科研之友
微信
新浪微博
Facebook
分享链接
摘要
To assess the effects of the orphan nuclear Estrogen receptor-related receptor gamma (ERR gamma) deficiency on skeletal development and bone turnover, we utilized an ERR gamma global knockout mouse line. While we observed no gross morphological anomalies or difference in skeletal length in newborn mice, by 8 weeks of age ERR gamma +/- males but not females exhibited increased trabecular bone, which was further increased by 14 weeks. The increase in trabecular bone was due to an increase in active osteoblasts on the bone surface, without detectable alterations in osteoclast number or activity. Consistent with the histomorphometric results, we observed an increase in gene expression of the bone formation markers alkaline phosphatase (Alp) and bone sialoprotein (Bsp) in bone and increase in serum ALP, but no change in the osteoclast regulators receptor activator of NF-kappa B ligand (RANKL) and osteoprotegerin (OPG) or the resorption marker carboxy-terminal collagen crosslinks (CTX). More colony forming units-alkaline phosphatase and - osteoblast (CFU-ALP, CFU-O respectively) but not CFU-fibroblast (CFU-F) formed in ERR gamma +/- versus ERR gamma +/+ stromal cell cultures, suggesting that ERR gamma negatively regulates osteoblast differentiation and matrix mineralization but not mesenchymal precursor number. By co-immunoprecipitation experiments, we found that ERR gamma and RUNX2 interact in an ERR gamma DNA binding domain (DBD)dependent manner. Treatment of post-confluent differentiating bone marrow stromal cell cultures with Runx2 antisense oligonucleotides resulted in a reduction of CFU-ALP/CFU-O in ERR gamma +/- but not ERR gamma +/+ mice compared to their corresponding sense controls. Our data indicate that ERR gamma is not required for skeletal development but is a sex-dependent negative regulator of postnatal bone formation, acting in a RUNX2-and apparently differentiation stage-dependent manner.
- 出版日期2014-10-14
