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Skeletal consequences of deletion of steroid receptor coactivator-2/transcription intermediary factor-2.

Abstract : 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.
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https://www.hal.inserm.fr/inserm-00420173
Contributor : Maité Peney Connect in order to contact the contributor
Submitted on : Monday, September 28, 2009 - 1:20:24 PM
Last modification on : Tuesday, October 19, 2021 - 11:03:43 AM

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Ulrike I. Mödder, David G. Monroe, Daniel G. Fraser, Thomas C. Spelsberg, Clifford J. Rosen, et al.. Skeletal consequences of deletion of steroid receptor coactivator-2/transcription intermediary factor-2.. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2009, 284 (28), pp.18767-77. ⟨10.1074/jbc.M109.000836⟩. ⟨inserm-00420173⟩

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