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.
Highlights
Multipotent mesenchymal stem cells in bone marrow are known to give rise to both osteoblasts and adipocytes [1,2,3], and there is accumulating evidence that there may be a differentiation switch between these cell lineages, resulting in a possible reciprocal relationship between bone marrow osteoblasts and adipocytes (4 – 6)
Both estrogen receptor (ER) and peroxisome proliferator-activated receptor ␥ (PPAR␥) regulate bone metabolism, and because steroid receptor coactivator (SRC)-2 (TIF-2) enhances ER and PPAR␥ activity, we examined the consequences of deletion of SRC-2 on bone using SRC-2 knock out (KO) mice
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 PPAR␥ target genes, resulting in an overall decrease in the expression of adipocyte-related genes and a marked decrease in adipocyte development
Summary
Generation and Care of Mice—The generation of the SRC-2 KO mice has previously been described [30], and the mice used in this study had been extensively back-crossed (for seven or more generations) into the mouse background strain 129. For the DXA measurements they were placed on the animal tray in a prone position on the Lunar PIXImus densitometer (software Version 1.44.005, Lunar Corp., Madison, WI). In this position, the head is partially outside the area scanned by the machine. Using two-dimensional data from scanned slices, three-dimensional analysis was conducted to calculate morphometric parameters defining trabecular bone mass and micro-architecture, including BV/TV, trabecular number, trabecular thickness, connectivity-density (1/mm3), and the structure model index (SMI), an indicator of plate-like versus rod-like trabecular architecture. 3-Month-old female SRC-2 KO and WT littermates had base-line bone mineral density scans by DXA and pQCT and were divided into three groups (n ϭ 8 –12 mice/group).
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