ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2011) 25 P23

Ablation of AMP-activated protein kinase (AMPK) [alpha]1 catalytic subunit in mice leads to decreased bone loss after ovariectomy and impaired bone response to intermittent PTH treatment

Mittal Shah1, Benoit Viollet2, Marta Korbonits3 & Chantal Chenu1

1Veterinary Basic Sciences, Royal Veterinary College, London, UK; 2INSERM U567, Paris, France; 3Endocrinology, Queen Mary University of London, London, UK.

AMPK is a key regulator of cellular and body energy homeostasis. We previously demonstrated that AMPK activation in osteoblasts increases bone formation in vitro while deletion of the AMPKα1 subunit leads to decreased bone mass in vivo. To determine whether bone turnover can be stimulated in the absence of AMPKα1 subunit, we subjected WT and AMPKα1−/− mice to catabolic (ovariectomy: OVX) and anabolic (intermittent PTH administration: iPTH) hormonal challenges. In vivo iPTH administration is a potent inducer of bone formation and can reverse OVX-induced bone loss.

A 3-month-old female AMPKα1−/− (n=16) and WT (n=16) mice were ovariectomised. Four weeks after OVX, mice were randomly divided into two groups, one receiving saline and the other PTH (1–34) treatment (80 μg/kg per day) for 4 weeks. Tibiae were harvested from these mice and bone micro-architecture determined by micro-computed tomography.

AMPKα1−/− mice displayed a decreased bone loss after OVX in the trabecular compartment. This was demonstrated by higher trabecular bone volume (+38%; P<0.01), trabecular number (+40%; P<0.001) and decreased trabecular separation (−37%; P<0.001) in AMPKα1−/− mice versus WT mice. The cortical indexes showed nonsignificant increases in bone area (+1%) and cortical thickness (+6%) in AMPKα1−/− mice versus WT mice after OVX. As expected, iPTH increased cortical and trabecular bone indexes. However, AMPKα1−/− mice showed lower trabecular bone volume (−17%; P<0.01), trabecular number (−10.4%; P<0.05), trabecular thickness (−10%; P<0.05) and increased trabecular separation (+13%; P<0.05) compared to WT mice in response to iPTH treatment. The cortical indexes, bone area (−15%; P<0.01) and cortical thickness (−9.8%), were similarly lower in AMPKα1−/− mice compared to WT mice. Neither AMPKα1−/− nor WT mice bone length or body weight were altered. Overall these results demonstrate that AMPKα1−/− mice are less affected by catabolic and anabolic changes in bone turnover induced by OVX and PTH respectively, suggesting that AMPK activation plays a role in the hormonal regulation of bone remodelling.

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