Absence of Estrogen Receptor-Related-α Increases Osteoblastic Differentiation and Cancellous Bone Mineral Density

Abstract

The nuclear orphan receptor human estrogen receptor-related receptor (ERR)-alpha is implicated in bone metabolism. We studied the effect of ERRalpha silencing in human mesenchymal stem cells (hMSCs) during osteoblastogenesis. We found that ERRalpha silencing led to an increase of bone sialoprotein and a decrease of osteopontin mRNA levels, suggesting enhanced osteoblastic differentiation. This was confirmed by an increased ability of hMSCs to deposit calcium. Concomitantly, knockdown of ERRalpha inhibited adipogenesis, resulting in a decrease in adipocyte number and adipocyte marker gene expression. In line with a negative role of ERRalpha in bone metabolism, we found that adult female and male ERRalpha-deficient mice displayed a moderate increase in femoral cancellous bone volume and density. Osteoblast surface was increased and marrow fat volume decreased in these animals. Furthermore, ERRalpha-deficient osteoblasts displayed increased differentiation properties in vitro in line with our observations in hMSCs. In summary, we identified a role for ERRalpha in bone mass regulation by affecting osteoblastic differentiation.

Estrogen receptor–related receptor α regulation by interleukin‐1β in prostaglandin E2– and cAMP‐dependent pathways in osteoarthritic chondrocytes

“…ERR␣ target gene in rodent cells (17), SOX9 was dose-dependently down-regulated in OA chondrocytes after 24 hours of XCT790 treatment ( Figure 6A). Interestingly, XCT790 dose-dependently decreased the IL-1␤-induced ERR␣ expression at both the mRNA and protein levels ( Figure 6B), suggesting an autoregulation of ERR␣ in the IL-1␤ pathway.…”

“…ERR␣ regulates fatty acid oxidation and the adaptive bioenergetic response (13,14). ERR␣ is highly expressed in skeletal (bone and cartilage) tissues (15,16) and has been reported to regulate osteoblast development and bone formation both in vitro (15,16) and in vivo (17,18). ERR␣ expression in fetal and adult articular chondrocytes suggests that it may be involved not only in cartilage formation, but also in its maintenance and integrity throughout the lifetime of the tissue.…”

Screening and functional microarray analysis of differentially expressed genes related to osteoporosis

“…Numerous population genetic studies have provided evidence of an association between ESR1 polymorphisms and osteoporotic risk (Liu et al, 2006). A mutant ESR1 gene has been found to result in reduced BMD in humans (Smith et al, 1994) and mice (Delhon et al, 2009). In addition, the ESR1 gene is also positively correlated with the expression of the IGF1 (insulin-like growth factor 1) gene (Mendez et al, 2006) and Runx2 (Khalid et al, 2008), another important osteogenic growth factor that enhances the function of osteoblasts and prevents osteoblastic apoptosis.…”

An energetic orphan in an endocrine tissue: A revised perspective of the function of estrogen receptor-related receptor alpha in bone and cartilage

“…(21) In contrast, two separate studies showed increased bone mineral density with deletion of ERRa in mice. (22,23) Speciesspecific responses, ie, differences between rats and mice in which studies were done, may underlie some of the differences. As likely, however, are the diverse contributions of both cellautonomous ERRa functions in OBs and nonautonomous functions (impact of ERRa-expressing adipocytes, mesenchymal …”

“…(21,22,24) Interestingly, some authors suggest that ERRa may play different roles in bone versus adipose tissues under different physiological conditions, depending on which PGC1 family member is regulated. (15,21,22) ERRa expression is dysregulated in OBs in a mouse rheumatoid arthritis model and in chondrocytes in human OA, both conditions more prevalent with aging.…”