Elucidation, Quantitative Refinement, and in Vivo Utilization of the HOXA13 DNA Binding Site

Knosp, Wendy M.; Saneyoshi, Chie; Shou, Siming; Bächinger, Hans Peter; Stadler, H. Scott

doi:10.1074/jbc.m610775200

Cited by 25 publications

(42 citation statements)

References 63 publications

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“…5I). Genes associated with joint interzone development or function, including Wnt9a (Archer et al, 2003;Pacifici et al, 2006) and doublecortin (Zhang et al, 2011;Zhang et al, 2007), as well as the BMP inhibitor sclerostin domain-containing protein 1 (Sostdc1) (Guo et al, 2010;Knosp et al, 2007), were also found to be expressed at significantly higher levels in Gdf5-treated cells than in the BMP4-treated populations (Fig. 5J-L).…”

Section: Research Articlementioning

confidence: 98%

Specification of chondrocytes and cartilage tissues from embryonic stem cells

et al. 2013

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SUMMARYOsteoarthritis primarily affects the articular cartilage of synovial joints. Cell and/or cartilage replacement is a promising therapy, provided there is access to appropriate tissue and sufficient numbers of articular chondrocytes. Embryonic stem cells (ESCs) represent a potentially unlimited source of chondrocytes and tissues as they can generate a broad spectrum of cell types under appropriate conditions in vitro. Here, we demonstrate that mouse ESC-derived chondrogenic mesoderm arises from a Flk-1 -/Pdgfrα + (F -P + ) population that emerges in a defined temporal pattern following the development of an early cardiogenic F -P + population. Specification of the late-arising F -P + population with BMP4 generated a highly enriched population of chondrocytes expressing genes associated with growth plate hypertrophic chondrocytes. By contrast, specification with Gdf5, together with inhibition of hedgehog and BMP signaling pathways, generated a population of non-hypertrophic chondrocytes that displayed properties of articular chondrocytes. The two chondrocyte populations retained their hypertrophic and non-hypertrophic properties when induced to generate spatially organized proteoglycan-rich cartilage-like tissue in vitro. Transplantation of either type of chondrocyte, or tissue generated from them, into immunodeficient recipients resulted in the development of cartilage tissue and bone within an 8-week period. Significant ossification was not observed when the tissue was transplanted into osteoblast-depleted mice or into diffusion chambers that prevent vascularization. Thus, through stage-specific manipulation of appropriate signaling pathways it is possible to efficiently and reproducibly derive hypertrophic and non-hypertrophic chondrocyte populations from mouse ESCs that are able to generate distinct cartilage-like tissue in vitro and maintain a cartilage tissue phenotype within an avascular and/or osteoblast-free niche in vivo.

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Section: Research Articlementioning

confidence: 98%

Specification of chondrocytes and cartilage tissues from embryonic stem cells

et al. 2013

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“…The gene has also been called Sostdc1 (Sclerostin domain-containing 1) or Sostl (Sclerostin-like) due to the homology with Sclerostin-encoding gene Sost (4,5). USAG-1/Wise/Ectodin/Sostdc1 is expressed in various tissues, such as the surface ectoderm of the posterior axis (1,6), branchial arches (3,6), the dermal papilla in hair follicles (7), vibrissae (3), mammalian tooth cusps (3,8), rat endometrium (2), developing testis (9 -11), interdigital tissues (12), and embryonic and adult kidneys (13,14).…”

mentioning

confidence: 99%

Characterization of Wise Protein and Its Molecular Mechanism to Interact with both Wnt and BMP Signals

Lintern

Guidato

Rowe

et al. 2009

Journal of Biological Chemistry

108

127

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“…HOXA13 is a transcriptional factor that negatively regulates USAG-1 expression. 27 We observed that renal expression of HOXA13 was significantly increased in the Ad þ SIM group compared with the Ad group (Figure 3h). These data indicate that SIM not only suppressed fibrotic pathway, but also enhanced anti-fibrotic pathway by downregulating a dominant BMP-7 antagonist USAG-1, and not by enhancing BMP-7 production.…”

Section: Evaluation Of the Molecules Associated With Fibrosis And Antmentioning

confidence: 81%

“…On the basis of the previous observation that homeobox protein Hox-A13 (HOXA13), a transcriptional factor, binds to USAG-1 coding DNA region and regulates USAG-1 expression in organogenesis, 27 0 . Subsequently, the cells were kept in serum-free medium for 24 h, and then they were placed into the 1% FBS-added medium containing recombinant human 5 ng/ml TGF-b1 (Sigma-Aldrich, St Louis, MO, USA) with or without 0.2 mM SIM for 72 h. 28,29 We decided the concentration of SIM to reduce toxicity and preserve efficacy of SIM based on the result of our preliminary experiments showing that MDCK cells were detached by 2 mM SIM treatment and USAG-1 expression was not changed by 0.02 mM SIM treatment (data not shown).…”

Section: Pathological Analysismentioning

confidence: 99%

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3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor simvastatin ameliorates renal fibrosis through HOXA13–USAG-1 pathway

Hamasaki

Doi

Okamoto

et al. 2012

Laboratory Investigation

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Epidemiological data have suggested that 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) prevent the progression of chronic kidney diseases (CKDs), whereas the precise mechanism explaining in vitro to in vivo is missing. This study is aimed at exploring a new mechanism of action by statins on renal fibrosis, a hallmark of CKD, using mouse renal fibrosis model in vivo and Madin-Darby canine kidney (MDCK) cells expressing USAG-1 in vitro. C57/BL6 mice fed a 0.2% adenine-containing diet for 4 weeks developed renal dysfunction accompanied with severe tubulointerstitial fibrosis. Subsequent simvastatin (SIM) treatment (50 mg/kg per day) for 2 weeks significantly suppressed fibrosis progression. We found that SIM enhanced bone morphogenetic protein-7 (BMP-7)-mediated anti-fibrotic signaling with the reduced expression of uterine sensitization-associated gene-1 (USAG-1), a BMP-7 antagonist produced by renal distal tubular epithelial cells. Therefore, MDCK cells were incubated with transforming growth factor-b1 and showed increased expression of USAG-1 and a-smooth muscle actin; SIM significantly reduced them. SIM significantly increased E-cadherin expression. Gene knockdown experiments using MDCK suggested that homeobox protein Hox-A13 (HOXA13) played a suppressive role in the USAG-1 gene and thus SIM reduced USAG-1 by increasing HOXA13 expression. The data from our study demonstrate that SIM, one of statins, contributes to prevent the progression of renal fibrosis by upregulating BMP-7-mediated anti-fibrotic signaling and that one aspect of crucial efficacies is achieved by regulating HOXA13 and USAG-1. HOXA13-USAG-1 pathway is a newly identified mechanism in renal fibrosis and will be a new therapeutic target for preventing renal fibrosis progression in CKDs.

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Elucidation, Quantitative Refinement, and in Vivo Utilization of the HOXA13 DNA Binding Site

Cited by 25 publications

References 63 publications

Specification of chondrocytes and cartilage tissues from embryonic stem cells

Specification of chondrocytes and cartilage tissues from embryonic stem cells

Characterization of Wise Protein and Its Molecular Mechanism to Interact with both Wnt and BMP Signals

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor simvastatin ameliorates renal fibrosis through HOXA13–USAG-1 pathway

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