LRP5

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Protein-coding gene in the species Homo sapiens

title: "LRP5" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public description: "Protein-coding gene in the species Homo sapiens" topic_path: "uncategorized" source: "https://en.wikipedia.org/wiki/LRP5" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Protein-coding gene in the species Homo sapiens ::

Low-density lipoprotein receptor-related protein 5 is a protein that in humans is encoded by the LRP5 gene. LRP5 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway. Mutations in LRP5 can lead to considerable changes in bone mass. A loss-of-function mutation causes osteoporosis pseudoglioma syndrome with a decrease in bone mass, while a gain-of-function mutation causes drastic increases in bone mass.

Structure

LRP5 is a transmembrane low-density lipoprotein receptor that shares a similar structure with LRP6. In each protein, about 85% of its 1600-amino-acid length is extracellular. Each has four β-propeller motifs at the amino terminal end that alternate with four epidermal growth factor (EGF)-like repeats. Most extracellular ligands bind to LRP5 and LRP6 at the β-propellers. Each protein has a single-pass, 22-amino-acid segment that crosses the cell membrane and a 207-amino-acid segment that is internal to the cell.

Function

LRP5 acts as a co-receptor with LRP6 and the Frizzled protein family members for transducing signals by Wnt proteins through the canonical Wnt pathway. This protein plays a key role in skeletal homeostasis.

Transcription

The LRP5 promoter contains binding sites for KLF15 and SP1. In addition, 5' 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.

Interactions

LRP5 has been shown to interact with AXIN1.

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.

Clinical significance

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. The majority of the current data supports the concept that bone mass is controlled by LRP5 through the osteocytes. Mice with the same Lrp5 gain-of-function mutations 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. There are promising osteoporosis clinical trials targeting sclerostin, an osteocyte-specific protein which inhibits Wnt signaling by binding to Lrp5. An alternative model that has been verified in mice and in humans is that Lrp5 controls bone formation by inhibiting expression of TPH1, the rate-limiting biosynthetic enzyme for serotonin, a molecule that regulates bone formation, in enterochromaffin cells of the duodenum and that excess plasma serotonin leads to inhibition in bone. Another study found that a different Tph1-inhibitor decreased serotonin levels in the blood and intestine, but did not affect bone mass or markers of bone formation.

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.

Mutations in LRP5 cause polycystic liver disease.

References

(Aug 1998). "Cloning of a novel member of the low-density lipoprotein receptor family". Gene.
(Feb 1999). "Molecular cloning of mouse Lrp7(Lr3) cDNA and chromosomal mapping of orthologous genes in mouse and human". Genomics.
"Entrez Gene: LRP5 low density lipoprotein receptor-related protein 5".
(Feb 2009). "Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone". Journal of Bone and Mineral Research.
(2010). "Sp1 and KLF15 regulate basal transcription of the human LRP5 gene". BMC Genetics.
(May 2011). "Functional relevance of the BMD-associated polymorphism rs312009: novel involvement of RUNX2 in LRP5 transcriptional regulation". Journal of Bone and Mineral Research.
(Nov 2008). "Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum". Cell.
(Oct 2012). "FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin". The Journal of Clinical Investigation.
(Mar 2010). "Patients with high-bone-mass phenotype owing to Lrp5-T253I mutation have low plasma levels of serotonin". Journal of Bone and Mineral Research.
(Feb 2009). "Breaking into bone biology: serotonin's secrets". Nature Medicine.
(Feb 2010). "Relation of serum serotonin levels to bone density and structural parameters in women". Journal of Bone and Mineral Research.
(Aug 2011). "Levels of serotonin, sclerostin, bone turnover markers as well as bone density and microarchitecture in patients with high-bone-mass phenotype due to a mutation in Lrp5". Journal of Bone and Mineral Research.
(Jun 2011). "Lrp5 functions in bone to regulate bone mass". Nature Medicine.
(Apr 2001). "Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway". Molecular Cell.
(Nov 2008). "SUMOylation target sites at the C terminus protect Axin from ubiquitination and confer protein stability". FASEB Journal.
(Sep 2006). "Cross-talk of WNT and FGF signaling pathways at GSK3beta to regulate beta-catenin and SNAIL signaling cascades". Cancer Biology & Therapy.
(Dec 2010). "Shared molecular mechanisms regulate multiple catenin proteins: canonical Wnt signals and components modulate p120-catenin isoform-1 and additional p120 subfamily members". Journal of Cell Science.
(Nov 2001). "LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development". Cell.
(Jan 2002). "A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait". American Journal of Human Genetics.
(May 2002). "High bone density due to a mutation in LDL-receptor-related protein 5". The New England Journal of Medicine.
(Mar 2012). "Potential role for therapies targeting DKK1, LRP5, and serotonin in the treatment of osteoporosis". Current Osteoporosis Reports.
(Feb 2013). "WNT signaling in bone homeostasis and disease: from human mutations to treatments". Nature Medicine.
(Jun 2003). "High bone mass in mice expressing a mutant LRP5 gene". Journal of Bone and Mineral Research.
(Aug 2006). "The Wnt co-receptor LRP5 is essential for skeletal mechanotransduction but not for the anabolic bone response to parathyroid hormone treatment". The Journal of Biological Chemistry.
(May 2013). "Inactivation of Lrp5 in osteocytes reduces young's modulus and responsiveness to the mechanical loading". Bone.
(Jun 2013). "Regulation of Wnt/β-catenin signaling within and from osteocytes". Bone.
(Jun 2008). "A model for familial exudative vitreoretinopathy caused by LPR5 mutations". Human Molecular Genetics.
(Sep 2010). "The Norrin/Frizzled4 signaling pathway in retinal vascular development and disease". Trends in Molecular Medicine.
(Jan 2003). "Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion". Proceedings of the National Academy of Sciences of the United States of America.
(Mar 2010). "Low-density lipoprotein receptor-related protein 5 (LRP5) expression in human osteoarthritic chondrocytes". Journal of Orthopaedic Research.
(Jun 2010). "Curcumin-induced suppression of adipogenic differentiation is accompanied by activation of Wnt/beta-catenin signaling". American Journal of Physiology. Cell Physiology.
(Apr 2014). "Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis". Proceedings of the National Academy of Sciences of the United States of America.

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