Decreased BMD and Limb Deformities in Mice Carrying Mutations in Both <i>Lrp5</i> and <i>Lrp6</i>

Holmen, Sheri L.; Giambernardi, Troy A.; Zylstra, Cassandra R.; Buckner-Berghuis, Bree D.; Resau, James H.; Hess, J. Fred; Glatt, Vaida; Bouxsein, Mary L.; Ai, Minrong; Warman, Matthew L.; Williams, Bart O.

doi:10.1359/jbmr.040907

Cited by 327 publications

(273 citation statements)

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“…LRP6 plays an essential role during embryogenesis and the severe developmental defects in Lrp6 −/− mice prevent the study of postnatal bone [53]. However, heterozygous Lrp6 +/− and hypomorphic ringelshwanz Lrp6 mutant mice exhibit delays in ossification and decreased bone mass in adults [11,54]. Recently a human LRP6 mutation was reported in a family with coronary artery disease and osteoporosis, further suggesting that loss of function LRP6 mutations result in low bone mass [55].…”

Section: Discussionmentioning

confidence: 99%

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Bone mass is inversely proportional to Dkk1 levels in mice

MacDonald

Joiner

Oyserman

et al. 2007

Bone

158

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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Section: Discussionmentioning

confidence: 99%

“…A transgenic mouse model carrying a human LRP5 high bone mass mutation exhibited significant increases in bone density and mechanical properties [9,10]. Studies have shown that removing one Lrp6 copy from Lrp5 −/− mice increases the osteoporosis severity, suggesting that both LRP5 and LRP6 are critical determinants of bone mass [11].…”

Section: Introductionmentioning

confidence: 99%

Bone mass is inversely proportional to Dkk1 levels in mice

MacDonald

Joiner

Oyserman

et al. 2007

Bone

158

106

View full text Add to dashboard Cite

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“…(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. Recently, it has been reported that sclerostin binds to LRP4, a singletransmembrane protein related to LRP5 and LRP6, and, additionally, that LRP4 is expressed in bone by osteoblasts and osteocytes.…”

mentioning

confidence: 89%

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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“…Similar to humans, Lrp5 -/-mice have a low bone mass phenotype due to reduced proliferation of precursor cells (Kato et al, 2002), which is enhanced by additional loss of one Lrp6 allele (Holmen et al, 2004). Conversely, mice that overexpress the G171V LRP5 mutant, have a high bone mass phenotype (Babij et al, 2003).…”

Section: Dkk1 and 2 In Bone Formationmentioning

confidence: 99%