Genetic determination of the cellular basis of the ghrelin-dependent bone remodeling.
OBJECTIVE
Bone mass is maintained through a balance of bone formation and resorption. This homeostatic balance is regulated by various systems involving humoral and local factors. The discovery that the anorexigenic hormone leptin regulates bone mass via neuronal pathways revealed that neurons and neuropeptides are intimately involved in bone homeostasis. Ghrelin is a stomach-derived orexigenic hormone that counteracts leptin's action. However, the physiological role of ghrelin in bone homeostasis remains unknown. In this study, through the global knockout of ghrelin receptor (Ghsr) followed by tissue-specific re-expression, we addressed the molecular basis of the action of ghrelin in bone remodeling in vivo.


METHODS
We performed molecular, genetic and cell biological analyses of Ghsr-null mice and Ghsr-null mice with tissue specific Ghsr restoration. Furthermore, we evaluated the molecular mechanism of ghrelin by molecular and cell-based assays.


RESULTS
Ghsr-null mice showed a low bone mass phenotype with poor bone formation. Restoring the expression of Ghsr specifically in osteoblasts, and not in osteoclasts or the central nervous system, ameliorated bone abnormalities in Ghsr-null mice. Cell-based assays revealed ghrelin induced the phosphorylation of CREB and the expression of Runx2, which in turn accelerated osteoblast differentiation.


CONCLUSIONS
Our data show that ghrelin regulates bone remodeling through Ghsr in osteoblasts by modulating the CREB and Runx2 pathways.
Department of Orthopedic Surgery and Global Center of Excellence (GCOE) Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo Medical and Dental University, Tokyo, Japan.
Chengshan
C
Ma
Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan ; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan.
Toru
T
Fukuda
Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan ; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan.
Hiroki
H
Ochi
Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan ; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan.
Satoko
S
Sunamura
Department of Orthopedic Surgery and Global Center of Excellence (GCOE) Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo Medical and Dental University, Tokyo, Japan.
Cheng
C
Xu
Department of Orthopedic Surgery and Global Center of Excellence (GCOE) Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo Medical and Dental University, Tokyo, Japan.
Ren
R
Xu
Department of Orthopedic Surgery and Global Center of Excellence (GCOE) Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo Medical and Dental University, Tokyo, Japan.
Atsushi
A
Okawa
Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan ; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan.
Shu
S
Takeda
Bone remodeling; CREB; Ghrelin; Osteoblast; RUNX2