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Estrogen receptors' roles in the control of mechanically adaptive bone (re)modeling.

ABSTRACT: The discovery that estrogen receptors (ERs) are involved in bone cells' responses to mechanical strain offered the prospect of establishing the link between declining levels of circulating estrogen and the progressive failure of the mechanically adaptive mechanisms that should maintain structurally appropriate levels of bone mass in age-related and post-menopausal osteoporosis. Such clarification remains elusive but studies have confirmed ligand-independent involvement of ERs as facilitators in a number of the pathways by which mechanical strain stimulates osteoblast proliferation and bone formation. The presence of α and β forms of ER that oppose, supplement or replace one another has complicated interpretation of studies to identify their individual roles when both are present in normal amounts. However, it appears that, in mice at least, ERα promotes cortical bone mass in both males and females through its effects in early members of the osteoblast lineage, but enhances loading-related cortical bone gain only in females. In addition to its role as a potential replacement for ERα, and modifier of ERα activity, the less well-studied ERβ appears to facilitate rapid early effects of strain including activation of extracellular signal-regulated kinase and downregulation of Sost in well-differentiated cells of the osteoblast lineage including osteocytes. If these different roles are substantiated by further studies, it would appear that under normal circumstances ERα contributes primarily to the size and extent of bones' osteogenic response to load bearing through facilitating anabolic influences in osteoblasts and osteoblast progenitors, whereas ERβ is more involved in the strain-related responses generated within resident cells including osteocytes.

SUBMITTER: Galea GL

PROVIDER: S-EPMC3789219 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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Project description:Muscle forces are necessary for the development and maintenance of a mineralized skeleton. Removal of loads leads to malformed bones and impaired musculoskeletal function due to changes in bone (re)modeling. In the current study, the development of a mineralized junction at the interface between muscle and bone was examined under normal and impaired loading conditions. Unilateral mouse rotator cuff muscles were paralyzed using botulinum toxin A at birth. Control groups consisted of contralateral shoulders injected with saline and a separate group of normal mice. It was hypothesized that muscle unloading would suppress bone formation and enhance bone resorption at the enthesis, and that the unloading-induced bony defects could be rescued by suppressing osteoclast activity. In order to modulate osteoclast activity, mice were injected with the bisphosphonate alendronate. Bone formation was measured at the tendon enthesis using alizarin and calcein fluorescent labeling of bone surfaces followed by quantitative histomorphometry of histologic sections. Bone volume and architecture was measured using micro computed tomography. Osteoclast surface was determined via quantitative histomorphometry of tartrate resistant acid phosphatase stained histologic sections. Muscle unloading resulted in delayed initiation of endochondral ossification at the enthesis, but did not impair bone formation rate. Unloading led to severe defects in bone volume and trabecular bone architecture. These defects were partially rescued by suppression of osteoclast activity through alendronate treatment, and the effect of alendronate was dose dependent. Similarly, bone formation rate was increased with increasing alendronate dose across loading groups. The bony defects caused by unloading were therefore likely due to maintained high osteoclast activity, which normally decreases from neonatal through mature timepoints. These results have important implications for the treatment of muscle unloading conditions such as neonatal brachial plexus palsy, which results in shoulder paralysis at birth and subsequent defects in the rotator cuff enthesis and humeral head.

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Estrogen receptors' roles in the control of mechanically adaptive bone (re)modeling.

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