SOST is a target gene for PTH in bone

Keller, H. J.; Kneissel, Michaela

doi:10.1016/j.bone.2005.03.018

Cited by 576 publications

(456 citation statements)

References 48 publications

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“…Cycloheximide alone appeared able to increase the basal ABCB1 expression in H69 cells. This increase, which has already been described for other genes (Keller and Kneissel, 2005), could suggest that ABCB1 expression would be controlled by short-lived repressor, or that CHX might directly stimulate ABCB1 gene transcription as reported for a-1B adrenergic gene (Hu and Hoffman, 1993). In drug-sensitive cells, several studies have reported an increase in ABCB1 expression by HDAC inhibitors, a phenomenon we also observed in H69WT cells.…”

Section: Discussionsupporting

confidence: 68%

The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model

et al. 2007

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Tumour drug-resistant ABCB1 gene expression is regulated at the chromatin level through epigenetic mechanisms. We examined the effects of the histone deacetylase inhibitor trichostatin A (TSA) on ABCB1 gene expression in small cell lung carcinoma (SCLC) drugsensitive (H69WT) or etoposide-resistant (H69VP) cells. We found that TSA induced an increase in ABCB1 expression in drugsensitive cells, but strongly decreased it in drug-resistant cells. These up-and downregulations occurred at the transcriptional level. Protein synthesis inhibition reduced these modulations, but did not completely suppress them. Differential temporal patterns of histone acetylation were observed at the ABCB1 promoter: increase in H4 acetylation in both cell lines, but different H3 acetylation with a progressive increase in H69WT cells but a transient one in H69VP cells. ABCB1 regulations were not related with the methylation status of the promoter À50GC, À110GC, and Inr sites, and did not result in further changes to these methylation profiles. Trichostatin A treatment did not modify MBD1 binding to the ABCB1 promoter and similarly increased PCAF binding in both H69 cell lines. Our results suggest that in H69 drug-resistant SCLC cell line TSA induces downregulation of ABCB1 expression through a transcriptional mechanism, independently of promoter methylation, and MBD1 or PCAF recruitment.

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Section: Discussionsupporting

confidence: 68%

The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model

et al. 2007

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“…As PTH is a known inhibitor of SOST transcription, sclerostin would not be expected to be induced if PTH was the initial driver for elevated bone formation. (72)(73)(74) Indeed, subsequent decline in sclerostin later in disease progression may be attributed to the rising levels of PTH (Figs. 1D and 8B).…”

Section: Discussionmentioning

confidence: 99%

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

Sabbagh

Graciolli

O’Brien

et al. 2012

Journal of Bone and Mineral Research

240

224

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Chronic kidney disease–mineral bone disorder (CKD‐MBD) is defined by abnormalities in mineral and hormone metabolism, bone histomorphometric changes, and/or the presence of soft‐tissue calcification. Emerging evidence suggests that features of CKD‐MBD may occur early in disease progression and are associated with changes in osteocyte function. To identify early changes in bone, we utilized the jck mouse, a genetic model of polycystic kidney disease that exhibits progressive renal disease. At 6 weeks of age, jck mice have normal renal function and no evidence of bone disease but exhibit continual decline in renal function and death by 20 weeks of age, when approximately 40% to 60% of them have vascular calcification. Temporal changes in serum parameters were identified in jck relative to wild‐type mice from 6 through 18 weeks of age and were subsequently shown to largely mirror serum changes commonly associated with clinical CKD‐MBD. Bone histomorphometry revealed progressive changes associated with increased osteoclast activity and elevated bone formation relative to wild‐type mice. To capture the early molecular and cellular events in the progression of CKD‐MBD we examined cell‐specific pathways associated with bone remodeling at the protein and/or gene expression level. Importantly, a steady increase in the number of cells expressing phosphor‐Ser33/37‐β‐catenin was observed both in mouse and human bones. Overall repression of Wnt/β‐catenin signaling within osteocytes occurred in conjunction with increased expression of Wnt antagonists (SOST and sFRP4) and genes associated with osteoclast activity, including receptor activator of NF‐κB ligand (RANKL). The resulting increase in the RANKL/osteoprotegerin (OPG) ratio correlated with increased osteoclast activity. In late‐stage disease, an apparent repression of genes associated with osteoblast function was observed. These data confirm that jck mice develop progressive biochemical changes in CKD‐MBD and suggest that repression of the Wnt/β‐catenin pathway is involved in the pathogenesis of renal osteodystrophy. © 2012 American Society for Bone and Mineral Research.

