Estrogen Receptor Related Receptor Alpha (ERRα) in Skeletal Tissues

Estrogen receptor related receptor alpha (ERRα) was the oldest orphan nuclear receptor with sequence identity to the estrogen receptors, ERα/β. The sequence alignment of the ERRα and the ERs reveals a high similarity (68%) in the DNA-binding domain and a moderate similarity (36%) in other parts of the proteins such as the ligand-binding E domain. If ERRα does not bind estrogen, cholesterol had been recently described as a potential agonist of the receptor.

Bone maintenance depends on a balance between bone resorption and bone formation that implicates bone-resorbing cells (osteoclasts), bone-forming cells (osteoblasts) and the osteocytes that modulate response of bone mechanical stress. In skeletal tissues, ERRα plays mainly a functional role in osteoclasts (bone resorbing cells) but also has a role in osteoblasts (bone-forming cells) and chondrocytes.

A recent study has reinforced the role for ERRa in osteoclasts differentiation and function. In osteoclastogenesis, ERRa was already known to act as a pro-osteoclastic factor in vivo, the ERRα knockout mice exhibiting osteopetrosis (excess of bone formation).

Concomitantly, osteoclastogenesis was dramatically disturbed in vitro and genes implicated in mitochondrial biogenesis were down regulated. Moreover, ERRα was also implicated in osteoclasts mobility and actin cytoskeletal organization by regulating the osteopontin (OPN)-integrin b3 chain-activated c-src (phosphorylated at the Tyr416) pathway causing the disruption of the specific actin structure (podosome belt) implicated in osteoclast adhesion, migration and invasion.