Bone mass is inversely proportional to Dkk1 levels in mice

MacDonald, Bryan T.; Joiner, Danese M.; Oyserman, Sivan M.; Sharma, Parul; Goldstein, Steven A.; He, Xi; Hauschka, Peter V.

doi:10.1016/j.bone.2007.05.009

Cited by 158 publications

(111 citation statements)

References 56 publications

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“…Interestingly, for one particular LRP5 gain-of-function mutation, G171V, decreased inhibition of LRP5 by Dkk1 was suggested to account for increased LRP5 signaling (Boyden et al 2002;Ai et al 2005). Similar to humans, heterozygous Dkk1 þ/2 mice show an increase in bone mineral density (Morvan et al 2006;MacDonald et al 2007). Conversely, transgenic mice overexpressing Dkk1 in bone develop osteopenia (Li et al 2006), suggesting that Dkk1 antagonizes Wnt -LRP5 signaling to regulate physiological levels of bone mass.…”

Section: Role Of Dkks In Embryonic Development and Diseasementioning

confidence: 99%

Secreted and Transmembrane Wnt Inhibitors and Activators

Cruciat

Niehrs

2012

Cold Spring Harbor Perspectives in Biology

537

450

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Section: Role Of Dkks In Embryonic Development and Diseasementioning

confidence: 99%

Secreted and Transmembrane Wnt Inhibitors and Activators

Cruciat

Niehrs

2012

Cold Spring Harbor Perspectives in Biology

537

450

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“…Skeletal trauma causes a local increase in Wnt signaling [11] and it has been shown that the pathways involved in bone Wnt signaling are necessary for bone healing [11][12] and for bone formation in general [13][14][15]. Fracture repair can be influenced by blocking Dkk1 in mice [16] and a decrease in Dkk1 gene expression leads to an increase in bone mass and strength [15,17].…”

Section: Introductionmentioning

confidence: 99%

The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions

Agholme

Isaksson

Kuhstoss

et al. 2011

Bone

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The secreted protein Dickkopf-1 (Dkk1) is an antagonist of canonical Wnt signaling, expressed during fracture healing. It is unknown if it is involved in the mechanical control of bone maintenance. We investigated the response to administration of a Dkk1 neutralizing antibody (Dkk1-ab) in metaphyseal bone under different loading conditions, with or without trauma. In this three part experiment, 120 rats had a screw or bone chamber inserted either unilaterally or bilaterally in the proximal tibia. Mechanical (pull-out) testing, µCT and histology were used for evaluation. The animals were injected with either 10 mg/kg Dkk1-ab or saline every 14 days for 14, 28, or 42 days. Antibody treatment increased bone formation around the screws and improved their fixation. After 28 days, the pull-out force was increased by over 100%. In cancellous bone, the bone volume fraction was increased by 50%. In some animals, one hind limb was paralyzed with Botullinum toxin A (Botox) to create a mechanically unloaded environment. This did not increase the response to antibody treatment with regard to screw fixation, but in cancellous bone, the bone volume fraction increased by 233 %. Thus, the response in unloaded, untraumatized bone was proportionally larger, suggesting that Dkk1 may be up-regulated in unloaded bone. There was also an increase in thickness of the metaphyseal cortex. In bone chambers, the antibody treatment increased the bone volume fraction. The results suggest that antibodies blocking Dkk1 might be used to stimulate bone formation especially during implant fixation, fracture repair, or bone disuse. It also seems that Dkk1 is up-regulated both after metaphyseal trauma and after unloading, and that Dkk1 is involved in mechano-transduction.

