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Endocrinology. 2017 Nov 3. doi: 10.1210/en.2017-00357. [Epub ahead of print]

Osteoblast AMP-activated protein kinase regulates postnatal skeletal development in male mice.

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1
Internal Medicine 1, Shimane University Faculty of Medicine, 89-1, Enya-cho, Izumo, Shimane, 693-8501, Japan.

Abstract

Studies have shown that AMP-activated protein kinase (AMPK), a crucial regulator of energy homeostasis, plays important roles in osteoblast differentiation and mineralization. However, little is known about in vivo roles of osteoblastic AMPK in bone development. Thus, to investigate in vivo roles of osteoblast AMPK, we conditionally inactivated Ampk in osterix (Osx)-expressing cells by crossing Osx-Cre mice with floxed AMPKα1 to generate mice lacking AMPKα1 in osteoblasts (Ampk-/- mice). Compared with wild-type and Ampk+/- mice, Ampk-/- mice displayed retardation of postnatal bone development, although bone deformity was not observed at birth. Micro-CT showed significant reductions in trabecular bone volume, cortical bone length and density, and increased cortical porosity in femur as well as development defects of skull in 8-week-old Ampk-/- mice. Surprisingly, histomorphometric analysis demonstrated that the number of osteoclasts was significantly increased, although bone formation rate was not altered. Loss of trabecular network connections and mass, as well as shortened growth plates and reduced thickness of cartilage adjacent to the growth plate, were observed in Ampk-/- mice. In primary cultured osteoblasts from calvaria, the expressions of alkaline phosphatase, type 1 collagen, osteocalcin, bone morphogenetic protein-2, Runx2, and osterix were significantly inhibited in Ampk-/- osteoblasts, whereas the expression of receptor activator of nuclear kappa-B ligand (RANKL) and the RANKL/osteoprotegerin ratio were significantly increased. These findings indicate that osteoblastic AMPK plays important roles in bone development in vivo, and that deletion of AMPK in osteoblasts decreases osteoblastic differentiation and enhances bone turnover by increasing RANKL expression.

PMID:
29126229
DOI:
10.1210/en.2017-00357
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