Adenomatous polyposis coli-mediated control of β-catenin is essential for both chondrogenic and osteogenic differentiation of skeletal precursors

Miclea, Razvan L.; Karperien, Marcel; Bosch, C.; Horst, Geertje van der; Valk, Martin A. van der; Kobayashi, Tatsuya; Kronenberg, Henry M.; Rawadi, Georges; Akçakaya, Pınar; Löwik, Clemens W.G.M.; Fodde, Riccardo; Wit, Jan M.; Robanus-Maandag, Els C.

doi:10.1186/1471-213x-9-26

Cited by 51 publications

(41 citation statements)

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“…(30)(31)(32)(33)(34) Using murine conditional genetic models, we and others have shown that Apc is involved in the regulation of both prenatal and postnatal bone mass accrual by regulating the levels of Wnt/b-catenin signalling. (11,12) This study confirms findings from these in vivo animal studies by demonstrating that heterozygous mutations in the APC gene are associated with a higher than normal bone mass in a majority of FAP patients.…”

Section: Discussionsupporting

confidence: 84%

“…Which particular APC mutation has the most beneficial effect on BMD thus remains to be elucidated. As observed in conditional heterozygous Apc mutant mice, (11,12) FAP patients display an average height similar to that of the general population, suggesting that one functional APC allele is sufficient for normal longitudinal bone growth.…”

Section: Discussionmentioning

confidence: 68%

“…(10) Several in vivo and in vitro studies further support the role of APC in both skeletal development and metabolism. Inactivation of Apc in skeletal progenitor cells has been shown to lead to an osteosclerotic bone phenotype owing to the formation of highly active osteoblasts, (11) whereas inactivation of Apc in mature osteoblasts results in an osteopetrotic bone phenotype owing to impaired osteoclast differentiation. (12) Interestingly, it has been reported that mice carrying a heterozygous loss-of-function mutation in Apc (Apc min/þ ) display a significantly increased bone mineral density (BMD) of the distal femur.…”

Section: Introductionmentioning

confidence: 99%

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APC mutations are associated with increased bone mineral density in patients with familial adenomatous polyposis

Miclea

Karperien

Langers

et al. 2010

Journal of Bone and Mineral Research

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The canonical Wnt pathway plays a key regulatory role in osteoblastogenesis and bone mass acquisition through its main effector, bcatenin. Adenomatous polyposis coli (APC) represents the key intracellular gatekeeper of b-catenin turnover, and heterozygous germline mutations in the APC gene cause familial adenomatous polyposis (FAP). Whether APC mutations affect bone mass has not been previously investigated. We conducted a cross-sectional study evaluating skeletal status in FAP patients with a documented APC mutation. Twenty-two FAP patients with a mean age of 42 years (54.5% women) were included in this study. Mean bone mineral density (BMD) Z-scores were significantly increased above normal at all measured sites: lumbar spine (p < .01), total hip (p < .01), femoral neck (p < .05), and trochanter (p < .01). Z-scores were þ1 or greater in 14 patients (63.6%) and þ2 or greater in 5 (22.7%). Mean values of bone turnover markers were within normal ranges. There was a significant positive correlation between procollagen type I N-terminal propeptide (P1NP) and b-crosslaps (b-CTX) (r ¼ 0.70, p < .001) and between these markers and sclerostin and BMD measurements. We demonstrate that FAP patients display a significantly higher than normal mean BMD compared with age-and sex-matched healthy controls in the presence of a balanced bone turnover. Our data suggest a state of ''controlled'' activation of the Wnt signaling pathway in heterozygous carriers of APC mutations, most likely owing to upregulation of cytoplasmic b-catenin levels. ß

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

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APC mutations are associated with increased bone mineral density in patients with familial adenomatous polyposis

Miclea

Karperien

Langers

et al. 2010

Journal of Bone and Mineral Research

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“…Interestingly, no quantifiable differences were observed in proliferation or density during in vitro osteoblast differentiation. Deletion of APC via the Col2aI-driven Cre promoter resulted in impaired skeletogenesis due to the inability of chondrocytes and osteoblasts to terminally differentiate (133). From these data, it is clear that the role of APC in regulating β-catenin activity is crucial for both cell autonomous and intercellular regulation of skeletal cell types.…”

