A Novel Ligand-independent Function of the Estrogen Receptor Is Essential for Osteocyte and Osteoblast Mechanotransduction

• Published in: The Journal of biological chemistry 2007-08, Vol.282 (35), p.25501-25508
• Main Authors: Aguirre, J. Ignacio, Plotkin, Lilian I., Gortazar, Arancha R., Millan, Marta Martin, O'Brien, Charles A., Manolagas, Stavros C., Bellido, Teresita
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Apoptosis - genetics; Bone and Bones - cytology; Bone and Bones - metabolism; Caveolin 1 - genetics; Caveolin 1 - metabolism; Cell Membrane - genetics; Cell Membrane - metabolism; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cell Survival - drug effects; Cell Survival - physiology; Enzyme Activation - drug effects; Enzyme Activation - genetics; Estradiol - analogs & derivatives; Estradiol - pharmacology; Estrogen Antagonists - pharmacology; Estrogen Receptor alpha - deficiency; Estrogen Receptor alpha - metabolism; Estrogen Receptor beta - deficiency; Estrogen Receptor beta - metabolism; Estrogens - genetics; Estrogens - metabolism; Extracellular Signal-Regulated MAP Kinases - metabolism; Fulvestrant; Humans; Ligands; MAP Kinase Signaling System - physiology; Mechanotransduction, Cellular - drug effects; Mechanotransduction, Cellular - physiology; Mice; Mice, Knockout; Mutation; Osteoblasts - cytology; Osteoblasts - metabolism; Osteocytes - cytology; Osteocytes - metabolism; Protein Binding - drug effects; Protein Binding - genetics; Protein Structure, Tertiary - genetics; Stress, Mechanical; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M702231200

Bone senses and adapts to meet mechanical needs by means of an extensive mechanotransduction network comprising osteocytes (former osteoblasts entrapped in mineral) and their cytoplasmic projections through which osteocytes communicate with osteoblasts and osteoclasts on the bone surface. Mechanical stimulation promotes osteocyte (and osteoblast) survival by activating the extracellular signal-regulated kinases, ERKs. Estrogens have similar effects and, intriguingly, the adaptive response of bone to mechanical forces is defective in mice lacking estrogen receptor (ER) α or ERβ. We report that ERKs are not activated by stretching in osteocytic and osteoblastic cells in which both ERα and ERβ have been knocked out or knocked down and this is reversed partially by transfection of either one of the two human ERs and fully by transfection of both receptors. ERK activation in response to stretching is also recovered by transfecting the ligand-binding domain (E) of either receptor or an ERα mutant that does not bind estrogens. Furthermore, mechano-responsiveness is restored by transfecting the Eα targeted to the plasma membrane, but not to the nucleus, whereas ERα mutants with impaired plasma membrane localization or binding to caveolin-1 fail to confer ERK activation in response to stretching. Lastly, the ER antagonist ICI 182,780 abrogates ERK activation and the anti-apoptotic effect of mechanical stimulation. We conclude that in addition to their role as ligand-dependent mediators of the effects of estrogens, the ERs participate in the transduction of mechanical forces into pro-survival signaling in bone cells, albeit in a ligand-independent manner.