Disease relevance of Lrp5

• Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor [1].
• Severe hypercholesterolemia, impaired fat tolerance, and advanced atherosclerosis in mice lacking both low density lipoprotein receptor-related protein 5 and apolipoprotein E [2].

High impact information on Lrp5

• Lrp5 is expressed in osteoblasts and is required for optimal Wnt signaling in osteoblasts [1].
• Here we show that mice with a targeted disruption of Lrp5 develop a low bone mass phenotype [1].
• In addition, Lrp5-deficient mice display persistent embryonic eye vascularization due to a failure of macrophage-induced endothelial cell apoptosis [1].
• Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice [3].
• We found that lithium activated canonical Wnt signaling in cultured calvarial osteoblasts from Lrp5(-/-) mice ex vivo and that lithium-treated mice had increased expression of Wnt-responsive genes in their bone marrow cells in vivo [3].

Biological context of Lrp5

• One of these sites within the Lrp5 locus was discovered to confer vitamin D response to a heterologous promoter when introduced into osteoblastic cells, permitting both the identification and characterization of the vitamin D response element located within [4].
• Interestingly, additional studies revealed that whereas the regulatory region in the mouse Lrp5 gene was highly conserved in the human genome, the vitamin D response element was not [4].
• RESULTS: Mice heterozygous for mutations in Lrp6 and either heterozygous or homozygous for a mutation in Lrp5 (Lrp6(+/-);Lrp5(+/-) or Lrp6(+/-);Lrp5(-/-)) display limb defects with incomplete penetrance and variable expression [5].
• The canonical pathway of Wnt signaling has been implicated by studies of Lrp5, a co-receptor for Wnt proteins, in postnatal bone mass homeostasis [6].
• Lrp5-null (Lrp5-/-) mice exhibited significantly lower bone mineral density and decreased strength [7].

Associations of Lrp5 with chemical compounds

• We gavage-fed lithium chloride to 8-week-old mice from three different strains (Lrp5(-/-), SAMP6, and C57BL/6) and assessed the effect on bone metabolism after 4 weeks of therapy [3].
• The high bone mass (HBM) mutation was identified as a glycine to valine substitution at amino acid residue 171 in the gene coding for low-density lipoprotein receptor-related protein 5 (LRP5) [Bone Miner. Res. 16(4) (2001) 758] [8].

Physical interactions of Lrp5

• The Dkk family of secreted cysteine-rich proteins regulates Wnt/beta-catenin signaling by interacting with the Wnt co-receptor Lrp5/6 [9].

Other interactions of Lrp5

• The Wnt co-receptors Lrp5 and Lrp6 are essential for gastrulation in mice [10].
• We demonstrated interaction between Dkk1 and the Wnt coreceptors Lrp5 and Lrp6 by analysis of several types of double mutants [11].
• The polydactyly of Dkk1(d/d) mice was corrected by reduced expression of Lrp5 or Lrp6 [11].
• Low density lipoprotein receptor-related protein 5 (LRP5) has been identified as a Wnt co-receptor involved in the activation of the beta-catenin signaling pathway [12].

Analytical, diagnostic and therapeutic context of Lrp5

• 4. The LRP7 gene was also localized by radiation hybrid mapping between markers D11S24270 and D11S1975 [13].
• Acupuncture was then applied to acupoints Yanglingquan (GB34) and Taichong (LR3) starting 2 h after the first MPTP administration and then at 48 h intervals until the mice were sacrificed for analyses at 1, 3, and 7 days after the last MPTP injection [14].

References