Estrogen Receptor-related Receptor Gamma (ERRg) is a Regulator of Skeletogenesis

Sex steroids, such as Estrogen, play important roles in physiological and pathological processes, including bone growth and bone homeostasis. Estrogen's effects are mediated through its receptors, Estrogen receptor alpha and beta (ER and ER). Despite its importance, loss of expression of ERs does not result in severe skeletal effects, suggesting that other factors are involved in the Estrogen pathway(s). Estrogen receptor related receptors (ERRs) are a family of orphan nuclear receptors, i.e., with no known natural ligands, comprising ERRα, ERRβ, and ERRγ. While ERR has been shown to be involved in various aspects of skeletogenesis, there is very little know about the potential role of ERR. To address this question, I used gain-of-function and loss-of-function approaches in mice. In the gain-of-function model with cartilage-specific ERR-overexpression, the size of the craniofacial, axial and appendicular skeletons was reduced compared to that in wild type (WT) mice. Histological analysis revealed a reduction in the length of the transgenic versus WT growth plate, attributable to a reduced proliferative zone accompanied by a decrease in the number of Ki67-positive proliferating cells, with no significant change in apoptosis. Quantification of expression of putative target genes suggested that ERRγ negatively regulates chondrocyte proliferation and positively regulates matrix synthesis to coordinate growth plate height and organization. In an ERRγ global knockout mouse line, I observed no gross morphological anomalies or difference in skeletal length in newborn mice, but by 8 weeks of age ERRγ +/- male but not female mice exhibited increased trabecular bone, which was further increased by 14 weeks. Histomorphometric and serum biochemistry data indicated that the trabecular bone increase was due to an increase in bone formation, with no apparent change in bone resorption. Analysis of ERRγ +/- versus ERRγ +/+ bone marrow stromal cell cultures indicated that ERRγ negatively regulates osteoblast differentiation and matrix mineralization but not mesenchymal precursor number. These data, together with results from co-immunoprecipitation and Runx2 antisense oligonucleotide treatment experiments in vitro, indicated 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. I conclude that ERRγ plays negative regulatory roles in both cartilage and bone in postnatal mice and may be an important new therapeutic target in skeletal diseases and conditions.

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