Switch from canonical to noncanonical Wnt signaling mediates high glucose-induced adipogenesis.
Human bone marrow mesenchymal progenitor cells (MPCs) are multipotent cells that play an essential role in endogenous repair and the maintenance of the stem cell niche. We have recently shown that high levels of glucose, conditions mimicking diabetes, cause impairment of MPCs, resulting in enhanced adipogenesis and suppression of osteogenesis. This implies that diabetes may lead to reduced endogenous repair mechanisms through altering the differentiation potential of MPCs and, consequently, disrupting the stem cell niche. Phenotypic alterations in the bone marrow of long-term diabetic patients closely resemble this observation. Here, we show that high levels of glucose selectively enhance autogenous Wnt11 expression in MPCs to stimulate adipogenesis through the Wnt/protein kinase C noncanonical pathway. This novel mechanism may account for increased bone marrow adipogenesis, severe bone loss, and reduced vascular stem cells leading to chronic secondary complications of diabetes.
Department of Pathology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
Emily C
EC
Keats
James M
JM
Dominguez
Maria B
MB
Grant
Zia A
ZA
Khan
D000071916:AC133 Antigen; D050156:Adipogenesis / Q000187:drug effects*; D000368:Aged; D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001853:Bone Marrow / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000494:pharmacology*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D010455:Peptides / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D054852:Small Molecule Libraries / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
D000071916:AC133 Antigen; D042702:Angiopoietin-2; D015703:Antigens, CD; D006023:Glycoproteins; D010455:Peptides; D054852:Small Molecule Libraries; D051153:Wnt Proteins; C540523:Wnt11 protein, human; D051176:beta Catenin; D011493:Protein Kinase C; D005947:Glucose
Adipogenesis; Cell-autogenous regulation; Diabetes; Noncanonical signaling; Protein kinase C; Wnt signaling