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

Julian M W Quinn, Shanna Tam, Natalie A. Sims, Hasnawati Saleh, Narelle E. McGregor, Ingrid J Poulton, John W Scott, Matthew T. Gillespie, Bruce E. Kemp, B. J W Van Denderen

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42 Citations (Scopus)

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 αβγ heterotrimer where the β subunit anchors the α catalytic and γ regulatory subunits. Germline deletion of either AMPK β1 or β2 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 β2 subunit expression, and when generated from AMPK β1 -/- mice displayed no detectable AMPK activity. Nevertheless, AICA-riboside was equally effective at stimulating OC differentiation from wildtype or β1 -/- 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.

Original languageEnglish
Pages (from-to)275-285
Number of pages11
JournalThe FASEB Journal
Volume24
Issue number1
DOIs
Publication statusPublished - Jan 2010
Externally publishedYes

Keywords

  • AICA-riboside
  • AMPK
  • Knockout mouse
  • Osteoblast
  • Osteolysis

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