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“…One such example is Dickkopf-1 (Dkk1), which inhibits Wnt signaling by binding to LRP6 (9,11,12). Dkk1 has been shown to play a crucial role in bone formation, vertebrate embryogenesis, and suppression of cancer cell proliferation (13)(14)(15). Therefore, Wnt ligands, receptors Fz and LRP, and their natural inhibitors are all of great therapeutic interest.…”

mentioning

confidence: 99%

Reconstitution of a Frizzled8·Wnt3a·LRP6 Signaling Complex Reveals Multiple Wnt and Dkk1 Binding Sites on LRP6

Bourhis

Tam²,

Franke³

et al. 2010

Journal of Biological Chemistry

198

236

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Wnt/␤-catenin signaling is initiated at the cell surface by association of secreted Wnt with its receptors Frizzled (Fz) and low density lipoprotein receptor-related protein 5/6 (LRP5/6). The study of these molecular interactions has been a significant technical challenge because the proteins have been inaccessible in sufficient purity and quantity. In this report we describe insect cell expression and purification of soluble mouse Fz8 cysteine-rich domain and human LRP6 extracellular domain and show that they inhibit Wnt/␤-catenin signaling in cellular assays. We determine the binding affinities of Wnts and Dickkopf 1 (Dkk1) to the relevant co-receptors and reconstitute in vitro the Fz8 CRD⅐Wnt3a⅐LRP6 signaling complex. Using purified fragments of LRP6, we further show that Wnt3a binds to a region including only the third and fourth ␤-propeller domains of LRP6 (E3E4). Surprisingly, we find that Wnt9b binds to a different part of the LRP6 extracellular domain, E1E2, and we demonstrate that Wnt3a and Wnt9b can bind to LRP6 simultaneously. Dkk1 binds to both E1E2 and E3E4 fragments and competes with both Wnt3a and Wnt9b for binding to LRP6. The existence of multiple, independent Wnt binding sites on the LRP6 co-receptor suggests new possibilities for the architecture of Wnt signaling complexes and a model for broad-spectrum inhibition of Wnt/␤-catenin signaling by Dkk1.Since its discovery more than 30 years ago, the Wnt signaling pathway has captured the interest of researchers due to its role in development, progression of cancer, and self-renewal and differentiation of stem cells (1, 2). Wnt signaling is initiated at the cell surface where secreted Wnt glycoprotein forms a complex with the receptors Frizzled (Fz) 2 (3) and low density lipoprotein receptor-related proteins 5 or 6 (LRP5/6) (4, 5). This results in stabilization of intracellular ␤-catenin ("Wnt/␤-catenin pathway") and its translocation to the nucleus. Nuclear ␤-catenin then initiates T-cell factor-dependent transcription of downstream Wnt target genes (6, 7). The interactions of LRP5/6 and Fz with Wnt are critical for mediating Wnt/␤-catenin signaling (5,8,9). Underscoring the central role that these receptors play in Wnt signaling, suppression of either Fz or LRPs has been shown to generate phenotypes associated with Wnt mutations (10). Furthermore, mechanisms have evolved to regulate the Wnt⅐Fz⅐LRP complex through secreted proteins that interfere with these extracellular interactions. One such example is Dickkopf-1 (Dkk1), which inhibits Wnt signaling by binding to LRP6 (9,11,12). Dkk1 has been shown to play a crucial role in bone formation, vertebrate embryogenesis, and suppression of cancer cell proliferation (13-15). Therefore, Wnt ligands, receptors Fz and LRP, and their natural inhibitors are all of great therapeutic interest. Indeed, recent findings show that the soluble extracellular domain of Fz8 interferes with Wnt-driven tumor growth in vivo (16).The detailed molecular arrangement of the Wnt⅐Fz⅐LRP ternary complex at the cell surface is ...

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Bone mass is inversely proportional to Dkk1 levels in mice

Cited by 158 publications

References 56 publications

Secreted and Transmembrane Wnt Inhibitors and Activators

Secreted and Transmembrane Wnt Inhibitors and Activators

The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions

Reconstitution of a Frizzled8·Wnt3a·LRP6 Signaling Complex Reveals Multiple Wnt and Dkk1 Binding Sites on LRP6

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