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, 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

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

“…APC may also be a nucleocytoplasmic shuttle protein (350), which has been speculated to chaperone β-catenin out of the nucleus (351,352) and thus preventing β-catenin from binding to TCF/LEF (350,353,354). As a negative regulator of β-catenin, defects in or loss of APC results in increased bone mass: FAP patients with APC mutations within the β-catenin binding domains have increased bone mineral density (355).…”

Reengineering autologous bone grafts with the stem cell activator WNT3A

“…We focused on the role of Wnt signaling in this regard because the pathway is widely recognized as a key regulator of bone mass [29e31]. Experimental and clinical evidence both indicate that elevated Wnt signaling induces bone formation [32e34] whereas reduced Wnt signaling induces bone loss [35,36].…”

Oral manifestations in patients with familial adenomatous polyposis: A systematic review and meta‐analysis

“…[47][48][49] Furthermore, the increase of bone mineral density in patients with FAP was described. 43,46 FAP patients displayed a significantly higher mean of bone mineral density compared with age and sex than healthy controls. These data suggested an activation of the Wnt pathway in heterozygous of APC mutations probably due to the regulation of β-catenin levels.…”

“…Recent studies have found the role of the Wnt pathway in tooth and bone development. [42][43][44][45][46][47] The expression of Wnt pathway was observed in the human oral epithelium during morphogenesis stages of the tooth development. 44 In addition, a study published in 2009 45 demonstrated in embryonic mice oral epithelium that the ablation of APC and activation of Wnt/β-catenin resulted in supernumerary tooth development.…”

“…These data suggested an activation of the Wnt pathway in heterozygous of APC mutations probably due to the regulation of β-catenin levels. 43 The APC is a large gene with 15 exons, 7 and more than 1100 different mutations have been described (LOVD Mutation Database-http://www.lovd.nl/2.0/). For this reason, there are many variations in the expression of the phenotype in families with FAP.…”