Hedgehog signaling in mature osteoblasts regulates bone formation and resorption by controlling PTHrP and RANKL expression.
Hedgehog (Hh) signaling is required for osteoblast differentiation from mesenchymal progenitors during endochondral bone formation. However, the role of Hh signaling in differentiated osteoblasts during adult bone homeostasis remains to be elucidated. We found that in the postnatal bone, Hh signaling activity was progressively reduced as osteoblasts mature. Upregulating Hh signaling selectively in mature osteoblasts led to increased bone formation and excessive bone resorption. As a consequence, these mutant mice showed severe osteopenia. Conversely, inhibition of Hh signaling in mature osteoblasts resulted in increased bone mass and protection from bone loss in older mice. Cellular and molecular studies showed that Hh signaling indirectly induced osteoclast differentiation by upregulating osteoblast expression of PTHrP, which promoted RANKL expression via PKA and its target transcription factor CREB. Our results demonstrate that Hh signaling in mature osteoblasts regulates both bone formation and resorption and that inhibition of Hh signaling reduces bone loss in aged mice.
Mak
Kinglun Kingston
KK
Genetic Disease Research Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
Bi
Yanming
Y
Wan
Chao
C
Chuang
Pao-Tien
PT
Clemens
Thomas
T
Young
Marian
M
Yang
Yingzi
Y
D000818:Animals; D001851:Bone Diseases, Metabolic / Q000378:metabolism; D001862:Bone Resorption / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D053823:Hedgehog Proteins / Q000378:metabolism*; D051379:Mice; D009929:Organ Size; D010006:Osteoblasts / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010010:Osteoclasts / Q000473:pathology; D010012:Osteogenesis; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics*; D053245:RANK Ligand / Q000235:genetics*; D015398:Signal Transduction; D015854:Up-Regulation / Q000235:genetics
D017362:Cyclic AMP Response Element-Binding Protein; D053823:Hedgehog Proteins; D044162:Parathyroid Hormone-Related Protein; D053245:RANK Ligand; D017868:Cyclic AMP-Dependent Protein Kinases