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Review
. 2021 May 29;22(11):5846.
doi: 10.3390/ijms22115846.

Extracellular Vesicles: Potential Mediators of Psychosocial Stress Contribution to Osteoporosis?

Yangyang He  1   2 , Karin Wuertz-Kozak  3   4 , Linn K Kuehl  1   2   5 , Pia-Maria Wippert  1   2
Affiliations
Review

Extracellular Vesicles: Potential Mediators of Psychosocial Stress Contribution to Osteoporosis?

Yangyang He et al. Int J Mol Sci. .

Abstract

Osteoporosis is characterized by low bone mass and damage to the bone tissue's microarchitecture, leading to increased fracture risk. Several studies have provided evidence for associations between psychosocial stress and osteoporosis through various pathways, including the hypothalamic-pituitary-adrenocortical axis, the sympathetic nervous system, and other endocrine factors. As psychosocial stress provokes oxidative cellular stress with consequences for mitochondrial function and cell signaling (e.g., gene expression, inflammation), it is of interest whether extracellular vesicles (EVs) may be a relevant biomarker in this context or act by transporting substances. EVs are intercellular communicators, transfer substances encapsulated in them, modify the phenotype and function of target cells, mediate cell-cell communication, and, therefore, have critical applications in disease progression and clinical diagnosis and therapy. This review summarizes the characteristics of EVs, their role in stress and osteoporosis, and their benefit as biological markers. We demonstrate that EVs are potential mediators of psychosocial stress and osteoporosis and may be beneficial in innovative research settings.

Keywords: allostatic load; bone remodeling; microRNA; osteoblast; osteoclast.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
The biogenesis and secretion of EVs and their effects on target cells. The formation of exosomes begins with the endocytosis of the cell membrane. The endosome membrane sprouts inward to form vesicles, which transform into MVB. MVB can be sent to lysosomes for degradation or secreted into the exosomes (40–200 nm) by fusion with the plasma membrane. Microvesicles (200–2000 nm) are vesicles formed through a process of membrane budding or exocytosis. EVs can interact with target cells through receptor-mediated binding. Additionally, target cells can internalize EVs by target cells through endocytosis, pinocytosis, and plasma membrane fusion [9], where EVs can release their cargoes to affect target cells, or be degraded by lysosomes.
Figure 2
Figure 2
The potential mechanisms of EV involvement in psychosocial stress contributed osteoporosis. Psychosocial stress induces the release of norepinephrine (NE) from sympathetic nerve terminals by activating the sympathetic nervous system (SNS); the released norepinephrine can bind to the α1-adrenergic receptor, which is coupled with the G-protein coupled receptor (GPCR). GPCR dissociates upon receptor activation and promotes phospholipase C (PLC), catalyzing the breakdown of phosphatidylinositol bisphosphate (PIP2) into inositol trisphosphate (IP3). IP3 binds to the IP3 receptor on the endoplasmic reticulum (ER), leading to elevated cytosolic Calcium (Ca2+) [117]. Cytosolic Ca2+ increases ubiquitination (Ub) and targets specific miRNAs to endosomes, and other miRNAs target endosomes via heat shock protein 90 (HSP90) [118]. Then, the endosomes are directed to the multivesicular bodies (MVBs). Through the mediation by Ca2+, the MVBs fuse with the cell’s plasma membrane, releasing endosomes into the extracellular space, where they are considered exosomes [64,119]. The circulating exosomes are internalized by osteoblasts or osteoclasts, where they release the genetic materials they carry, impact their physiological function, and thus, participate in osteoporosis development.
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