Absence of estrogen receptor-related-alpha increases osteoblastic differentiation and cancellous bone mineral density.
The nuclear orphan receptor human estrogen receptor-related receptor (ERR)-alpha is implicated in bone metabolism. We studied the effect of ERRalpha silencing in human mesenchymal stem cells (hMSCs) during osteoblastogenesis. We found that ERRalpha silencing led to an increase of bone sialoprotein and a decrease of osteopontin mRNA levels, suggesting enhanced osteoblastic differentiation. This was confirmed by an increased ability of hMSCs to deposit calcium. Concomitantly, knockdown of ERRalpha inhibited adipogenesis, resulting in a decrease in adipocyte number and adipocyte marker gene expression. In line with a negative role of ERRalpha in bone metabolism, we found that adult female and male ERRalpha-deficient mice displayed a moderate increase in femoral cancellous bone volume and density. Osteoblast surface was increased and marrow fat volume decreased in these animals. Furthermore, ERRalpha-deficient osteoblasts displayed increased differentiation properties in vitro in line with our observations in hMSCs. In summary, we identified a role for ERRalpha in bone mass regulation by affecting osteoblastic differentiation.
Delhon
I
I
Novartis Institutes for Biomedical Research, Musculoskeletal Diseases, 4002 Basel, Switzerland.
Gutzwiller
S
S
Morvan
F
F
Rangwala
S
S
Wyder
L
L
Evans
G
G
Studer
A
A
Kneissel
M
M
Fournier
B
B
D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D050156:Adipogenesis; D000818:Animals; D015519:Bone Density; D001853:Bone Marrow / Q000033:anatomy & histology; D001842:Bone and Bones / Q000166:cytology*; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D005260:Female; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D016086:Lentivirus; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D011960:Receptors, Estrogen / Q000378:metabolism*; D000097983:ERRalpha Estrogen-Related Receptor
D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor