LRP5 mutations in osteoporosis-pseudoglioma syndrome and high-bone-mass disorders
- PMID: 15850991
- DOI: 10.1016/j.jbspin.2004.10.008
LRP5 mutations in osteoporosis-pseudoglioma syndrome and high-bone-mass disorders
Abstract
The LDL receptor-related protein 5 (LRP5) is a member of the LDL receptor family, which also includes the VLDL receptor and the apolipoprotein E receptor 2. The LRP5 is a co-receptor of Wnt located on the osteoblast membrane between two other receptors, Frizzled and Kremen. Frizzled and LRP5 bind to Wnt, thereby stabilizing beta-catenin and activating bone formation. When the dickkopf protein (Dkk) binds to Kremen and LRP5, this last undergoes internalization and therefore becomes unable to bind Wnt; this leads to degradation of beta-catenin and to inhibition of bone formation. In humans, loss of LRP5 function causes osteoporosis-pseudoglioma syndrome, which is characterized by congenital blindness and extremely severe childhood-onset osteoporosis (lumbar spine Z-score often < -4) with fractures. The G171V mutation prevents Dkk from binding to LRP5, thereby increasing LRP5 function; the result is high bone mass due to uncoupling of bone formation and resorption. The Z-scores in this condition can exceed +6 at the hip and spine. The LRP5 and Wnt/beta-catenin reflect the level of bone formation and play a central role in bone mass accrual and normal distribution. Furthermore, LRP5 may contribute to mediate mechanical loads within bone tissue. Identification of the Wnt/beta-catenin pathway is a breakthrough in the elucidation of pathophysiological mechanisms affecting bone tissue and suggests new treatment targets for patients with osteoporosis or specific malignant conditions such as myeloma and sclerotic bone metastases.
Similar articles
-
Pathogenic mutations and polymorphisms in the lipoprotein receptor-related protein 5 reveal a new biological pathway for the control of bone mass.Curr Opin Lipidol. 2005 Apr;16(2):207-14. doi: 10.1097/01.mol.0000162326.62419.e4. Curr Opin Lipidol. 2005. PMID: 15767861 Review.
-
Novel LRP5 missense mutation in a patient with a high bone mass phenotype results in decreased DKK1-mediated inhibition of Wnt signaling.J Bone Miner Res. 2007 May;22(5):708-16. doi: 10.1359/jbmr.070211. J Bone Miner Res. 2007. PMID: 17295608
-
Clinical and molecular findings in osteoporosis-pseudoglioma syndrome.Am J Hum Genet. 2005 Nov;77(5):741-53. doi: 10.1086/497706. Epub 2005 Sep 27. Am J Hum Genet. 2005. PMID: 16252235 Free PMC article.
-
[Wnt-beta-catenin signaling in bone metabolism].Clin Calcium. 2006 Jan;16(1):54-60. Clin Calcium. 2006. PMID: 16397351 Review. Japanese.
-
High bone density due to a mutation in LDL-receptor-related protein 5.N Engl J Med. 2002 May 16;346(20):1513-21. doi: 10.1056/NEJMoa013444. N Engl J Med. 2002. PMID: 12015390
Cited by
-
An LRP5 receptor with internal deletion in hyperparathyroid tumors with implications for deregulated WNT/beta-catenin signaling.PLoS Med. 2007 Nov 27;4(11):e328. doi: 10.1371/journal.pmed.0040328. PLoS Med. 2007. PMID: 18044981 Free PMC article.
-
Fibroblast Growth Factor 2 and Its Receptors in Bone Biology and Disease.J Endocr Soc. 2018 May 28;2(7):657-671. doi: 10.1210/js.2018-00105. eCollection 2018 Jul 1. J Endocr Soc. 2018. PMID: 29942929 Free PMC article. Review.
-
Osteoporosis-pseudoglioma syndrome: description of 9 new cases and beneficial response to bisphosphonates.Bone. 2008 Sep;43(3):584-90. doi: 10.1016/j.bone.2008.04.020. Epub 2008 May 7. Bone. 2008. PMID: 18602879 Free PMC article.
-
Polymorphisms of FDPS, LRP5, SOST and VKORC1 genes and their relation with osteoporosis in postmenopausal Romanian women.PLoS One. 2019 Nov 27;14(11):e0225776. doi: 10.1371/journal.pone.0225776. eCollection 2019. PLoS One. 2019. PMID: 31774873 Free PMC article.
-
Whole exome sequencing reveals potentially pathogenic variants in a small subset of premenopausal women with idiopathic osteoporosis.Bone. 2022 Jan;154:116253. doi: 10.1016/j.bone.2021.116253. Epub 2021 Nov 4. Bone. 2022. PMID: 34743040 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Miscellaneous