Skeletal consequences of deletion of steroid receptor coactivator-2/transcription intermediary factor-2.
Both estrogen receptor (ER) and peroxisome proliferator-activated receptor gamma (PPARgamma) regulate bone metabolism, and because steroid receptor coactivator (SRC)-2 (TIF-2) enhances ER and PPARgamma activity, we examined the consequences of deletion of SRC-2 on bone using SRC-2 knock out (KO) mice. Loss of SRC-2 resulted in increased bone mass, with SRC-2 KO mice having 80% higher trabecular bone volume as compared with wild type mice. SRC-2 KO mice also had a marked decrease (by 50%) in bone marrow adipocytes. These data suggested that marrow precursor cells in the SRC-2 KO mice may be resistant to the inhibitory effects of endogenous PPARgamma ligands on bone formation. Consistent with this, compared with cultures from wild type mice, marrow stromal cultures from SRC-2 KO mice formed significantly more mineralized nodules (by 3-fold) in the presence of the PPARgamma agonist, rosiglitazone. Using chromatin immunoprecipitation analysis, we demonstrated that in bone marrow stromal cells, loss of SRC-2 leads to destabilization of the transcription complex at the peroxisome proliferator response elements of a number of PPARgamma target genes, resulting in an overall decrease in the expression of adipocyte-related genes and a marked decrease in adipocyte development. Using ovariectomy with or without estrogen replacement, we also demonstrated that SRC-2 KO mice were partially resistant to the skeletal actions of estrogen. Collectively, these findings indicate that loss of SRC-2 leads to partial skeletal resistance to the ER and PPARgamma, but resistance to PPARgamma is dominant, leading to increased bone mass. Modulating SRC-2 action may, thus, represent a novel therapeutic target for osteoporosis.
Endocrine Research Unit, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Ulrike I
UI
Mödder
David G
DG
Monroe
Daniel G
DG
Fraser
Thomas C
TC
Spelsberg
Clifford J
CJ
Rosen
Martine
M
Géhin
Pierre
P
Chambon
Bert W
BW
O'Malley
Sundeep
S
Khosla
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003720:Densitometry; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics* / Q000502:physiology*; D010024:Osteoporosis / Q000628:therapy; D047495:PPAR gamma / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D014057:Tomography, X-Ray Computed / Q000379:methods
D051958:Nuclear Receptor Coactivator 2; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone