|Low density lipoprotein receptor-related protein 5|
|Symbols||; BMND1; EVR1; EVR4; HBM; LR3; LRP-5; LRP7; OPPG; OPS; OPTA1; VBCH2|
|RNA expression pattern|
- Function 1
- Transcription 2
- Interactions 3
- Clinical Significance 4
- References 5
- Further reading 6
- External links 7
LRP5 is a transmembrane low-density lipoprotein receptor that binds and internalizes ligands in the process of receptor-mediated endocytosis. This protein also acts as a co-receptor with Frizzled protein family members for transducing signals by Wnt proteins and was originally cloned on the basis of its association with diabetes mellitus type 1 in humans. This protein plays a key role in skeletal homeostasis.
The LRP5 promoter contains binding sites for KLF15 and SP1. In addition, 5' region region of the LRP5 gene contains four RUNX2 binding sites. LRP5 has been shown in mice and humans to inhibit expression of TPH1, the rate-limiting biosynthetic enzyme for serotonin in enterochromaffin cells of the duodenum and that excess plasma serotonin leads to inhibition in bone. On the other hand one study in mouse has shown a direct effect of Lrp5 on bone.
Canonical WNT signals are transduced through Frizzled receptor and LRP5/LRP6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser-9 phosphorylation. Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin degradation.
The Wnt signaling pathway was first linked to bone development when a loss-of-function mutation in LRP5 was found to cause osteoporosis-pseudoglioma syndrome. Shortly thereafter, two studies reported that gain-of-function mutations in LRP5 caused high bone mass. Many bone density related diseases are caused by mutations in the LRP5 gene. There is controversy whether bone grows through Lrp5 through bone or the intestine. Few studies support the concept that bone mass is controlled by LRP5 through the osteoblasts or osteocytes. Mice with the same Lrp5 gain-of-function mutations as also have high bone mass. The high bone mass is maintained when the mutation only occurs in limbs or in cells of the osteoblastic lineage. Bone mechanotransduction occurs through Lrp5 and is suppressed if Lrp5 is removed in only osteocytes. An alternative model is that Lrp5 controls bone formation by suppressing serotonin synthesis in the duodenum by regulating TPH1 independent of Wnt signaling. There are promising osteoporosis clinical trials targeting an osteocyte-specific Wnt antagonist, sclerostin. It must be pointed out that activation of Wnts in mice and humans leads to cancer and we therefore need to view therapies targeting Wnt signaling with utmost care.
LRP5 in humans and mice regulats bone formation while Wnt signaling regulats bone resorption. Lrp6 is therefore a more bonafide Wnt coreceptor in bone than Lrp5 as Lrp6 mutation in mice and humans regulates bone resorption like the Wnt signaling does. Clarification of this issue needs further investigation. An alternative model to Wnt signaling where in LRP5 inhibits expression of TPH1, the rate-limiting biosynthetic enzyme for serotonin, a molecule that regulates bone formation, in enterochromaffin cells of the duodenum in mice and humans  and that excess plasma serotonin leads to inhibition in bone.
LRP5 may be essential for the development of retinal vasculature, and may play a role in capillary maturation. Mutations in this gene also cause familial exudative vitreoretinopathy.
A glial-derived extracellular ligand, Norrin, acts on a transmembrane receptor, Frizzled4, a coreceptor, Lrp5, and an auxiliary membrane protein, TSPAN12, on the surface of developing endothelial cells to control a transcriptional program that regulates endothelial growth and maturation.
LRP5 knockout in mice led to increased plasma cholesterol levels on a high-fat diet because of the decreased hepatic clearance of chylomicron remnants. When fed a normal diet, LRP5-deficient mice showed a markedly impaired glucose tolerance with marked reduction in intracellular ATP and Ca2+ in response to glucose, and impairment in glucose-induced insulin secretion. IP3 production in response to glucose was also reduced in LRP5—islets possibly caused by a marked reduction of various transcripts for genes involved in glucose sensing in LRP5—islets. LRP5-deficient islets lacked the Wnt-3a-stimulated insulin secretion. These data suggest that WntLRP5 signaling contributes to the glucose-induced insulin secretion in the islets.
In osteoarthritic chondrocytes the Wnt/beta-catenin pathway is activated with a significant up-regulation of beta-catenin mRNA expression. LRP5 mRNA and protein expression are also significantly up-regulated in osteoarthritic cartilage compared to normal cartilage, and LRP5 mRNA expression was further increased by vitamin D. Blocking LRP5 expression using siRNA against LRP5 resulted in a significant decrease in MMP13 mRNA and protein expressions. The catabolic role of LRP5 appears to be mediated by the Wnt/beta-catenin pathway in human osteoarthritis.
The polyphenol curcumin increases the mRNA expression of LRP5.
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- GeneReviews/NCBI/NIH/UW entry on Familial Exudative Vitreoretinopathy, Autosomal Dominant