title: APC mutations are associated with increased bone mineral density in patients with familial adenomatous polyposis.
abstract: The canonical Wnt pathway plays a key regulatory role in osteoblastogenesis and bone mass acquisition through its main effector, β-catenin. Adenomatous polyposis coli (APC) represents the key intracellular gatekeeper of β-catenin turnover, and heterozygous germ-line 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 +1 or greater in 14 patients (63.6%) and +2 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 β-crosslaps (β-CTX) (r = 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 β-catenin levels.
authors.affiliation: Department of Pediatrics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Razvan L
authors.initials: RL
authors.lastname: Miclea
authors.forename: Marcel
authors.initials: M
authors.lastname: Karperien
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Langers
authors.forename: Els C
authors.initials: EC
authors.lastname: Robanus-Maandag
authors.forename: Antoon
authors.initials: A
authors.lastname: van Lierop
authors.forename: Bernies
authors.initials: B
authors.lastname: van der Hiel
authors.forename: Marcel P
authors.initials: MP
authors.lastname: Stokkel
authors.forename: Bart E
authors.initials: BE
authors.lastname: Ballieux
authors.forename: Wilma
authors.initials: W
authors.lastname: Oostdijk
authors.forename: Jan M
authors.initials: JM
authors.lastname: Wit
authors.forename: Hans F
authors.initials: HF
authors.lastname: Vasen
authors.forename: Neveen A
authors.initials: NA
authors.lastname: Hamdy
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000328:Adult; D015519:Bone Density / Q000235:genetics*; D016723:Bone Remodeling / Q000502:physiology; D003094:Collagen / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics; D003710:Demography; D005091:Exons / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000235:genetics; D011877:Radionuclide Imaging; D055815:Young Adult
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D024042:Collagen Type I; D010446:Peptide Fragments; C110762:glutamyl-lysyl-alanyl-histidyl-aspartyl-glycyl-glycyl-arginine; D003094:Collagen