LRP5 Mutations in osteoporosis-pseudoglioma syndrome and high-bone-mass disorders
Rheumatology Department, Angers Teaching Hospital, 49933 Angers cedex 9, France. Joint Bone Spine
(Impact Factor: 2.9).
06/2005; 72(3):207-14. DOI: 10.1016/j.jbspin.2004.10.008
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.
Available from: Vincenzo Desiderio
- "Inactivating mutation of LRP5 Osteoporosis pseudoglioma syndrome Levasseur et al. (2005) Gain of function missense mutation of LRP5 Increased bone density Boyden et al. (2002) Missense mutation of LRP6 Osteoporosis Riancho et al. (2011) Polymorphisms of LRP6 Reduced bone density Riancho et al. (2011) Mutation of SOST gene Sclerosteosis with high bone density Costa and Bilezikian (2012) Deletion of ␤ catenin Chondrocytes differentation Day et al. (2005) HDACs deletion HDAC1 Embryonic lethality Chang et al. (2006) HDAC2 Reduced body size Zimmermann et al. (2007) HDAC3 Embryonic lethal or bone loss Jensen et al. (2008) HDAC4 Chondrocytes hypertrophy and enhanced ossification Vega et al. (2004) HDAC5 Bone loss and decreased bone formation rate Li et al. (2009a,b) HDAC6 Increased trabecular bone density Jensen et al. (2008) HDAC7 Embryonic lethality Chang et al. (2006) HDAC8 Ossification defects in frontal and interparietal bones Haberland et al. (2009) microRNA miR-29 Increased bone differentiation by suppression of Wnt inhibitors Kapinas et al. (2010) miR-29b Increased bone differentiation by suppression of HDAC4 Li et al. (2009a,b) miR-128 Increased bone differentiation by suppression of Wnt inhibitors Hassan et al. (2012) miR-218 Increased bone differentiation by suppression of Wnt inhibitors Hassan et al. (2012) miR-335-5p Increased bone differentiation by suppression of Wnt inhibitors Zhang et al. (2011) miR-2861 Increased bone differentiation by suppression of HDAC5 Li et al. (2009a,b) Suppression of HDAC3 or HDAC1 expression by RNA interference accelerated the course of osteoblastic differentiation (Lee et al., 2006). All these data suggest that distinct HDACs have a role in osteogenic differentiation (Fig. 2). "
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ABSTRACT: Bone defects are one of the most serious pathologies that need tissue regeneration therapies. Studies on mesenchymal stem cells are changing the way we treat bone diseases. MSCs have been used for the treatment of osteogenesis imperfecta, hypophosphatasia, osteonecrosis of the femoral head, osteoporosis, rheumatoid arthritis and osteoarthritis. In this context, it is becoming ever more clear that the future of therapies will be based on the use of stem cells. In this concise review, we highlight the importance of the use of MSCs in bone diseases, focusing on the role of histone deacetylases and Wnt pathways involved in osteogenesis. A better understanding of MSC biology and osteogenesis is needed in order to develop new and targeted therapeutic strategies for the treatment of bone diseases/disorders.
The international journal of biochemistry & cell biology 06/2014; 51(1). DOI:10.1016/j.biocel.2014.03.025 · 4.05 Impact Factor
Available from: Ning Wang
- "The most noteworthy example of altered Wnt signaling causing an osteogenic pathology is the inactivating mutation of LRP5 leading to osteoporosis pseudoglioma syndrome (OPPG). OPPG is an autosomal recessive disorder characterized by early-onset osteoporosis, low bone mineral density (BMD) and blindness [Levasseur et al. 2005]. A loss-of-function mutation of LRP5 has been linked to the pathogenesis of OPPG through genetic analyses [Gong et al. 2001] and later confirmed by animal studies. "
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ABSTRACT: The Wnt signaling pathway plays an important role not only in embryonic development but also in the maintenance and differentiation of the stem cells in adulthood. In particular, Wnt signaling has been shown as an important regulatory pathway in the osteogenic differentiation of mesenchymal stem cells. Induction of the Wnt signaling pathway promotes bone formation while inactivation of the pathway leads to osteopenic states. Our current understanding of Wnt signaling in osteogenesis elucidates the molecular mechanisms of classic osteogenic pathologies. Activating and inactivating aberrations of the canonical Wnt signaling pathway in osteogenesis results in sclerosteosis and osteoporosis respectively. Recent studies have sought to target the Wnt signaling pathway to treat osteogenic disorders. Potential therapeutic approaches attempt to stimulate the Wnt signaling pathway by upregulating the intracellular mediators of the Wnt signaling cascade and inhibiting the endogenous antagonists of the pathway. Antibodies against endogenous antagonists, such as sclerostin and dickkopf-1, have demonstrated promising results in promoting bone formation and fracture healing. Lithium, an inhibitor of glycogen synthase kinase 3β, has also been reported to stimulate osteogenesis by stabilizing β catenin. Although manipulating the Wnt signaling pathway has abundant therapeutic potential, it requires cautious approach due to risks of tumorigenesis. The present review discusses the role of the Wnt signaling pathway in osteogenesis and examines its targeted therapeutic potential.