Section: Adenomatous Polyposis Coli (Apc)mentioning

confidence: 80%

A Comprehensive Overview of Skeletal Phenotypes Associated with Alterations in Wnt/β-catenin Signaling in Humans and Mice

2013

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The Wnt signaling pathway plays key roles in differentiation and development and alterations in this signaling pathway are causally associated with numerous human diseases. While several laboratories were examining roles for Wnt signaling in skeletal development during the 1990s, interest in the pathway rose exponentially when three key papers were published in 2001-2002. One report found that loss of the Wnt co-receptor, Low-density lipoprotein related protein-5 (LRP5), was the underlying genetic cause of the syndrome Osteoporosis pseudoglioma (OPPG). OPPG is characterized by early-onset osteoporosis causing increased susceptibility to debilitating fractures. Shortly thereafter, two groups reported that individuals carrying a specific point mutation in LRP5 (G171V) develop high-bone mass. Subsequent to this, the causative mechanisms for these observations heightened the need to understand the mechanisms by which Wnt signaling controlled bone development and homeostasis and encouraged significant investment from biotechnology and pharmaceutical companies to develop methods to activate Wnt signaling to increase bone mass to treat osteoporosis and other bone disease. In this review, we will briefly summarize the cellular mechanisms underlying Wnt signaling and discuss the observations related to OPPG and the high-bone mass disorders that heightened the appreciation of the role of Wnt signaling in normal bone development and homeostasis. We will then present a comprehensive overview of the core components of the pathway with an emphasis on the phenotypes associated with mice carrying genetically engineered mutations in these genes and clinical observations that further link alterations in the pathway to changes in human bone. Keywords: Wnt signaling; mouse models; Lrp5/Lrp6; β-catenin; skeletal phenotypes Bone Research (2013) 1: 27-71. doi: 10.4248/BR201301004 Overview of Wnt signal transductionWnts are a family of 19 mammalian proteins characterized by a conserved pattern of cysteine residues( 1). Wnts can activate several signaling pathways after binding to their cognate receptors, however, the bulk of this review will focus on the best characterized of these pathways, the so-called canonical pathway (Figure 1). This pathway results in the stabilization of the β-catenin protein and subsequent transactivation of target genes (2). It is initiated by Wnt ligands binding to a receptor complex that includes a member of the Frizzled (Fzd) family of seven-transmembrane receptors and either Lrp5, or the related Lrp6 protein(3). Engagement of this complex results in the phosphorylation of the cytoplasmic domain of Lrp5 or Lrp6, creating a binding site for the Axin protein.In the absence of an upstreamsignal, Axin exists in a multiprotein complex that also includes Adenomatous polyposis coli (APC) and the serine/ threonine protein kinase, Glycogen synthase kinase 3 α/β. This complex facilitates β-catenin for GSK3-dependent phosphorylation, targeting it for ubiquitin-depen- 28 dent proteolysis. Binding of Axin to phosphoryl...

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“…Amhr2Cre mice were bred with Rosa26 reporter mice (Soriano, 1999) to review Cre expression, and were bred with Apc 15lox mice (Miclea et al, 2009;Robanus-Maandag et al, 2010) to obtain Apc 15flox/15flox mice ("flox" means that the sequence between two loxP sites has been deleted by Cre). PgrCre animals (Soyal et al, 2005) …”

Section: Animals and Genotypingmentioning

confidence: 99%

Loss of APC function in mesenchymal cells surrounding the Müllerian duct leads to myometrial defects in adult mice

Wang¹,

Jia²,

Franken³

et al. 2011

Molecular and Cellular Endocrinology

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Adenomatous polyposis coli-mediated control of β-catenin is essential for both chondrogenic and osteogenic differentiation of skeletal precursors

Cited by 51 publications

References 51 publications

APC mutations are associated with increased bone mineral density in patients with familial adenomatous polyposis

APC mutations are associated with increased bone mineral density in patients with familial adenomatous polyposis

A Comprehensive Overview of Skeletal Phenotypes Associated with Alterations in Wnt/β-catenin Signaling in Humans and Mice

Loss of APC function in mesenchymal cells surrounding the Müllerian duct leads to myometrial defects in adult mice

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