Targeted Deletion of a Distant Transcriptional Enhancer of the Receptor Activator of Nuclear Factor-κB Ligand Gene Reduces Bone Remodeling and Increases Bone Mass

Galli, Carlo; Zella, Lee A.; Fretz, Jackie A.; Fu, Qiang; Pike, J. Wesley; Weinstein, Robert S.; Manolagas, Stavros C.; O’Brien, Charles A.

doi:10.1210/en.2007-0734

Cited by 87 publications

(87 citation statements)

References 38 publications

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“…Currently, there is only one other report of a distal transcriptional enhancer: the RankL distal regulatory enhancer (DCR) that affects bone mass. When deleted, DCR caused HBM due to reduced osteoclast activity, leading to a lower rate of bone remodeling similar to that observed in humans and mice with hypoparathyroidism (25,26).…”

Section: Discussionsupporting

confidence: 68%

Targeted deletion of Sost distal enhancer increases bone formation and bone mass

Collette

Genetos

Economides

et al. 2012

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

123

109

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The Wnt antagonist Sost has emerged as a key regulator of bone homeostasis through the modulation of Lrp4/5/6 Wnt coreceptors. In humans, lack of Sclerostin causes sclerosteosis and van Buchem (VB) disease, two generalized skeletal hyperostosis disorders that result from hyperactive Wnt signaling. Unlike sclerosteosis, VB patients lack SOST coding mutations but carry a homozygous 52 kb noncoding deletion that is essential for the transcriptional activation of SOST in bone. We recently identified a putative bone enhancer, ECR5, in the VB deletion region, and showed that the transcriptional activity of ECR5 is controlled by Mef2C transcription factor in vitro. Here we report that mice lacking ECR5 or Mef2C through Col1-Cre osteoblast/osteocyte-specific ablation result in high bone mass (HBM) due to elevated bone formation rates. We conclude that the absence of the Sost-specific long-range regulatory element ECR5 causes VB disease in rodents, and that Mef2C is the main transcription factor responsible for ECR5-dependent Sost transcriptional activation in the adult skeleton. osteocytes S everal rare genetic disorders that interfere with Wnt signaling have provided strong evidence that the "canonical" Wnt signaling pathway is critical in bone (1). The Wnt coreceptor LRP5 has been described as a modulator of bone mass where loss-offunction mutations cause osteoporosis-pseudoglioma syndrome (OPPG) (2), an autosomal recessive disorder characterized by low bone mass and skeletal fragility; conversely, gain-of-function Lrp5 alleles cause high bone mass (HBM) (3). Similar hyperactive osteoblast activity due to elevated Wnt signaling was observed when Sost, a secreted Wnt inhibitor, was mutated in knockout (KO) mice or in sclerosteosis patients who suffer from generalized hyperostosis (4-6). Lrp5 gene targeting or SOST overexpression in transgenic (TG) mice causes osteopenia (3, 7), whereas TG overexpression of G171V Lrp5 allelic variant causes HBM, similar to the Sost KO phenotypes (4,8,9). The recapitulation of the human phenotypes in mouse models supports the conclusion that canonical Wnt signaling plays a critical role in bone metabolism, and points to Sost and Lrp5 as key regulators of bone mass.The skeletal phenotype describing sclerosteosis patients is similar to what has been documented for van Buchem (VB) disease. Although both VB and sclerosteosis map to the same locus on human chromosome 17 that includes the SOST transcript, the Sclerostin transcription unit was not affected in VB. All VB patients examined to date carry a 52-kb noncoding deletion, 35 kb downstream of SOST that results in the absence of postnatal SOST transcript and protein (10, 11). Although both sclerosteosis and VB are caused by sclerostin deficiency, the VB phenotype is a result of dysregulated SOST transcription. To identify the potential transcriptional regulatory elements responsible for Sost transcription in bone, we have characterized the expression of a human SOST transgene or an engineered allele corresponding to VB in mice. Only the wi...

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Section: Discussionsupporting

confidence: 68%

Targeted deletion of Sost distal enhancer increases bone formation and bone mass

Collette

Genetos

Economides

et al. 2012

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

123

109

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“…20 OSM induces RANKL transcription by promoting STAT3 and RNA polymerase II binding to a subset 21 of 5 distal enhancer regions of the RANKL gene also utilized by parathyroid hormone (PTH) and 1,25-dihydroxyvitamin-D 3 , 22 and a third more distal enhancer region. 23 Notably, genetic deletion of the distal control region led to a significant increase in bone mass owing to a low level of RANKL expression and limited bone resorption, 24 a phenotype strikingly similar to that of OSMR-null mice. 25 The influence of OSM in driving osteoclast formation was the focus of much early work in osteoclast biology, particularly in the context of osteolytic bone disease.…”

Section: Multiple Cellular Interactions Regulate Bone Structurementioning

confidence: 99%

Osteoimmunology: oncostatin M as a pleiotropic regulator of bone formation and resorption in health and disease

