Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease

Loots, Gabriela G.; Kneissel, Michaela; Keller, H. J.; Baptist, Myma; Chang, Jessie; Collette, Nicole M.; Ovcharenko, Dmitriy; Plajzer-Frick, Ingrid; Rubin, Edward M.

doi:10.1101/gr.3437105

Cited by 410 publications

(360 citation statements)

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“…Inactivating mutations in the human sclerostin gene (SOST) are associated with sclerosteosis (Mendelian Inheritance in Man, MIM 269500) or van Buchem disease (MIM 239100) (6), both of which are characterized by progressive overgrowth and sclerosis of the axial and appendicular skeleton and an increase in bone mineral density (6,13,14). These results are supported by data from sost knockout mice, which have markedly increased bone density (15)(16)(17).…”

supporting

confidence: 72%

Sclerostin alters serum vitamin D metabolite and fibroblast growth factor 23 concentrations and the urinary excretion of calcium

Ryan¹,

Ketha²,

McNulty³

et al. 2013

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

118

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Inactivating mutations of the SOST (sclerostin) gene are associated with overgrowth and sclerosis of the skeleton. To determine mechanisms by which increased amounts of calcium and phosphorus are accreted to enable enhanced bone mineralization in the absence of sclerostin, we measured concentrations of calciotropic and phosphaturic hormones, and urine and serum calcium and inorganic phosphorus in mice in which the sclerostin (sost) gene was replaced by the β-D-galactosidase (lacZ) gene in the germ line. Knockout (KO) (sost −/− ) mice had increased bone mineral density and content, increased cortical and trabecular bone thickness, and greater net bone formation as a result of increased osteoblast and decreased osteoclast surfaces compared with wild-type (WT) mice. β-Galactosidase activity was detected in osteocytes of sost KO mice but was undetectable in WT mice. Eight-week-old, male sost KO mice had increased serum 1α,25-dihydroxyvitamin D, decreased 24,25-dihydroxyvitamin D, decreased intact fibroblast growth factor 23, and elevated inorganic phosphorus concentrations compared with age-matched WT mice. 25-Hydroxyvitamin D 1α-hydroxylase cytochrome P450 (cyp27B1) mRNA was increased in kidneys of sost KO mice compared with WT mice. Treatment of cultured proximal tubule cells with mouse recombinant sclerostin decreased cyp27B1 mRNA transcripts. Urinary calcium and renal fractional excretion of calcium were decreased in sost KO mice compared with WT mice. Sost KO and WT mice had similar serum calcium and parathyroid hormone concentrations. The data show that sclerostin not only alters bone mineralization, but also influences mineral metabolism by altering concentrations of hormones that regulate mineral accretion.S clerostin, an osteocyte-derived, secreted, cystine-knot protein inhibits bone formation by interacting with and altering the activity of bone morphogenetic proteins (BMPs), low-density lipoprotein-receptor-related protein 5 (LRP 5/6), cysteine-rich protein 61, the receptor tyrosine kinase v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (erb B3), among other proteins (1-12). Inactivating mutations in the human sclerostin gene (SOST) are associated with sclerosteosis (Mendelian Inheritance in Man, MIM 269500) or van Buchem disease (MIM 239100) (6), both of which are characterized by progressive overgrowth and sclerosis of the axial and appendicular skeleton and an increase in bone mineral density (6,13,14). These results are supported by data from sost knockout mice, which have markedly increased bone density (15-17).The physiological adaptations that occur in human sclerosteosis and mouse models of the disease that permit the increased accretion of calcium (Ca) and phosphorus (P) required for bone formation are unknown. For example, it is unknown whether sclerostin influences vitamin D metabolite concentrations, the concentrations of phosphaturic peptides such as fibroblast growth factor 23 (FGF-23), and the renal handling of calcium and phosphorus. It is important to understand the adaptations ...

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supporting

confidence: 72%

Sclerostin alters serum vitamin D metabolite and fibroblast growth factor 23 concentrations and the urinary excretion of calcium

Ryan¹,

Ketha²,

McNulty³

et al. 2013

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

118

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“…In addition, the hypomorphic Dkk1 d allele bears a resemblance to the Van Buchem mutation that affects SOST expression. The Dkk1 d mutation is a 60 kb deletion at the transgene insertion site which is located over 150 kb downstream from the Dkk1 gene and the Van Buchem disease mutation results from a 52-kb deletion of a regulatory region that is 35 kb downstream from SOST [46]. It is unknown if the reduced expression from the Dkk1 d allele is due to transgene induced silencing or the deletion of a regulatory element [37].…”

