Regulation of the human SOX9 promoter by Sp1 and CREB

Piera-Velázquez, Sonsoles; Hawkins, David F.; Whitecavage, Mary Kate; Colter, David C.; Stokes, David G.; Jimenez, Sergio A.

doi:10.1016/j.yexcr.2007.01.001

Cited by 74 publications

(68 citation statements)

References 52 publications

(67 reference statements)

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“…Tissue sections were also immunostained for the early cartilage marker Sox9 [23]. The results show significant overlap of TR and Sox 9 (Figure 4C), indicating endoneurial cells may also contribute to chondrogenic progenitors during HO.…”

Section: Resultsmentioning

confidence: 99%

Progenitors in Peripheral Nerves Launch Heterotopic Ossification

Olmsted-Davis

Salisbury²,

Hoang³

et al. 2017

Stem Cells Translational Medicine

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Studies presented here, using a murine model of bone morphogenetic protein type 2 (BMP2)-induced HO show that the protein initiates HO by signaling through progenitors in the endoneurium of peripheral nerves. In the mouse, these cells were identified in the endoneurium one day after BMP2 induction using antibody against phosphoSMAD (PS) 1, 5, and 8. Studies conducted in a tracking mouse that contains a tamoxifen-regulated Wnt1-Cre recombinase crossed with a td Tomato red (TR) reporter (Wnt1CreErt:Ai9Tm) confirmed their neural origin. In this model both BMP2 induction and tamoxifen are absolutely required to induce TR. SP7+(osterix+)TR+ cells were found in the endoneurium on day 1 and associated with bone on day 7. Quantification of TR+ and TR− cells isolated by FACS showed that all SP7+ cells were found in the TR+ population, whereas only about 80 percent of the TR+ cells expressed SP7. Pre-chondrocytes (Sox 9+) and transient brown fat (tBAT, UCP1+) also co-expressed TR, suggesting that the progenitor in nerves is multi-potential. The endoneurium of human nerves near the site of HO contained many PS+ cells, and SP7+ cells were found in nerves and on bone in tissue from patients with HO. Control tissues and nerves did not contain these PS+ and SP7+ cells. Some osteoblasts on bone from patients with HO were positive for PS, suggesting the continued presence of BMP during bone formation. The data suggests that the progenitors for HO are derived from the endoneurium in both the mouse model of HO and in humans with HO.

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Section: Resultsmentioning

confidence: 99%

Progenitors in Peripheral Nerves Launch Heterotopic Ossification

Olmsted-Davis

Salisbury²,

Hoang³

et al. 2017

Stem Cells Translational Medicine

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“…Even though Sox9 is crucial in chondrogenesis, its regulation remains unclear, and only a few transcriptional factors were found to regulate Sox9 expression directly. For example, Sp1, the cyclic-AMP response element binding protein, NF-κB, and CCAAT binding factor can bind to the promoter region of Sox9 and promote its expression in chondrocytes (75)(76)(77). We identified an NFAT binding motif (TTTCC) in the mouse Sox9 promoter that was required for Ca v 3.2-dependent Sox9 regulation on Luc reporter assay.…”

Section: Discussionmentioning

confidence: 96%

Ca _v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

Lin

Tzeng

Lee

et al. 2014

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

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Significance The tracheal cartilage rings are important for protecting and maintaining the airway. However, the chondrogenesis of tracheal cartilage is not completely understood. We demonstrate that the Ca v 3.2 T-type calcium channel is required for normal tracheal cartilage ring formation. Calcium influx via Ca v 3.2 induces chondrogenesis and up-regulates a chondrogenic master gene, sex determination region of Y chromosome (SRY)-related high-mobility group-Box gene 9 (Sox9), via a calcium and calcineurin-dependent pathway. Ca v 3.2-dependent regulation of Sox9 is mediated by a newly identified nuclear factor of activated T-cell binding site on the Sox9 promoter. Our study provides novel insight into the roles of Ca v 3.2 T-type calcium channels in tracheal development. Moreover, CACNA1H , the human homolog of the mouse Ca v 3.2-encoding gene, may be a potential candidate gene involved in congenital tracheal stenosis in humans.

