Sclerostin Binds to LRP5/6 and Antagonizes Canonical Wnt Signaling

Li, Xiaofeng; Zhang, Yazhou; Kang, Heeseog; Liu, Wenzhong; Liu, Peng; Zhang, Jianghong; Harris, S. E.; Wu, Dianqing

doi:10.1074/jbc.m413274200

Cited by 1,186 publications

(821 citation statements)

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“…(42,43) Above and beyond the reported associations with LRP5 and BMPs, hints that sclerostin's mechanism of action at the molecular level might contain additional complexity came from the observation that sclerostin's inhibitory activity was notably variable across different osteoblast-lineage cell-based assays, much more so than the Wnt signaling inhibitor DKK1 and the BMP signaling inhibitor Gremlin. (44) With regard to other possible molecular interactions for sclerostin, data from in vitro experiments had shown that sclerostin could bind LRP6 and inhibit Wnt signaling, (32)(33)(34) similar to the findings for LRP5. This, coupled with mouse genetic data showing that LRP6 appeared to play a role in achieving and/or maintaining normal bone mass, (45)(46)(47) suggested that sclerostin also might interact with LRP6 in vivo.…”

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confidence: 60%

“…Several groups subsequently confirmed that sclerostin did indeed bind LRP5 and inhibit Wnt signaling in vitro. (32)(33)(34) Additionally, it was shown that both sclerostin and another Wnt signaling antagonist, Dickkopf1 (DKK1), had decreased binding affinity to HBM LRP5 and reduced ability to inhibit HBM LRP5-mediated Wnt signaling. (34)(35)(36)(37)(38) As such, the gain of function for HBM LRP5 appeared to be primarily from enhanced resistance to inhibition by sclerostin and/or DKK1.…”

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confidence: 99%

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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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confidence: 60%

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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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“…21 Sclerostin, expressed in osteocytes exclusively, inhibits osteoblastogenesis and bone formation in vivo by binding to Wnt coreceptors low-density lipoprotein receptor-related protein 5 and 6. 22 These two extracellular antagonists of the Wnt/β-catenin pathway showed bone tissue-specific expression, and bone formation was accelerated following their genetic ablation or functional inhibition. 5 Here we identified that CXXC5 is an osteoblastspecific interacellular negative-feedback regulator of the Wnt/ β-catenin pathway and osteoblast differentiation.…”

Section: Discussionmentioning

confidence: 99%

CXXC5 is a negative-feedback regulator of the Wnt/β-catenin pathway involved in osteoblast differentiation

Yoon

Yun

et al. 2015

Cell Death Differ

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The positive roles of the Wnt/β-catenin pathway in osteoblast differentiation and bone mineral density (BMD) maintenance have been clearly demonstrated in both animal experiments and clinical investigations. CXXC finger protein 5 (CXXC5), a recently identified negative regulator of the Wnt/β-catenin pathway, showed altered cellular localization and function, which were dependent on the cell type in previous studies. However, the in vivo function of CXXC5 has not been clearly investigated yet. Here, we characterized CXXC5 as a negative regulator of osteoblast differentiation and bone formation. Deficiency of CXXC5 resulted in elevated BMD in mice without any severe gross developmental abnormalities. CXXC5 exerted a negative-feedback effect on the Wnt/β-catenin pathway via Wnt-dependent binding to Dishevelled (Dvl) during osteoblast differentiation. Suppression of the Dvl-CXXC5 interaction using a competitor peptide resulted in the activation of the Wnt/β-catenin pathway and osteoblast differentiation, and accelerated thickness growth of ex vivo-cultured calvariae. Overall, CXXC5 is a negative-feedback regulator induced by Wnt/β-catenin signaling that inhibits osteoblast differentiation and bone formation via interaction with Dvl. Cell Death and Differentiation (2015) 22, 912-920; doi:10.1038/cdd.2014.238; published online 30 January 2015Bone is an extremely dynamic tissue at the microscopic level. A dynamic process, called bone remodeling, takes place seamlessly in the bone to repair microdamage and to replace old bone with new bone. 1 The resorption of old bone and the formation of new bone must be in balance to maintain homeostasis and a constant mass of bone. Osteoblasts have been identified as an essential factor in regulation of the bone remodeling process, which produce bone matrix and differentiate into osteocytes for bone formation, as well as regulate differentiation and activation of osteoclasts for bone resorption. 2 The Wnt/β-catenin pathway is receiving increased attention as a main regulatory pathway for osteoblast differentiation. [2][3][4] Wnt-dependent nuclear accumulation of an effector protein of the pathway, β-catenin, is a major trigger of osteoblast differentiation and bone formation. 2 Many other intracellular and extracellular components of the Wnt/β-catenin pathway are known to regulate osteoblast differentiation. 4 Especially two negative regulators of this pathway, Dickkopf 1 and sclerostin, have been highlighted as osteoblast and osteocytespecific negative regulators of bone formation. 5 CXXC finger protein 5 (CXXC5) is a member of a small protein family in which the members contain CXXC-type zincfinger domain. 6 However, unlike other members of this family, CXXC5 lacks a KFGG motif, which is essential for non-methylated CpG recognition that regulates chromatin remodeling. 7 CXXC5 localizes to the cytosol or nucleus depending on particular cell type in different tissues. Localization of CXXC5 in the nucleus was observed in promyelocytic leukemia cells. 7 CXXC5 has a role as a nuclear t...

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“…Consistent with the removal of a Wnt inhibitor, the mouse knockout for Sfrp1 −/− displays an increase in trabecular bone mass in adult animals [22]. Previously identified as a BMP antagonist, SOST also binds to LRP5 and LRP6 in the extracellular region and antagonizes Wnt signaling [23,24]. SOST loss-of-function mutations are responsible for Sclerosteosis, a human disorder characterized by increased bone density and excessive bone overgrowth [25,26].…”

Section: Introductionmentioning

confidence: 97%

Bone mass is inversely proportional to Dkk1 levels in mice

MacDonald

Joiner

Oyserman

et al. 2007

Bone

155

103

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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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Sclerostin Binds to LRP5/6 and Antagonizes Canonical Wnt Signaling

Cited by 1,186 publications

References 42 publications

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

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

CXXC5 is a negative-feedback regulator of the Wnt/β-catenin pathway involved in osteoblast differentiation

Bone mass is inversely proportional to Dkk1 levels in mice

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