Work in mouse models has demonstrated that estrogen receptor-α (ERα) plays an important role in bone remodeling in response to mechanical loading, as well as in response to the bone sparing effect seen in female mice. Windalh et al. recently investigated the role of endogenous estrogen in the ERα-mediated response to loading1 and the role of the same receptor on bone formation in male mice.2
In the first study, the response to mechanical loading of the tibia was assessed in knockout mice that lacked any ERα function, and was compared with that observed in mice with a specific inactivation either at the N-terminal of the molecule (activation function 1[AF-1]) or at the ligand binding domain (AF-2). In response to mechanical loading, control mice showed an increase in cortical bone area and overall bone formation rate, which occurred in both normal and ovariectomized mice, so was independent of endogenous estrogen. This response did not occur in mice with the ERα knockout or with the AF-2 knockout, but mice with no AF-1ERα function showed a similar increase in bone formation to wild-type mice. The pathways involved remain to be elucidated.
In the second study, mice with a specific ERα knockout in osteocytes were generated. Male mice showed a significant reduction in trabecular bone volume (down by 42% in the femur and 25% in the tibia [P<0.01]) and a reduced bone formation rate (down by 45% compared with controls [P<0.01]). The early osteoblast markers RUNX2 and osterix were elevated, as was the late marker bone-sialoprotein. The osteocyte marker DMP1 showed a rise in expression but the expression levels of TRAP and RANK were similar to those seen in wild-type mice. Trabecular bone volume in female mice with intact ovaries was unaffected by the knockout. Further experiments suggested that protection of trabecular bone formation in males depends on the interaction between estrogen and its receptor in osteocytes, but the protective effect seen in female mice is probably related to ERα activity in osteoblasts.
Editor's comment: These studies build on previous work3,4and provide further evidence that estrogen-independent ERα signaling is important for the cortical bone response to biomechanical loading and for trabecular bone formation in males. The latter involves a highly specific role for ERα in osteocytes.
References
- Windahl SH, Saxon L, Börjesson AE, Lagerquist MK, Frenkel B, Henning P et al. Estrogen receptor-α is required for the osteogenic response to mechanical loading in a ligand-independent manner involving its activation function 1 but not 2. J Bone Miner Res 2013;28:291–301. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Windahl SH, Börjesson AE, Farman HH, Engdahl C, Movérare-Skrtic S, Sjögren K et al. Estrogen receptor-α in osteocytes is important for trabecular bone formation in male mice. Proc Natl Acad Sci U S A 2013;110:2294–2299. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Saxon LK, Galea G, Meakin L, Price J, Lanyon LE. Estrogen receptors α and β have different gender-dependent effects on the adaptive responses to load bearing in cancellous and cortical bone. Endocrinology 2012;153:2254–2266. [DOI] [PubMed] [Google Scholar]
- Almeida M, Iyer S, Martin-Millan M, Bartell SM, Han L, Ambrogini E et al. Estrogen receptor-α signaling in osteoblast progenitors stimulates cortical bone accrual. J Clin Invest 2013;123:394–404. [DOI] [PMC free article] [PubMed] [Google Scholar]