Therapeutic advances in musculoskeletal disease 02/2013; 5(1):13-31. DOI:10.1177/1759720X12466608
Available from: Johanna Korvala
- "LRP5 has an essential role in the Wnt signaling pathway, since it acts as a co-receptor that binds Wnt proteins with Frizzled-receptors [5,6]. Mutations within the gene are known to lead to various bone disorders: gain-of-function mutations in the LRP5 gene can cause high-bone-mass (HBM) phenotypes in humans [7,8], whereas homozygous loss-of-function mutations cause osteoporosis-pseudoglioma syndrome (OPPG) characterized by early-onset osteoporosis and complications in eye development [9-11]. Similarly, transgenic mice with interrupted Lrp5 express a low bone mass phenotype, independent of Cbfa-1, including decreased osteoblast proliferation, osteopenia and persistent embryonic eye vascularization . "
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ABSTRACT: Primary osteoporosis is a rare childhood-onset skeletal condition whose pathogenesis has been largely unknown. We have previously shown that primary osteoporosis can be caused by heterozygous missense mutations in the Low-density lipoprotein receptor-related protein 5 (LRP5) gene, and the role of LRP5 is further investigated here.
LRP5 was analyzed in 18 otherwise healthy children and adolescents who had evidence of osteoporosis (manifested as reduced bone mineral density i.e. BMD, recurrent peripheral fractures and/or vertebral compression fractures) but who lacked the clinical features of osteogenesis imperfecta (OI) or other known syndromes linked to low BMD. Also 51 controls were analyzed. Methods used in the genetic analyses included direct sequencing and multiplex ligation-dependent probe amplification (MLPA). In vitro studies were performed using luciferase assay and quantitative real-time polymerase chain reaction (qPCR) to examine the effect of two novel and three previously identified mutations on the activity of canonical Wnt signaling and on expression of tryptophan hydroxylase 1 (Tph1) and 5-hydroxytryptamine (5-Htr1b).
Two novel LRP5 mutations (c.3446 T > A; p.L1149Q and c.3553 G > A; p.G1185R) were identified in two patients and their affected family members. In vitro analyses showed that one of these novel mutations together with two previously reported mutations (p.C913fs, p.R1036Q) significantly reduced the activity of the canonical Wnt signaling pathway. Such reductions may lead to decreased bone formation, and could explain the bone phenotype. Gut-derived Lrp5 has been shown to regulate serotonin synthesis by controlling the production of serotonin rate-limiting enzyme, Tph1. LRP5 mutations did not affect Tph1 expression, and only one mutant (p.L1149Q) reduced expression of serotonin receptor 5-Htr1b (p < 0.002).
Our results provide additional information on the role of LRP5 mutations and their effects on the development of juvenile-onset primary osteoporosis, and hence the pathogenesis of the disorder. The mutations causing primary osteoporosis reduce the signaling activity of the canonical Wnt signaling pathway and may therefore result in decreased bone formation. The specific mechanism affecting signaling activity remains to be resolved in future studies.
BMC Medical Genetics 04/2012; 13(1):26. DOI:10.1186/1471-2350-13-26 · 2.08 Impact Factor
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