Control of osteoblastic bone formation involves the cumulative action of numerous transcription factors, including both activating and repressive functions that are important during specific stages of differentiation. The nuclear receptor retinoic acid receptor-related orphan receptor beta (Ror beta) has been recently shown to suppress the osteogenic phenotype in cultured osteoblasts, and is highly upregulated in bone marrow-derived osteogenic precursors isolated from aged osteoporotic mice, suggesting Ror beta is an important regulator of osteoblast function. However the specific gene expression patterns elicited by Ror beta are unknown. Using microarray analysis, we identified 281 genes regulated by Ror beta in an MC3T3-E1 mouse osteoblast cell model (MC3T3-Ror beta-GFP). Pathway analysis revealed alterations in genes involved in MAPK signaling, genes involved in extracellular matrix (ECM) regulation, and cytokine-receptor interactions. Whereas the identified Ror beta-regulated ECM genes normally decline during osteoblastic differentiation, they were highly upregulated in this non-mineralizing MC3T3-Ror beta-GFP model system, suggesting that Ror beta may exert its anti-osteogenic effects through ECM disruption. Consistent with these in vitro findings, the expression of both ROR beta and a subset of ROR beta-regulated genes were increased in bone biopsies from postmenopausal women (73 +/- 7 years old) compared to premenopausal women (30 +/- 5 years old), suggesting a role for ROR beta in human age-related bone loss. Collectively, these data demonstrate that Ror beta regulates known osteogenic pathways, and may represent a novel therapeutic target for age-associated bone loss. (C) 2013 Elsevier Inc. All rights reserved.