Role of estrogen-related receptor alpha in osteogenic differentiation

Estrogen-related receptor alpha (ERRα) is an orphan nuclear receptor that regulates cellular energy metabolism, mitochondrial function, and transcriptional programs involved in cell differentiation. Although ERRα has been implicated in bone biology and cardiovascular pathology, its role in osteogenic differentiation and endothelial-mediated regulation of physiological and pathological calcification remains poorly understood. Endothelial cells are increasingly recognized as key regulators of osteogenic differentiation through metabolic and paracrine interactions with neighboring cells. To clarify the contribution of ERRα to these processes, we investigated its function in osteoblasts, aortic valve interstitial cells, and endothelial cells using lentiviral overexpression and knockdown combined with co-culture and transcriptomic analyses. Increased ERRα expression enhanced extracellular matrix mineralization in both osteoblasts and aortic valve interstitial cells, whereas its suppression reduced mineralization and decreased expression of the key osteogenic regulators RUNX2 and NOTCH3. In contrast, ERRα overexpression in endothelial cells had no significant effect on osteogenic differentiation in co-culture, while its suppression resulted in loss of viability of endothelial and neighboring osteogenic cells. Transcriptomic profiling demonstrated that endothelial ERRα overexpression induced limited gene expression changes, whereas knockdown altered inflammatory signaling, extracellular matrix remodeling, amino acid and lipid metabolism, and genes involved in intercellular communication, including NOS1 and NOTCH3. These findings identify ERRα as a critical regulator of endothelial metabolic and inflammatory homeostasis and a modulator of osteogenic differentiation in osteoblasts and aortic valve interstitial cells, highlighting its potential as a therapeutic target for impaired bone formation and pathological cardiovascular calcification.