Mice lacking AMP-activated protein kinase α1 catalytic subunit have increased bone remodelling and modified skeletal responses to hormonal challenges induced by ovariectomy and intermittent PTH treatment

AMP-activated protein kinase (AMPK) is a key regulator of cellular and body energy homeostasis. We previously demonstrated that AMPK activation in osteoblasts increases in vitro bone formation while deletion of the Ampk alpha 1 (Prkaa1) subunit, the dominant catalytic subunit expressed in bone, leads to decreased bone mass in vivo. To investigate the cause of low bone mass in the Ampk alpha 1(-/-) mice, we analysed bone formation and resorption in the tibia of these mice by dynamic histomorphometry and determined whether bone turnover can be stimulated in the absence of the Ampk alpha 1 subunit. We subjected 12-week-old Ampk alpha 1(+/+) and Ampk alpha 1(-/-) mice to ovariectomy (OVX), intermittent PTH (iPTH) administration (80 mu g/kg per day, 5 days/week) or both OVX and iPTH hormonal challenges. Tibiae were harvested from these mice and bone micro-architecture was determined by micro-computed tomography. We show for the first time that Ampk alpha 1(-/-) mice have a high bone turnover at the basal level in favour of bone resorption. While both Ampk alpha 1(+/+) and Ampk alpha 1(-/-) mice lost bone mass after OVX, the bone loss in Ampk alpha 1(-/-) mice was lower compared with controls. iPTH increased trabecular and cortical bone indexes in both ovariectomised Ampk alpha 1(+/+) and Ampk alpha 1(-/-) mice. However, ovariectomised Ampk alpha 1(-/-) mice showed a smaller increase in bone parameters in response to iPTH compared with Ampk alpha 1(+/+) mice. By contrast, non-ovariectomised Ampk alpha 1(-/-) mice responded better to iPTH treatment than non-ovariectomised Ampk alpha 1(+/+) mice. Overall, these data demonstrate that Ampk alpha 1(-/-) mice are less affected by changes in bone turnover induced by OVX but respond better to the anabolic challenge induced by iPTH. These results suggest that AMPK alpha 1 activation may play a role in the hormonal regulation of bone remodelling. Journal of Endocrinology (2012) 214, 349-358