Sims

Quinn

2014

BoneKEy Reports

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Bone remodeling in health and disease is carried out by osteoblasts and osteoclasts, which respectively produce bone matrix and resorb it. Endocrine and paracrine control of these cells can be direct, but they are also exerted indirectly, either by influencing progenitor cell differentiation or by stimulating paracrine signals from local accessory cells including osteocytes (which form a critical communication and regulation network within the bone matrix), macrophages and T lymphocytes. Here we review the osteotropic actions of the interleukin-6 family member cytokine oncostatin M (OSM), which is of particular interest because of its ability to stimulate bone accrual. OSM is produced within the bone microenvironment by cells of both mesenchymal and hematopoietic origin, including osteocytes, osteoblasts, macrophages and T lymphocytes, and can act via two receptor complexes: OSM receptor:gp130 and leukemia inhibitory factor receptor (LIFR):gp130. Although OSM can directly stimulate osteoblast mineralization activity and differentiation, it can also stimulate mesenchymal stem cell osteoblastic commitment at the expense of adipogenesis. In osteocytes, OSM can suppress the production of the bone formation inhibitor sclerostin, an action that is mediated by LIFR:gp130. OSM also stimulates the production of receptor activator of nuclear factor kB ligand by osteoblasts and thereby drives the formation of osteoclasts particularly in pathological conditions. Thus, cellular effects of OSM on bone metabolism include direct and indirect actions mediated by two related receptor/ligand complexes. OSM therefore provides an example of paracrine and endocrine control mechanisms that regulate bone mass by controlling both bone formation and resorption.

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“…TNFSF11 gene expression is controlled by a variety of distal and proximal regulatory regions (21,24,25). We focused on a conserved regulatory region located 76 kb upstream of the transcriptional start site that had been described by two independent groups as important for calciotropic agent responsiveness in vitro and in vivo (26). Shn3 overexpression can enhance activity of this upstream promoter element but not that of the proximal RANKL and OPG gene regulatory regions (Fig.…”

Section: Reduced Expression Of Rankl By Osteoblastic/stromal Cells Lamentioning

confidence: 99%

Control of bone resorption in mice by Schnurri-3

Wein

Jones

Shim

et al. 2012

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

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Mice lacking the large zinc finger protein Schnurri-3 (Shn3) display increased bone mass, in part, attributable to augmented osteoblastic bone formation. Here, we show that in addition to regulating bone formation, Shn3 indirectly controls bone resorption by osteoclasts in vivo. Although Shn3 plays no cell-intrinsic role in osteoclasts, Shn3-deficient animals show decreased serum markers of bone turnover. Mesenchymal cells lacking Shn3 are defective in promoting osteoclastogenesis in response to selective stimuli, likely attributable to reduced expression of the key osteoclastogenic factor receptor activator of nuclear factor-κB ligand. The bone phenotype of Shn3-deficient mice becomes more pronounced with age, and mice lacking Shn3 are completely resistant to disuse osteopenia, a process that requires functional osteoclasts. Finally, selective deletion of Shn3 in the mesenchymal lineage recapitulates the high bone mass phenotype of global Shn3 KO mice, including reduced osteoclastic bone catabolism in vivo, indicating that Shn3 expression in mesenchymal cells directly controls osteoblastic bone formation and indirectly regulates osteoclastic bone resorption.cAMP response element binding protein | receptor activator of nuclear factor-κB ligand | secondary hyperparathyroidism S chnurri-3 (Shn3) is a large zinc finger protein belonging to the small group of zinc finger, acid-rich, and serine-threonine rich (ZAS) family proteins (1). Previous in vitro studies have implicated a role for Shn3 in diverse processes, such as Ig gene rearrangement, cell survival, TNF signaling in macrophages, and IL-2 gene expression in helper T lymphocytes (2-6). We recently discovered that mice with germline deletion of Shn3 displayed a massive increase in bone mass, revealing an unexpected role for this protein in the skeletal system (5). Shn3-deficient animals showed markedly augmented osteoblastic bone formation in vivo. Consistently, cultured primary osteoblasts lacking Shn3 express increased levels of classic osteoanabolic genes and produce increased amounts of mineralized ECM. In osteoblasts, Shn3 functions, at least in part, by regulating Runx2 protein levels via its ubiquitination.A central dogma in skeletal biology is that bone formation and resorption are coupled, such that manipulations that increase bone production by osteoblasts typically increase bone catabolism by osteoclasts (7-9). Pharmacological augmentation of bone production in humans with recombinant parathyroid hormone (PTH) leads to a compensatory increase in serum markers of bone turnover. Likewise, inhibition of bone resorption following bisphosphonate or denosumab treatment leads to decreased bone production (10, 11). In most murine models of increased bone production attributable to osteoblast-intrinsic manipulations, a compensatory increase in osteoclastic activity is typically seen (12, 13). However, this is not always the case (14-16). Although the mechanisms controlling mesenchymal/osteoclast cross-talk are incompletely understood, expression of the cruci...

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Targeted Deletion of a Distant Transcriptional Enhancer of the Receptor Activator of Nuclear Factor-κB Ligand Gene Reduces Bone Remodeling and Increases Bone Mass

Cited by 87 publications

References 38 publications

Targeted deletion of Sost distal enhancer increases bone formation and bone mass

Targeted deletion of Sost distal enhancer increases bone formation and bone mass

Osteoimmunology: oncostatin M as a pleiotropic regulator of bone formation and resorption in health and disease

Control of bone resorption in mice by Schnurri-3

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