Background: Bone and energy metabolism are closely associated with each other. AMP-activated protein kinase (AMPK) is a crucial regulator of energy and metabolic homeostasis. Previous in vitro studies have shown that AMPK plays important roles in osteoblast differentiation and mineralization. However, little is known about in vivo roles of osteoblast AMPK in bone.

Methods: To examine the roles of osteoblast AMPK in bone development, we conditionally inactivated Ampk in osterix (Osx)-expressing cells by crossing Osx-Cre mice with floxed AMPKα1 (Ampk^f/f) to generate mice lacking AMPKα1 in osteoblasts (Ampk_osb^-/- mice). Micro-architecture of trabecular and cortical bone in distal femur was analyzed by micro-computed tomography (μCT) and histomorphometric analysis, and gene expression analysis was performed by real-time PCR in primary cultured osteoblasts from calvaria.

Results: Compared with the control mice, Ampk_osb^-/- mice displayed retardation of postnatal bone development although bone deformity was not observed at the birth. μCT analysis showed significant reductions in trabecular bone volume, cortical bone length and density, and increased cortical porosity in 8-week Ampk_osb^-/- mice. Surprisingly, histomorphometric analysis demonstrated that the number of osteoclasts was significantly increased, although the number of osteoblasts or bone formation rate was not altered. Moreover, loss of trabecular network connections and mass as well as shortened growth palate and reduced thickness of cartilage adjacent to the growth plate were observed in Ampk_osb^-/- mice, compared to the controls. In primary cultured osteoblasts, the expressions of alkaline phosphatase, type 1 collagen, osteocalcin, BMP-2, Runx2, and osterix were significantly inhibited in the Ampk^-/- osteoblasts, whereas the expression of RANKL and RANKL/osteoprotegerin ratio were significantly increased.

Conclusion: These findings indicated that osteoblastic AMPK plays important roles in bone development in vivo, and that deletion of AMPK in osteoblasts decreased osteoblastic differentiation and enhanced bone turnover by increasing RANKL expression.