Abstract

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) alpha or ERbeta. We report that ERKs are not activated by stretching in osteocytic and osteoblastic cells in which both ERalpha and ERbeta 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 ERalpha mutant that does not bind estrogens. Furthermore, mechano-responsiveness is restored by transfecting the Ealpha targeted to the plasma membrane, but not to the nucleus, whereas ERalpha 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.

Highlights

  • Bone senses and adapts to meet mechanical needs by means of an extensive mechanotransduction network comprising osteocytes and their cytoplasmic projections through which osteocytes communicate with osteoblasts and osteoclasts on the bone surface

  • Bisphosphonates, intermittent parathyroid hormone administration, and sex steroids all prevent osteocyte apoptosis, suggesting that preservation of osteocytes contributes to the antifracture efficacy of these agents that is disproportional to their effects on bone mass (9 –11)

  • The ligand-binding domain (E) of either receptor is sufficient to confer responsiveness to mechanical stimuli, albeit in a ligandindependent fashion. Both plasma membrane localization of estrogen receptor (ER)␣ and its interaction with caveolin-1 are required for stretching-induced ERK activation and anti-apoptosis. These findings reveal a novel function of the membrane-associated ERs that is independent of the ligand and is essential for the transduction of mechanical forces into intracellular survival signaling in osteocytes and osteoblasts

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Summary

Introduction

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. We report that ERKs are not activated by stretching in osteocytic and osteoblastic cells in which both ER␣ and ER␤ 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.

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