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“…3A-B). As the archetypal downstream target for PKA is CREB that is known to regulate the Sox9 promoter [13]; furthermore, as it is reported to directly associate with Sox9 during osteochondral differentiation [14], we also looked at its expression following the loading regime. Although CREB expression (either at mRNA or at the protein level) did not respond to these treatments, its phosphorylation status (at Ser 133) was found to be augmented (approx.…”

Section: Enhanced Cartilage Matrix Production Is Mediated Via the Pkamentioning

confidence: 99%

“…Since the Sox transcription factors, Sox9 in particular, are pivotal elements of chondrogenesis, many signalling events regulate its expression and/or function in chondrogenic cells. Among other factors, the Sox9 promoter is known to be regulated by the cAMP response element binding protein (CREB) that binds to a CRE site upstream of Sox9 [13]. Apart from transcriptional control, direct physical association between Sox9 and CREB, the prototypical downstream transcription factor of the cAMP-dependent Ser/Thr protein kinase A (PKA), was recently demonstrated by Zhao and colleagues [14].…”

Section: Introductionmentioning

confidence: 99%

Mechanical loading stimulates chondrogenesis via the PKA/CREB-Sox9 and PP2A pathways in chicken micromass cultures

Juhász

Matta

Somogyi

et al. 2014

Cellular Signalling

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Biomechanical stimuli play important roles in the formation of articular cartilage during early foetal life, and optimal mechanical load is a crucial regulatory factor of adult chondrocyte metabolism and function. In this study, we undertook to analyse mechanotransduction pathways during in vitro chondrogenesis. Chondroprogenitor cells isolated from limb buds of 4-day-old chicken embryos were cultivated as high density cell cultures for 6 days. Mechanical stimulation was carried out by a self-designed bioreactor that exerted uniaxial intermittent cyclic load transmitted by the culture medium as hydrostatic pressure and fluid shear to differentiating cells. The loading scheme (0.05 Hz, 600 Pa; for 30 min) was applied on culturing days 2 and 3, when final commitment and differentiation of chondroprogenitor cells occurred in this model. The applied mechanical load significantly augmented cartilage matrix production and elevated mRNA expression of several cartilage matrix constituents, including collagen type II and aggrecan core protein, as well as matrixproducing hyaluronan synthases through enhanced expression, phosphorylation and nuclear signals of the main chondrogenic transcription factor Sox9. Along with increased cAMP levels, a significantly enhanced protein kinase A (PKA) activity was also detected and CREB, the archetypal downstream transcription factor of PKA signalling, exhibited elevated phosphorylation levels and stronger nuclear signals in response to mechanical stimuli. All the above effects were diminished by the PKA-inhibitor H89. Inhibition of the PKA-independent cAMP-mediators Epac1 and Epac2 with HJC0197 resulted in enhanced cartilage formation, which was additive to that of the mechanical stimulation, implying that the chondrogenesispromoting effect of mechanical load was independent of Epac. At the same time, PP2A activity was reduced following mechanical load and treatments with the PP2A-inhibitor okadaic acid were able to mimic the effects of the intervention. Our results indicate that proper mechanical stimuli augment in vitro cartilage formation via promoting both Juhász and Matta et al. 3 differentiation and matrix production of chondrogenic cells, and the opposing regulation of the PKA/CREB-Sox9 and the PP2A signalling pathways is crucial in this phenomenon.

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Regulation of the human SOX9 promoter by Sp1 and CREB

Cited by 74 publications

References 52 publications

Progenitors in Peripheral Nerves Launch Heterotopic Ossification

Progenitors in Peripheral Nerves Launch Heterotopic Ossification

Ca _v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

Mechanical loading stimulates chondrogenesis via the PKA/CREB-Sox9 and PP2A pathways in chicken micromass cultures

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Regulation of the human SOX9 promoter by Sp1 and CREB

Cited by 74 publications

References 52 publications

Progenitors in Peripheral Nerves Launch Heterotopic Ossification

Progenitors in Peripheral Nerves Launch Heterotopic Ossification

Ca v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

Mechanical loading stimulates chondrogenesis via the PKA/CREB-Sox9 and PP2A pathways in chicken micromass cultures

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Ca _v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage