scholarly journals High-bone-mass-producing mutations in the Wnt signaling pathway result in distinct skeletal phenotypes

Bone ◽  
2011 ◽  
Vol 49 (5) ◽  
pp. 1010-1019 ◽  
Author(s):  
Paul J. Niziolek ◽  
Takeisha L. Farmer ◽  
Yajun Cui ◽  
Charles H. Turner ◽  
Matthew L. Warman ◽  
...  
Keyword(s):  
Bone Mass ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
High Bone Mass ◽  
High Bone

scholarly journals In Vivo Analysis of Wnt Signaling in Bone

Endocrinology ◽  
2007 ◽  
Vol 148 (6) ◽  
pp. 2630-2634 ◽  
Author(s):  
Donald A. Glass ◽  
Gerard Karsenty
Keyword(s):  
Bone Mass ◽  
Wnt Signaling ◽  
Bone Remodeling ◽  
Signaling Pathway ◽  
Mouse Models ◽  
Osteoclast Differentiation ◽  
Wnt Signaling Pathway ◽  
Human Beings ◽  
High Bone Mass ◽  
High Bone

Bone remodeling requires osteoblasts and osteoclasts working in concert to maintain a constant bone mass. The dysregulation of signaling pathways that affect osteoblast or osteoclast differentiation or function leads to either osteopenia or high bone mass. The discovery that activating and inactivating mutations in low-density lipoprotein receptor-related protein 5, a putative Wnt coreceptor, led to high bone mass and low bone mass in human beings, respectively, generated a tremendous amount of interest in the possible role of the Wnt signaling pathway in the regulation of bone remodeling. A number of mouse models have been generated to study a collection of Wnt signaling molecules that have been identified as regulators of bone mass. These mouse models help establish the canonical Wnt signaling pathway as a major regulator of chondrogenesis, osteoblastogenesis, and osteoclastogenesis. This review will summarize these advances.

scholarly journals Novel LRP5 Missense Mutation in a Patient With a High Bone Mass Phenotype Results in Decreased DKK1-Mediated Inhibition of Wnt Signaling*

2007 ◽  
Vol 22 (5) ◽  
pp. 708-716 ◽  
Author(s):  
Wendy Balemans ◽  
Jean-Pierre Devogelaer ◽  
Erna Cleiren ◽  
Elke Piters ◽  
Emanuelle Caussin ◽  
...  
Keyword(s):  
Bone Mass ◽  
Wnt Signaling ◽  
Missense Mutation ◽  
High Bone Mass ◽  
High Bone ◽  
High Bone Mass Phenotype

scholarly journals Reduced Affinity to and Inhibition by DKK1 Form a Common Mechanism by Which High Bone Mass-Associated Missense Mutations in LRP5 Affect Canonical Wnt Signaling

2005 ◽  
Vol 25 (12) ◽  
pp. 4946-4955 ◽  
Author(s):  
Minrong Ai ◽  
Sheri L. Holmen ◽  
Wim Van Hul ◽  
Bart O. Williams ◽  
Matthew L. Warman
Keyword(s):  
Cell Surface ◽  
Bone Mass ◽  
Wnt Signaling ◽  
Common Mechanism ◽  
Missense Mutations ◽  
Canonical Wnt Signaling ◽  
High Bone Mass ◽  
Mutant Proteins ◽  
High Bone ◽  
Canonical Wnt

ABSTRACT The low-density-lipoprotein receptor-related protein 5 (LRP5), a coreceptor in the canonical Wnt signaling pathway, has been implicated in human disorders of low and high bone mass. Loss-of-function mutations cause the autosomal recessive osteoporosis-pseudoglioma syndrome, and heterozygous missense mutations in families segregating autosomal dominant high bone mass (HBM) phenotypes have been identified. We expressed seven different HBM-LRP5 missense mutations to delineate the mechanism by which they alter Wnt signaling. None of the mutations caused activation of the receptor in the absence of ligand. Each mutant receptor was able to reach the cell surface, albeit at differing amounts, and transduce exogenously supplied Wnt1 and Wnt3a signal. All HBM mutant proteins had reduced physical interaction with and reduced inhibition by DKK1. These data suggest that HBM mutant proteins can transit to the cell surface in sufficient quantity to transduce Wnt signal and that the likely mechanism for the HBM mutations' physiologic effects is via reduced affinity to and inhibition by DKK1.

