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Germline deletion of AMP-activated protein kinase beta subunits reduces bone mass without altering osteoclast differentiation or function.

ABSTRACT: 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.

SUBMITTER: Quinn JM

PROVIDER: S-EPMC2797037 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Germline deletion of AMP-activated protein kinase beta subunits reduces bone mass without altering osteoclast differentiation or function.

Quinn Julian M W JM 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

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20090901 1

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 oste ...[more]

PMID: 19723702

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Project description:RATIONALE:AMP-activated protein kinase (AMPK) has been reported to play a protective role in atherosclerosis. However, whether AMPK?2 controls atherosclerotic plaque stability remains unknown. OBJECTIVE:The aim of this study was to evaluate the impact of AMPK?2 deletion on atherosclerotic plaque stability in advanced atherosclerosis at the brachiocephalic arteries and to elucidate the underlying mechanisms. METHODS AND RESULTS:Features of atherosclerotic plaque stability and the markers for contractile or synthetic vascular smooth muscle cell (VSMC) phenotypes were monitored in the brachiocephalic arteries from Apoe(-/-)AMPK?2(-/-) mice or VSMC-specific AMPK?2(-/-) mice in an Apoe(-/-) background (Apoe(-/-)AMPK?2(sm-/-)) fed Western diet for 10 weeks. We identified that Apoe(-/-)AMPK?2(-/-) mice and Apoe(-/-)AMPK?2(sm-/-) mice exhibited similar unstable plaque features, aggravated VSMC phenotypic switching, and significant upregulation of Kruppel-like factor 4 (KLF4) in the plaques located in the brachiocephalic arteries compared with those found in Apoe(-/-) and Apoe(-/-)AMPK?2(sm+/+) control mice. Pravastatin, an AMPK activator, suppressed VSMC phenotypic switching and alleviated features of atherosclerotic plaque instability in Apoe(-/-)AMPK?2(sm+/+) mice, but not in Apoe(-/-)AMPK?2(sm-/-) mice. VSMC isolated from AMPK?2(-/-) mice displayed a significant reduction of contractile proteins(smooth muscle actin-?, calponin, and SM-MHC [smooth muscle-mysion heavy chain]) in parallel with increased detection of synthetic proteins (vimentin and osteopontin) and KLF4, as observed in vivo. KLF4-specific siRNA abolished AMPK?2 deletion-induced VSMC phenotypic switching. Furthermore, pharmacological or genetic inhibition of nuclear factor-?B significantly decreased KLF4 upregulation in VSMC from AMPK?2(-/-) mice. Finally, we found that AMPK?2 deletion markedly promoted the binding of nuclear factor-?Bp65 to KLF4 promoter. CONCLUSIONS:This study demonstrated that AMPK?2 deletion induces VSMC phenotypic switching and promotes features of atherosclerotic plaque instability in nuclear factor-?B-KLF4-dependent manner.

Dataset Information

Germline deletion of AMP-activated protein kinase beta subunits reduces bone mass without altering osteoclast differentiation or function.

Publications

Germline deletion of AMP-activated protein kinase beta subunits reduces bone mass without altering osteoclast differentiation or function.

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