Abstract
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.
Highlights
The Estrogen receptor-related receptors (ERR) are orphan nuclear receptors comprising three family members: ERRa, ERRb and Estrogen receptor-related receptor gamma (ERRc) (NR3B1, NR3B2 and NR3B3 respectively) [1]
The increase in trabecular bone volume seen in ERRc +/2 male mice was due to increased trabecular number and thickness, as a consequence of an increased number of osteoblasts on the bone surface, increased bone formation rate (BFR) and increased mineralizing surface (MS)/BS ratio, indicating an overall increase in active osteoblasts occupying the bone surface
We found no significant change in osteoclast number or surface, suggesting that ERRc regulates bone formation and osteoblast differentiation, but not bone resorption
Summary
The Estrogen receptor-related receptors (ERR) are orphan nuclear receptors comprising three family members: ERRa, ERRb and ERRc (NR3B1, NR3B2 and NR3B3 respectively) [1]. There have been conflicting data published on ERRa activity on bone in vivo, with data supporting both a negative regulatory [9,10] and a positive regulatory [11] role. These latter differences may reflect inherent differences in different knockout mouse strains, differences in activities in female [9,10] versus male [11] mice, and age-related cell autonomous versus non-autonomous roles in bone cells (osteoblasts, osteoclasts) versus other lineages in the bone environment (e.g., adipocytes) [7]
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