning

confidence: 99%

Heparan sulfate Ndst1 gene function variably regulates multiple signaling pathways during mouse development

Pallerla

Pan

Zhang

et al. 2006

Developmental Dynamics

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“…S4). We also retrovirally transduced Arhgap36 into C3H10T1/2 cells, which differentiate into alkaline phosphatase-expressing osteoblasts upon Hh pathway activation (19). Arhgap36 promoted alkaline phosphatase expression in these cells, and its activity could be further enhanced by ShhN (Fig.…”

Section: Significancementioning

confidence: 99%

Arhgap36-dependent activation of Gli transcription factors

Rack¹,

Ni²,

Payumo³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Hedgehog (Hh) pathway activation and Gli-dependent transcription play critical roles in embryonic patterning, tissue homeostasis, and tumorigenesis. By conducting a genome-scale cDNA overexpression screen, we have identified the Rho GAP family member Arhgap36 as a positive regulator of the Hh pathway in vitro and in vivo. Arhgap36 acts in a Smoothened (Smo)-independent manner to inhibit Gli repressor formation and to promote the activation of full-length Gli proteins. Arhgap36 concurrently induces the accumulation of Gli proteins in the primary cilium, and its ability to induce Gli-dependent transcription requires kinesin family member 3a and intraflagellar transport protein 88, proteins that are essential for ciliogenesis. Arhgap36 also functionally and biochemically interacts with Suppressor of Fused. Transcriptional profiling further reveals that Arhgap36 is overexpressed in murine medulloblastomas that acquire resistance to chemical Smo inhibitors and that ARHGAP36 isoforms capable of Gli activation are upregulated in a subset of human medulloblastomas. Our findings reveal a new mechanism of Gli transcription factor activation and implicate ARHGAP36 dysregulation in the onset and/or progression of GLI-dependent cancers.

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“…Transfection of HaCaT cells with GLI2b resulted in a fivefold increase in GLI1 mRNA levels, suggesting a positive feedback mechanism between GLI1 and GLI2 in human keratinocytes (Figure 2a). Since it is conceivable that this mechanism applies to human cells only, we turned to mouse C3H10T1/2 fibroblasts, which are frequently used to assay Hh-signalling (Kinto et al, 1997). We transfected C3H10T1/2 cells with either human GLI1, GLI2b or control expression plasmids and measured mouse Gli1 or mouse Gli2 transcripts by real-time PCR.…”

Section: Gli2b Activates Expression Of Gli1 and Induces Osteoblast DImentioning

confidence: 99%

Human GLI2 and GLI1 are part of a positive feedback mechanism in Basal Cell Carcinoma

et al. 2002

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Fibroblasts expressing Sonic hedgehog induce osteoblast differentiation and ectopic bone formation

Cited by 118 publications

References 25 publications

Heparan sulfate Ndst1 gene function variably regulates multiple signaling pathways during mouse development

Heparan sulfate Ndst1 gene function variably regulates multiple signaling pathways during mouse development

Arhgap36-dependent activation of Gli transcription factors

Human GLI2 and GLI1 are part of a positive feedback mechanism in Basal Cell Carcinoma

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