Germline deletion of AMP‐activated protein kinase β 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 αβy hetero‐trimer where the β subunit anchors the a catalytic and y regulatory subunits. Germline deletion of either AMPK β 1orβ2 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. Consis‐tent with this, AICA‐riboside strongly stimulated OC differentiation in vitro, in an adenosine kinase‐depen‐dent 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.—Quinn, J. M. W., Tam, S., Sims, N. A., Saleh, H., McGregor, N. E., Poulton, I. J., Scott, J. W., Gillespie, M. T., Kemp, B. E., van Denderen, B. J. W. Germline deletion of AMP‐activated protein kinase β subunits reduces bone mass without altering osteoclast differentiation or function. FASEB J . 24, 275–285 (2010). www.fasebj.org