Estrogen-related receptor α regulates osteoblast differentiation via Wnt/β-catenin signaling

Abstract

Based on its homology to the estrogen receptor and its roles in osteoblast and chondrocyte differentiation, the orphan nuclear receptor estrogen-related receptor a (ERRa (ESRRA)) is an intriguing therapeutic target for osteoporosis and other bone diseases. The objective of this study was to better characterize the molecular mechanisms by which ERRa modulates osteoblastogenesis. Experiments from multiple systems demonstrated that ERRa modulates Wnt signaling, a crucial pathway for proper regulation of bone development. This was validated using a Wnt-luciferase reporter, where ERRa showed co-activator-dependent (peroxisome proliferator-activated receptor gamma co-activator 1a, PGC-1a) stimulatory effects. Interestingly, knockdown of ERRa expression also enhanced WNT signaling. In combination, these data indicated that ERRa could serve to either activate or repress Wnt signaling depending on the presence or absence of its co-activator PGC-1a. The observed Wnt pathway modulation was cell intrinsic and did not alter b-catenin nuclear translocation but was dependent on DNA binding of ERRa. We also found that expression of active ERRa correlated with Wnt pathway effects on osteoblastic differentiation in two cell types, consistent with a role for ERRa in modulating the Wnt pathway. In conclusion, this work identifies ERRa, in conjunction with co-activators such as PGC-1a, as a new regulator of the Wnt-signaling pathway during osteoblast differentiation, through a cell-intrinsic mechanism not affecting b-catenin nuclear translocation.

Mesenchymal stem cells: mechanisms and role in bone regeneration

“…Various hormones have also been shown to affect MSCs including estrogen, the mechanism and effect of which have been elucidated 14. Auld et al 15 showed that estrogen can bind and activate the estrogen receptor (ER) to regulate expression of downstream genes to perform cellular functions. In particular, the orphan nuclear receptor estrogen-related receptor α (ESRα) has been shown to bind with estrogen and activate the Wnt/β-catenin pathway to promote MSC osteogenic differentiation.…”

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“…Estrogen prevents osteoblast apoptosis and increases the production of IGF-1 and procollagen [23,24]. Increased autocrine production of bone morphogenetic protein-4 and upregulation of Wnt signaling produce strong osteoblast anabolic signals as a result of estrogen treatment of osteoblasts [25,26]. Moreover, estrogen influences the capacity for osteoblast renewal and bone repair [27].…”