LRP4 association to bone properties and fracture and interaction with genes in the Wnt- and BMP signaling pathways

Kumar, Jitender; Swanberg, Maria; McGuigan, Fiona; Callréus, Mattias; Gerdhem, Paul; Åkesson, Kristina

doi:10.1016/j.bone.2011.05.018

Cited by 39 publications

(23 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5 B and C), indicating the specificity of the effect. Moreover, the inhibitory effect of sclerostin and Wise was attenuated by Lrp4-extracellular domain (Lrp4-ECD), the polypeptide containing the entire Lrp4 extracellular domain that is able to interact with sclerostin, Wise, and agrin (7,8,11,18,22). This suggested that sclerostin/Wise inhibition is mediated by direct binding to the extracellular region of Lrp4, supporting Lrp4 as a receptor.…”

Section: Increased Bone Formation In Mr-lrp4 Mitt and Lrp4mentioning

confidence: 89%

“…Lrp4 interacts with multiple extracellular proteins, including sclerostin (SOST), Wise (a paralog of sclerostin that is also called Sostdc1), dickkopf-1 (DKK1), and agrin ( Fig. 5A) (7,8,11,22). Sclerostin, Wise, and DKK1 are negative regulators of Wnt/β-catenin signaling and/or bone formation (1,13,23,24).…”

Section: Increased Bone Formation In Mr-lrp4 Mitt and Lrp4mentioning

confidence: 99%

See 1 more Smart Citation

Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption

Xiong

Jung

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Bone mass is maintained by balanced activity of osteoblasts and osteoclasts. Lrp4 (low-density lipoprotein receptor related protein 4) is a member of the LDL receptor family, whose mutations have been identified in patients with high-bone-mass disorders, such as sclerosteosis and van Buchem diseases. However, it remains unknown whether and how Lrp4 regulates bone-mass homeostasis in vivo. Here we provide evidence that Lrp4-null mutation or specific mutation in osteoblast-lineage cells increased cortical and trabecular bone mass, which was associated with elevated bone formation and impaired bone resorption. This phenotype was not observed in osteoclast-selective Lrp4 knockout mice. Mechanistic studies indicate that loss of Lrp4 function in osteoblast-lineage cells increased serum levels of sclerostin, a key factor for bone-mass homeostasis that interacts with Lrp4, but abolished the inhibition of Wnt/β-catenin signaling and osteoblastic differentiation by sclerostin. Concomitantly, sclerostin induction of RANKL (receptor activator of nuclear kappa B ligand) was impaired, leading to a lower ratio of RANKL over OPG (osteoprotegerin) (a key factor for osteoclastogenesis). Taken together, these results support the view for Lrp4 as a receptor of sclerostin to inhibit Wnt/β-catenin signaling and bone formation and identify Lrp4 as a critical player in bonemass homeostasis.one remodeling is a dynamic process essential for maintenance of skeletal integrity and bone homeostasis (1). Bone mass is tightly regulated by bone-forming osteoblasts (OBs) and bone-resorbing osteoclasts (OCs). OBs are differentiated from bone marrow stromal cells (BMSCs) or mesenchymal progenitor cells, whereas OCs are derived from hematopoietic bone marrow macrophages or myeloid monocytes (BMMs). The balance of bone formation and resorption is critical for maintenance of healthy bone mass. The imbalance of bone formation and resorption could result in high-bone-mass disorders such as sclerosteosis and van Buchem disease or bone loss such as osteoporosis.The canonical Wnt/β-catenin signaling is critical to regulate bone-mass homeostasis (1, 2). Binding of Wnt ligands to a dualreceptor complex of frizzled and Lrp5/6 leads to accumulation of cytoplasmic β-catenin and translocation of β-catenin into the nucleus to regulate gene expression. This pathway is required for commitment of mesenchymal stem cells to the OB lineage, OB precursor cell proliferation and differentiation, and OC genesis and activation (1-3). Clinically, Lrp5 mutations are associated with the osteoporosis-pseudoglioma syndrome, a low-bone-mass disorder (4), as well as with high-bone-mass disorders (5, 6).Lrp4 is a member of LDL family protein, containing a large extracellular region with multiple LDLa, EGF-like, and β-propeller repeats, a transmembrane domain, and a short C-terminal region. Lrp4 is a receptor of agrin (7,8), critical for neuromuscular junction formation. Mice lacking Lrp4 (null allele) die at birth because of inability to breathe (9). Lrp4 is also highly related to...