scholarly journals The LRP5 High-Bone-Mass G171V Mutation Disrupts LRP5 Interaction with Mesd

2004 ◽  
Vol 24 (11) ◽  
pp. 4677-4684 ◽  
Author(s):  
Yazhou Zhang ◽  
Yang Wang ◽  
Xiaofeng Li ◽  
Jianhong Zhang ◽  
Junhao Mao ◽  
...  
Keyword(s):  
Cell Surface ◽  
Bone Mass ◽  
Wnt Signaling ◽  
Cell Surfaces ◽  
Osteoblast Cells ◽  
High Bone Mass ◽  
Chaperone Protein ◽  
Repeat Domain ◽  
High Bone ◽  
Canonical Wnt

ABSTRACT The mechanism by which the high-bone-mass (HBM) mutation (G171V) of the Wnt coreceptor LRP5 regulates canonical Wnt signaling was investigated. The mutation was previously shown to reduce DKK1-mediated antagonism, suggesting that the first YWTD repeat domain where G171 is located may be responsible for DKK-mediated antagonism. However, we found that the third YWTD repeat, but not the first repeat domain, is required for DKK1-mediated antagonism. Instead, we found that the G171V mutation disrupted the interaction of LRP5 with Mesd, a chaperone protein for LRP5/6 that is required for transport of the coreceptors to cell surfaces, resulting in fewer LRP5 molecules on the cell surface. Although the reduction in the number of cell surface LRP5 molecules led to a reduction in Wnt signaling in a paracrine paradigm, the mutation did not appear to affect the activity of coexpressed Wnt in an autocrine paradigm. Together with the observation that osteoblast cells produce autocrine canonical Wnt, Wnt7b, and that osteocytes produce paracrine DKK1, we think that the G171V mutation may cause an increase in Wnt activity in osteoblasts by reducing the number of targets for paracrine DKK1 to antagonize without affecting the activity of autocrine Wnt.

The Molecular Mechanisms of Estrogen Receptor α on Two Single Nucleotide Polymorphisms to Regulate WNT Signaling in Osteoblasts

2021 ◽  
Author(s):  
◽  
Sarocha Suthon ◽  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Bone Mass ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Osteoblast Differentiation ◽  
Association Studies ◽  
Wnt Signaling Pathway ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

Osteoporosis is the most common bone metabolic disorder, affecting over 200 million people globally. It is characterized by bone mass depletion and microarchitectural deterioration, leading to bone fragility and susceptibility to bone fracture. Genetic factors, estrogen deficiency, and dysregulation of the WNT signaling pathway contribute to the development of this disease. Genome-wide association studies have predicted that the single nucleotide polymorphisms (SNPs) rs2887571 and rs9921222 associate with low bone mass, but the mechanism of these SNPs has remained unknown. Analysis of osteoblasts from 112 different joint replacement patients reveals that the genotype of rs2887571 correlates with WNT5B expression, and the genotype of rs9921222 correlates with AXIN1 expression. Mechanistically, SNP rs2887571 has less binding of ERα and NFATc1 to allele A than allele G, resulting in more expression of WNT5B in homozygous AA than homozygous GG. Furthermore, WNT5B exhibits distinct effects from other WNTs on osteoblastogenesis. WNT5B increases mesenchymal stem cell proliferation, promotes adipogenesis, and suppresses osteoblast differentiation via ROR1/2, then activates DVL2/3, Rac1/Cdc42, JNK, and SIN3A signaling, as well as inhibits ROCK2 and β-catenin activity. For SNP rs9921222, homozygous TT has a higher expression of AXIN1 than homozygous CC. Molecular analysis shows that GATA4 favors binding at rs9921222 allele T to promote AXIN1 expression; in contrast, ERα prefers to bind at allele C to suppress the expression, resulting in more expression of AXIN1 in homozygous TT than homozygous CC. Functionally, the level of AXIN1 negatively correlates with the level of active β-catenin, which enhances osteoblast differentiation. Taken together, the biological mechanisms of SNPs rs2887571 and rs9921222, which are associated with osteoporosis via the WNT signaling pathway, are revealed, as well as the inhibitory effect of WNT5B on osteoblastogenesis. These data will be the fundamental knowledge for the development of osteoporosis prediction and therapeutic strategies.

