Extracellular vesicles in bone: "dogrobbers" in the "eternal battle field"

Abstract

Throughout human life, bone is constantly in a delicate dynamic equilibrium of synthesis and resorption, hosting finely-tuned bone mineral metabolic processes for bone homeostasis by collaboration or symphony among several cell types including osteoclasts (OCs), osteoblasts (OBs), osteocytes (OYs), vascular endothelial cells (ECs) and their precursors. Beyond these connections, a substantial level of communication seems to occur between bone and other tissues, and together, they form an organic unit linked to human health and disease. However, the current hypothesis, which includes growth factors, hormones and specific protein secretion, incompletely explains the close connections among bone cells or between bone and other tissues. Extracellular vesicles (EVs) are widely-distributed membrane structures consisting of lipid bilayers, membrane proteins and intravesicular cargo (including proteins and nucleic acids), ranging from 30 nm to 1000 nm in diameter, and their characters have been highly conserved throughout evolution. EVs have targeting abilities and the potential to transmit multidimensional, abundant and complicated information, as powerful and substantial "dogrobbers" mediating intercellular communications. As research has progressed, EVs have gradually become thought of as "dogrobbers" in bone tissue-the "eternal battle field" -in a delicate dynamic balance of destruction and reconstruction. In the current review, we give a brief description of the major constituent cells in bone tissues and explore the progress of current research on bone-derived EVs. In addition, this review also discusses in depth not only potential directions for future research to breakthrough in this area but also problems existing in current research that need to be solved for a better understanding of bone tissues.

Keywords: Bone; Exosomes; Extracellular vesicles; Intercellular communications; Signalling pathways.

Fig. 1

Bone remodelling compartment. OBs: osteogenic cells; OCs: osteoclasts; preOCs: pre-osteoclasts; OYs: osteocytes; HSCs: haematopoietic stem cells; BMSCs: bone mesenchymal stem cells; H-type ECs: endothelial cells strongly expressing both CD31 and endomucin (Emcn); L-type ECs: endothelial cells strongly expressing Emcn but not CD31

Fig. 2

Constituents of EVs. EVs are composed of lipid bilayers, membrane proteins, intravesicular proteins, DNA, messenger RNAs (mRNAs), microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs). The lipid bilayers provide protection from the complex and potentially harmful body fluid environment to the bioactive substances within EVs, the membrane proteins give EVs targeting abilities, and the various intravesicular contents give EVs the ability to transmit multidimensional, abundant and complicated information

Fig. 3

‘Micro-damage-driven’ remodelling orchestrated by OYs via sclerostin. OYs are responsible for directly sensing ‘damage’ that interrupts the canaliculi. Sclerostin has been reported to maintain the status ‘inhibition of OB differentiation’. However, mechanical loading or ‘damage’ would shut down sclerostin, causing a loss of efficacy of the ‘inhibition of OB differentiation’ function; in other words, increasing OB differentiation and bone mass

Fig. 4

RANK–RANKL interaction mediated by EVs. RANK-containing OC-EVs target OBs via the RANK–RANKL interaction. RANKL-containing OB-EVs target HSCs/preOCs/OCs via the RANK–RANKL interaction. In addition, RANK-containing OC-EVs and RANKL-containing OB-EVs can block the functions of each other