Amp-Activated Protein Kinase Regulates Thyroid Hormone-Stimulated Osteocalcin Synthesis In Osteoblasts

AMP-activated protein kinase (AMPK) is recognized as a main regulator of energy homeostasis. Osteocalcin (OC), which is produced specifically by mature osteoblasts, is stored in bone matrix, strongly binds to hydroxyapatite and is released into the circulation, has been recognized as a marker of bone metabolism. It has recently been shown that OC released from osteoblasts influences energy metabolism as a hormone. We previously reported that triiodothyronine (T-3) stimulates the synthesis of OC in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether AMPK participates in T-3-stimulated OC synthesis in osteoblasts. T-3 time-dependently induced the phosphorylation of the AMPK alpha-subunit (Thr-172), whereas T-3 failed to induce the phosphorylation of AMPK alpha-subunit (Ser-485), AMPK beta-subunit (Ser-108) and AMPK beta-subunit (Ser-182). Both the release and the mRNA expression of OC induced by T-3 were significantly inhibited by compound C, an AMPK inhibitor. Compound C suppressed the T-3-induced phosphorylation of acetyl-CoA carboxylase, a direct substrate of AMPK. T-3-stimulated OC release was significantly reduced in AMPK-knockdown cells using AMPK-siRNA. These results strongly suggest that AMPK positively regulates T-3-stimulated OC synthesis in osteoblasts.