Germline deletion of AMP-activated protein kinase beta subunits reduces bone mass without altering osteoclast differentiation or function.
Since AMP-activated protein kinase (AMPK) plays important roles in modulating metabolism in response to diet and exercise, both of which influence bone mass, we examined the influence of AMPK on bone mass in mice. AMPK is an alphabetagamma heterotrimer where the beta subunit anchors the alpha catalytic and gamma regulatory subunits. Germline deletion of either AMPK beta1 or beta2 subunit isoforms resulted in reduced trabecular bone density and mass, but without effects on osteoclast (OC) or osteoblast (OB) numbers, as compared to wild-type littermate controls. We tested whether activating AMPK in vivo would enhance bone density but found AICA-riboside treatment caused a profound loss of trabecular bone volume (49.5%) and density and associated increased OC numbers. Consistent with this, AICA-riboside strongly stimulated OC differentiation in vitro, in an adenosine kinase-dependent manner. OCs and macrophages (unlike OBs) lacked AMPK beta2 subunit expression, and when generated from AMPK beta1(-/-) mice displayed no detectable AMPK activity. Nevertheless, AICA-riboside was equally effective at stimulating OC differentiation from wild-type or beta1(-/-) progenitors, indicating that AMPK is not essential for OC differentiation or the stimulatory action of AICA-riboside. These results show that AMPK is required to maintain normal bone density, but not through bone cell differentiation, and does not mediate powerful osteolytic effects of AICA-riboside.
Quinn
Julian M W
JM
Prince Henry's Institute, Monash Medical Centre, Clayton, Australia.
Tam
Shanna
S
Sims
Natalie A
NA
Saleh
Hasnawati
H
McGregor
Narelle E
NE
Poulton
Ingrid J
IJ
Scott
John W
JW
Gillespie
Matthew T
MT
Kemp
Bruce E
BE
van Denderen
B J W
BJ
D055372:AMP-Activated Protein Kinases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015519:Bone Density / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D017353:Gene Deletion; D018095:Germ-Line Mutation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D010641:Phenotype; D021122:Protein Subunits; D012263:Ribonucleosides / Q000494:pharmacology
D021122:Protein Subunits; D012263:Ribonucleosides; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D055372:AMP-Activated Protein Kinases