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“…It gives us new insights into the communicating networks among bone cells and, importantly, to new ways of restoring bone once it has been lost. In the current issue of JBMR, Kramer and colleagues complement their earlier demonstration that parathyroid hormone (PTH) inhibits sclerostin expression (3) to show that the anabolic effect of PTH is blunted both in mice overexpressing sclerostin and in SOST null mice. (4) PTH administered by daily injection is the only currently available anabolic therapy for bone.…”

mentioning

confidence: 86%

“…Another contributory mechanism was introduced by the discovery of sclerostin and its regulation by both PTH and PTH-related protein (PTHrP) via a distal enhancer of the SOST gene. (3,10) The experiments reported by Kramer and colleagues (4) provide further evidence that sclerostin regulation may play a part in PTH anabolic action. Mice overexpressing sclerostin have less bone as a result of decreased bone-formation rate, as described previously.…”

mentioning

confidence: 98%

Building bone with a SOST-PTH partnership

Sims

2010

Journal of Bone and Mineral Research

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T he discovery of the SOST gene, whose protein product, sclerostin, is an osteocyte-derived inhibitor of Wnt signalling and bone formation, (1,2) has provided a major advance in bone biology. It gives us new insights into the communicating networks among bone cells and, importantly, to new ways of restoring bone once it has been lost. In the current issue of JBMR, Kramer and colleagues complement their earlier demonstration that parathyroid hormone (PTH) inhibits sclerostin expression (3) to show that the anabolic effect of PTH is blunted both in mice overexpressing sclerostin and in SOST null mice. (4) PTH administered by daily injection is the only currently available anabolic therapy for bone. (5,6) While a number of contributing pathways, including direct prodifferentiation (7) and antiapoptotic (8) actions on osteoblasts, as well as couplingrelated activity through the osteoclast, (9) have been proposed, the full mechanism of action of anabolic PTH remains obscure. Another contributory mechanism was introduced by the discovery of sclerostin and its regulation by both PTH and PTH-related protein (PTHrP) via a distal enhancer of the SOST gene. (3,10) The experiments reported by Kramer and colleagues (4) provide further evidence that sclerostin regulation may play a part in PTH anabolic action. Mice overexpressing sclerostin have less bone as a result of decreased bone-formation rate, as described previously. (11) When these mice were treated with a high dose of PTH, sufficient to increase trabecular bone volume (BV/TV) in wild-type mice, no increase in trabecular bone volume was detected despite a robust reduction in sclerostin expression. It is worth noting that even though sclerostin mRNA levels are reduced by PTH in the transgenic model, total sclerostin expression after PTH treatment is still greater than in wild-type mice. This high level of sclerostin expression, the basal phenotype of a mild reduction in bone remodeling, or both impair the effect of PTH on BV/TV. Surprisingly, even though BV/ TV was not increased, all histomorphometric markers of bone formation, as well as the osteoclast surface, were substantially elevated by PTH treatment in the sclerostin transgenic mice to approximately the same extent as that observed in wild-type mice. Thus a question in the sclerostin transgenic model remains as to how PTH can increase bone turnover without altering BV/ TV. Is osteoclast function enhanced? No evidence was obtained for that. An alternative explanation could be that the sclerostin overexpressing mice lay down bone of reduced quality that is easier for osteoclasts to resorb. The quality of bone in the sclerostin overexpressing mouse is not yet known. Resolving this paradox may provide useful information about the interaction between osteoclasts and osteoblasts in the presence of high levels of sclerostin and, presumably, low levels of b-cateninactivated gene transcription.In SOST null mice, as expected from the skeletal abnormalities observed in van Buchem disease and sclerosteosis, (12) trabecular...

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SOST is a target gene for PTH in bone

Cited by 576 publications

References 48 publications

The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model

The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

Building bone with a SOST-PTH partnership

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