Section: Discussionmentioning

confidence: 99%

Bone mass is inversely proportional to Dkk1 levels in mice

MacDonald

Joiner

Oyserman

et al. 2007

Bone

156

106

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The Wnt/β-catenin signaling pathway has emerged as a key regulator in bone development and bone homeostasis. Loss-of-function mutations in the Wnt co-receptor LRP5 result in osteoporosis and "activating" mutations in LRP5 result in high bone mass. Dickkopf-1 (DKK1) is a secreted Wnt inhibitor that binds LRP5 and LRP6 during embryonic development, therefore it is expected that a decrease in DKK1 will result in an increase in Wnt activity and a high bone mass phenotype. Dkk1 −/− knockout mice are embryonic lethal, but mice with hypomorphic Dkk1 d (doubleridge) alleles that express low amounts of Dkk1 are viable. In this study we generated an allelic series by crossing Dkk1 +/− and Dkk1 +/d mice resulting in the following genotypes with decreasing Dkk1 expression levels: +/+, +/d, +/− and d/−. Using μCT imaging we scanned dissected left femora and calvariae from eight week old mice (n=60). We analyzed the distal femur to represent trabecular bone and the femur diaphysis for cortical endochondral bone. A region of the parietal bones was used to analyze intramembranous bone of the calvaria. We found that trabecular bone volume is increased in Dkk1 mutant mice in a manner that is inversely proportional to the level of Dkk1 expression. Trabeculae number and thickness were significantly higher in the low Dkk1 expressing genotypes from both female and male mice. Similar results were found in cortical bone with an increase in cortical thickness and cross sectional area of the femur diaphysis that correlated with lower Dkk1 expression. No consistent differences were found in the calvaria measurements. Our results indicate that the progressive Dkk1 reduction increases trabecular and cortical bone mass and that even a 25% reduction in Dkk1 expression could produce significant increases in trabecular bone volume fraction. Thus DKK1 is a negative regulator of normal bone homeostasis in vivo. Our study suggests that manipulation of DKK1 function or expression may have therapeutic significance for the treatment of low bone mass disorders.

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“…Van Buchem disease, another very rare, recessively inherited high-bone-mass disorder, was determined to be caused by a 52-kb deletion 35 kb downstream of SOST, (19,20) resulting in absence of postnatal sclerostin expression. (21,22) For osteoporosis pseudoglioma syndrome (OPPG), a recessively inherited low-bone-mass disease, loss-of-function mutations were found in a Wnt signaling coreceptor, the low-density lipoprotein receptor-PERSPECTIVE J JBMR …”

mentioning

confidence: 99%

Sclerostin: A gem from the genome leads to bone-building antibodies

Pászty

Turner

Robinson

2010

Journal of Bone and Mineral Research

113

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Discovery of SclerostinG enomics technologies and DNA sequencing have had a transformative impact on biological research, giving us unprecedented access to the genomes of numerous organisms and ushering in such new fields as systems biology (1) and, more recently, synthetic biology. (2,3) In the 1990s, the advent of highthroughput sequencing spurred application of this powerful new technology to the challenging endeavor of trying to understand the genetic basis of various inherited human diseases. One such disease was sclerosteosis, a very rare, recessively inherited highbone-mass disorder that was thought to be caused primarily by excessive osteoblast-mediated bone formation rather than by defective osteoclast-mediated bone resorption. (4,5) Within the realm of inherited high-bone-mass disorders, (6) it was the hope for a discovery in the area of osteoblast biology that made sclerosteosis particularly interesting.Indeed, the identification of new bone-building pathways that might yield novel anabolic agents had been a long-standing goal in bone biology, with hopes for therapeutic application in fracture healing, orthopedic procedures, and low-bone-mass conditions such as osteoporosis. Against this backdrop came the exciting news, independently from Mary Brunkow's group at Celltech R&D, Inc., (7,8) and from Wim Van Hul's group at the University of Antwerp, (9) that sclerosteosis was caused by mutations in a single gene (SOST) encoding a novel secreted protein. Because these were inactivating mutations, it was clear that this protein, aptly given the name sclerostin, functioned either directly or indirectly as an inhibitor of bone formation. During this same general time period, large-scale cDNA/ expressed sequence tag (EST) (10)(11)(12) and genomic DNA sequencing efforts were being made in academia and industry to rapidly identify new human genes. A novel secreted protein of unknown function, which turned out to be sclerostin, was discovered by computational mining of large DNA sequence databases using either homology-based programs (eg, BLAST) (13,14) or a special CxGxC-class cystine-knot search pattern (C Paszty, unpublished) (15) designed to identify new families of cystine-knot proteins. (16,17) Thus sclerostin emerged during an exciting era of gene discovery that was fueled, in part, by the development of important genomics technologies and the advent of high-throughput DNA sequencing.Similar to sclerostin inactivation in humans, mice with a targeted deletion of the sclerostin gene (SOST knockout mice) were found to have high bone mass, demonstrating evolutionary conservation of sclerostin's function as a negative regulator of bone formation. (18) Analysis of bones from these mice revealed that bone formation was markedly increased on each of the key skeletal surfaces where new bone is normally formed (surface of trabecular bone and internal and external surfaces of cortical bone). Consistent with the increases in bone formation and bone mass, robust increases in bone strength also were found in these anima...

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Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease

Cited by 410 publications

References 36 publications

Sclerostin alters serum vitamin D metabolite and fibroblast growth factor 23 concentrations and the urinary excretion of calcium

Sclerostin alters serum vitamin D metabolite and fibroblast growth factor 23 concentrations and the urinary excretion of calcium

Bone mass is inversely proportional to Dkk1 levels in mice

Sclerostin: A gem from the genome leads to bone-building antibodies

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