show abstract

Section: Increased Bone Formation In Mr-lrp4 Mitt and Lrp4mentioning

confidence: 89%

Section: Increased Bone Formation In Mr-lrp4 Mitt and Lrp4mentioning

confidence: 99%

Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption

Xiong

Jung

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Details of the two cohorts have been published [45], [46]. Participants gave written informed consent and the study was approved by the Regional Ethical Review Board in Lund according to the Helsinki agreement.…”

Section: Methodsmentioning

confidence: 99%

Variation in the MC4R Gene Is Associated with Bone Phenotypes in Elderly Swedish Women

et al. 2014

Self Cite

View full text Add to dashboard Cite

Osteoporosis is characterized by reduced bone mineral density (BMD) and increased fracture risk. Fat mass is a determinant of bone strength and both phenotypes have a strong genetic component. In this study, we examined the association between obesity associated polymorphisms (SNPs) with body composition, BMD, Ultrasound (QUS), fracture and biomarkers (Homocysteine (Hcy), folate, Vitamin D and Vitamin B12) for obesity and osteoporosis. Five common variants: rs17782313 and rs1770633 (melanocortin 4 receptor (MC4R); rs7566605 (insulin induced gene 2 (INSIG2); rs9939609 and rs1121980 (fat mass and obesity associated (FTO) were genotyped in 2 cohorts of Swedish women: PEAK-25 (age 25, n = 1061) and OPRA (age 75, n = 1044). Body mass index (BMI), total body fat and lean mass were strongly positively correlated with QUS and BMD in both cohorts (r2 = 0.2–0.6). MC4R rs17782313 was associated with QUS in the OPRA cohort and individuals with the minor C-allele had higher values compared to T-allele homozygotes (TT vs. CT vs. CC: BUA: 100 vs. 103 vs. 103; p = 0.002); (SOS: 1521 vs. 1526 vs. 1524; p = 0.008); (Stiffness index: 69 vs. 73 vs. 74; p = 0.0006) after adjustment for confounders. They also had low folate (18 vs. 17 vs. 16; p = 0.03) and vitamin D (93 vs. 91 vs. 90; p = 0.03) and high Hcy levels (13.7 vs 14.4 vs. 14.5; p = 0.06). Fracture incidence was lower among women with the C-allele, (52% vs. 58%; p = 0.067). Variation in MC4R was not associated with BMD or body composition in either OPRA or PEAK-25. SNPs close to FTO and INSIG2 were not associated with any bone phenotypes in either cohort and FTO SNPs were only associated with body composition in PEAK-25 (p≤0.001). Our results suggest that genetic variation close to MC4R is associated with quantitative ultrasound and risk of fracture.

show abstract

“…Interestingly, the Wls gene itself is activated by β-catenin and Lef1/Tcf-dependent transcription, which then assists the cellular trafficking of Wnt proteins in a positive feedback mechanism (Fu et al, 2009). Several genome-wide association studies identified WLS as a gene linked to altered bone mineral density (Hsu et al, 2010; Kumar et al, 2011; Rivadeneira et al, 2009; Styrkarsdottir et al, 2010). …”

Section: Wnts and Wntlessmentioning

confidence: 99%

Update on Wnt signaling in bone cell biology and bone disease

Monroe

McGee‐Lawrence

Oursler

et al. 2012

Gene

357

302

View full text Add to dashboard Cite

For more than a decade, Wnt signaling pathways have been the focus of intense research activity in bone biology laboratories because of their importance in skeletal development, bone mass maintenance, and therapeutic potential for regenerative medicine. It is evident that even subtle alterations in the intensity, amplitude, location, and duration of Wnt signaling pathways affects skeletal development, as well as bone remodeling, regeneration, and repair during a lifespan. Here we review recent advances and discrepancies in how Wnt/Lrp5 signaling regulates osteoblasts and osteocytes, introduce new players in Wnt signaling pathways that have important roles in bone development, discuss emerging areas such as the role of Wnt signaling in osteoclastogenesis, and summarize progress made in translating basic studies to clinical therapeutics and diagnostics centered around inhibiting Wnt pathway antagonists, such as sclerostin, Dkk1 and Sfrp1. Emphasis is placed on the plethora of genetic studies in mouse models and genome wide association studies that reveal the requirement for and crucial roles of Wnt pathway components during skeletal development and disease.

show abstract

LRP4 association to bone properties and fracture and interaction with genes in the Wnt- and BMP signaling pathways

Cited by 39 publications

References 37 publications

Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption

Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption

Variation in the MC4R Gene Is Associated with Bone Phenotypes in Elderly Swedish Women

Update on Wnt signaling in bone cell biology and bone disease

Contact Info

Product

Resources

About