scholarly journals A Rare Mutation in SMAD9 Associated With High Bone Mass Identifies the SMAD‐Dependent BMP Signaling Pathway as a Potential Anabolic Target for Osteoporosis

2019 ◽  
Vol 35 (1) ◽  
pp. 92-105 ◽  
Author(s):  
Celia L Gregson ◽  
Dylan J. M. Bergen ◽  
Paul Leo ◽  
Richard B Sessions ◽  
Lawrie Wheeler ◽  
...  
Keyword(s):  
Bone Mass ◽  
Signaling Pathway ◽  
Bmp Signaling ◽  
High Bone Mass ◽  
Rare Mutation ◽  
High Bone

Thyroid Hormone Actions and Bone Remodeling – The Role of the Wnt Signaling Pathway

2020 ◽  
Vol 128 (06/07) ◽  
pp. 450-454
Author(s):  
Franziska Lademann ◽  
Elena Tsourdi ◽  
Lorenz C. Hofbauer ◽  
Martina Rauner
Keyword(s):  
Thyroid Hormone ◽  
Bone Resorption ◽  
Bone Mass ◽  
Thyroid Hormones ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Bone Development ◽  
Wnt Signaling Pathway ◽  
Bone Homeostasis ◽  
Normal Thyroid Function

AbstractThyroid hormones are indispensable for bone development and growth. Also in adults, bone mass maintenance is under the control of thyroid hormones. Preclinical and clinical studies established untreated hyperthyroidism as a cause for secondary osteoporosis with increased fracture risk. Thus, normal thyroid function is essential for bone health. Mechanistically, thyroid hormone excess accelerates bone turnover with predominant bone resorption. How thyroid hormones affect osteoblast and osteoclast functions, however, still remains ill-defined. The Wnt signaling pathway is a major determinant of bone mass and strength as it promotes osteoblastogenesis and bone formation, while inhibiting bone resorption. So far, only few studies investigated a possible link between thyroid hormones, bone metabolism and the Wnt pathway. In this review, we summarize the literature linking thyroid hormones to bone homeostasis through Wnt signaling and discuss its potential as a therapeutic approach to treat hyperthyroidism-induced bone loss.

Wnt signaling pathway regulates the differentiation of hepatic progenitor cells

2010 ◽  
Vol 34 (8) ◽  
pp. S41-S41
Author(s):  
Yang Bi ◽  
Yun He ◽  
Tingyu Li ◽  
Tao Feng ◽  
Tongchuan He
Keyword(s):  
Wnt Signaling ◽  
Progenitor Cells ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Hepatic Progenitor Cells

417: The Human Androgen Receptor Gene is a Primary Target of the WNT Signaling Pathway

2006 ◽  
Vol 175 (4S) ◽  
pp. 136-136
Author(s):  
Ralph Buttyan ◽  
Xuezhen Yang ◽  
Min-Wei Chen ◽  
Debra L. Bemis ◽  
Mitchell C. Benson ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Receptor Gene ◽  
Wnt Signaling Pathway ◽  
Androgen Receptor Gene ◽  
Primary Target ◽  
Human Androgen Receptor Gene ◽  
Human Androgen Receptor

Wnt Signaling Pathway in Right Ventricular Remodeling

Pneumologie ◽  
2012 ◽  
Vol 66 (06) ◽  
Author(s):  
A Tretyn ◽  
KD Schlüter ◽  
W Janssen ◽  
HA Ghofrani ◽  
F Grimminger ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Ventricular Remodeling ◽  
Wnt Signaling Pathway ◽  
Right Ventricular Remodeling
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