WNT Signaling and Cartilage: Of Mice and Men

In adult articular cartilage, the extracellular matrix is maintained by a balance between the degradation and the synthesis of matrix components. Chondrocytes that sparsely reside in the matrix and rarely proliferate are the key cellular mediators for cartilage homeostasis. There are indications for the involvement of the WNT signaling pathway in maintaining articular cartilage. Various WNTs are involved in the subsequent stages of chondrocyte differentiation during development, and deregulation of WNT signaling was observed in cartilage degeneration. Even though gene expression and protein synthesis can be activated upon injury, articular cartilage has a limited ability of self-repair and efforts to regenerate articular cartilage have so far not been successful. Because WNT signaling was found to be involved in the development and maintenance of cartilage as well as in the degeneration of cartilage, interfering with this pathway might contribute to improving cartilage regeneration. However, most of the studies on elucidating the role of WNT signaling in these processes were conducted using in vitro or in vivo animal models. Discrepancies have been found in the role of WNT signaling between chondrocytes of mouse and human origin, and extrapolation of results from mouse models to the human situation remains a challenge. Elucidation of detailed WNT signaling functions will provide knowledge to improve cartilage regeneratio

Apc bridges Wnt/beta-catenin and BMP signaling during osteoblast differentiation of 16483 cells

Developmen

UV exposure inhibits intestinal tumor growth and progression to malignancy in intestine-specific Apc mutant mice kept on low vitamin D diet

Dermatology-oncolog

The Complete Genome Sequence of the Murine Pathobiont Helicobacter typhlonius

Molecular Technology and Informatics for Personalised Medicine and Healt

A new conditional Apc-mutant mouse model for colorectal cancer

Mutations of the adenomatous polyposis coli (APC) gene predispose individuals to familial adenomatous polyposis (FAP), characterized by multiple tumours in the large intestine. Most mouse models heterozygous for truncating mutant Apc alleles mimic FAP, however, the intestinal tumours occur mainly in the small intestine. To model large intestinal tumours, we generated a new conditional Apc-mutant allele, Apc(15lox), with exon 15 flanked by loxP sites. Similar survival of Apc(1638N/15lox) and Apc(1638N/+) mice indicated that the normal function of Apc was not impaired by the loxP sites. Deletion of exon 15, encoding nearly all functional Apc domains and containing the polyadenylation signal, resulted in a mutant allele expressing low levels of a 74 kDa truncated Apc protein. Germ line Cre-mediated deletion of exon 15 resulted in Apc(delta 15/+) mice, showing a severe Apc(Min/+)-like phenotype characterized by multiple tumours in the small intestine and early lethality. In contrast, conditional Cre-mediated deletion of exon 15 specifically directed to the epithelia of distal small and large intestine of FabplCre;Apc(15lox/+) mice led to longer survival and to tumours that developed predominantly in the large intestine, mimicking human FAP-associated colorectal cancer and sporadic colorectal cancer. We conclude that the FabplCre;Apc(15lox/+) mouse should be an attractive model for studies on prevention and treatment of colorectal cancer.MTG1 - Moleculaire genetica en pathologie van borstkanke

A dietary supplement attenuates IL-6 and CRP after eccentric exercise in untrained males

Gastrointestinal tumor growth is thought to be promoted by gastrointestinal bacteria and their inflammatory products. We observed that intestine-specific conditional Apc mutant mice (FabplCre;Apc (15lox/+)) developed many more colorectal tumors under conventional than under pathogen-low housing conditions. Shotgun metagenomic sequencing plus quantitative PCR analysis of feces DNA revealed the presence of two bacterial species in conventional mice, absent from pathogen-low mice. One, Helicobacter typhlonius, has not been associated with cancer in man, nor in immune-competent mice. The other species, mucin-degrading Akkermansia muciniphila, is abundantly present in healthy humans, but reduced in patients with inflammatory gastrointestinal diseases and in obese and type 2 diabetic mice. Eradication of H.typhlonius in young conventional mice by antibiotics decreased the number of intestinal tumors. Additional presence of A.muciniphila prior to the antibiotic treatment reduced the tumor number even further. Colonization of pathogen-low FabplCre;Apc (15lox/+) mice with H.typhlonius or A.muciniphila increased the number of intestinal tumors, the thickness of the intestinal mucus layer and A.muciniphila colonization without H.typhlonius increased the density of mucin-producing goblet cells. However, dual colonization with H.typhlonius and A.muciniphila significantly reduced the number of intestinal tumors, the mucus layer thickness and goblet cell density to that of control mice. By global microbiota composition analysis, we found a positive association of A.muciniphila, and of H.typhlonius, and a negative association of unclassified Clostridiales with increased tumor burden. We conclude that A.muciniphila and H.typhlonius can modulate gut microbiota composition and intestinal tumor development in mice

APC Mutations Are Associated With Increased Bone Mineral Density in Patients With Familial Adenomatous Polyposis

The canonical Wnt pathway plays a key regulatory role in osteoblastogenesis and bone mass acquisition through its main effector, beta-catenin Adenomatous polyposis coli (APC) represents the key intracellular gatekeeper of beta-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 (545% 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 beta-crosslaps (beta-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 beta-catenin levels (C) 2010 American Society for Bone and Mineral ResearchDiabetes mellitus: pathophysiological changes and therap

A new conditional Apc-mutant mouse model for colorectal cancer

Mutations of the adenomatous polyposis coli (APC) gene predispose individuals to familial adenomatous polyposis (FAP), characterized by multiple tumours in the large intestine. Most mouse models heterozygous for truncating mutant Apc alleles mimic FAP, however, the intestinal tumours occur mainly in the small intestine. To model large intestinal tumours, we generated a new conditional Apc-mutant allele, Apc15lox, with exon 15 flanked by loxP sites. Similar survival of Apc1638N/15loxand Apc1638N/1mice indicated that the normal function of Apc was not impaired by the loxP sites. Deletion of exon 15, encoding nearly all functional Apc domains and containing the polyadenylation signal, resulted in a mutant allele expressing low levels of a 74 kDa truncated Apc protein. Germ line Cre-mediated deletion of exon 15 resulted in ApcD15/1mice, showing a severe ApcMin/1-like phenotype characterized by multiple tumours in the small intestine and early lethality. In contrast, conditional Cre-mediated deletion of exon 15 specifically directed to the epithelia of distal small and large intestine of FabplCre;Apc15lox/1mice led to longer survival and to tumours that developed predominantly in the large intestine, mimicking human FAP-associated colorectal cancer and sporadic colorectal cancer. We conclude that the FabplCre;Apc15lox/1mouse should be an attractive model for studies on prevention and treatment of colorectal cancer