ERRγ Is Not Required for Skeletal Development but Is a RUNX2-Dependent Negative Regulator of Postnatal Bone Formation in Male MiceReport as inadecuate




ERRγ Is Not Required for Skeletal Development but Is a RUNX2-Dependent Negative Regulator of Postnatal Bone Formation in Male Mice - Download this document for free, or read online. Document in PDF available to download.

To assess the effects of the orphan nuclear Estrogen receptor-related receptor gamma ERRγ deficiency on skeletal development and bone turnover, we utilized an ERRγ global knockout mouse line. While we observed no gross morphological anomalies or difference in skeletal length in newborn mice, by 8 weeks of age ERRγ +-− 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-κB 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 ERRγ +-− versus ERRγ +-+ stromal cell cultures, suggesting that ERRγ negatively regulates osteoblast differentiation and matrix mineralization but not mesenchymal precursor number. By co-immunoprecipitation experiments, we found that ERRγ and RUNX2 interact in an ERRγ 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 ERRγ +-− but not ERRγ +-+ mice compared to their corresponding sense controls. Our data indicate that ERRγ 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.



Author: Marco Cardelli, Jane E. Aubin

Source: http://plos.srce.hr/



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