Exosomes: mediators of bone diseases, protection, and therapeutics potential

Abstract

Bone remodeling is a continuous lifelong process in the repair of micro-damage to bone architecture and replacement of aging tissue in bone. A failure to such process leads to pathological destructive bone diseases such as osteoporosis, rheumatoid arthritis, and osteoarthritis. However, this active process is regulated by; osteoclasts, which are involved in the bone resorption process; osteoblasts, with involvement in the bone formation process and bone-derived endothelial cells, which promote angiogenesis. In the bone micro-environment, these cellular interactions are mediated by a complex interplay between cell types via direct interaction of cell secreted growth factors, such as cytokines. Recently, the discovery of exosomes (∼ 40-100 nm in size), has attracted more attention in the field of the bone remodeling process. Exosomes and microvesicles are derived from different types of bone cells such as mesenchymal stem cells, osteoblasts, osteoclasts and their precursors. They are also recognized to play pivotal roles in bone remodeling processes including osteogenesis, osteoclastogenesis, and angiogenesis. In this review, we especially emphasize the origin and biogenesis of exosomes and bone cell derived exosomes in the regulatory process of bone remodeling. Moreover, this review article also focuses on exosomal secreted proteins and microRNAs and their involvement in the regulation of bone remodeling.

Keywords: angiogenesis; osteoclastgenesis; osteogenesis; osteoporosis.

Figure 1. Biogenesis, secretion, and uptake of primary cell-derived exosomes in the target cells

Exosomes are initiated by inward invaginations of clathrin-coated micro-domains on the plasma membrane and are converted into early endosomes (EE), carrying ubiquitinated cargos, facilitated by endosomal sorting complex required for transport (ESCRT). Then EEs, upon secondary invagination and maturation, convert into intraluminal vesicles (ILVs), which accumulate inside the endosomes called large multivesicular bodies (MVBs). The matured MVB can either be processed to lysosomes for degradation or fused with the plasma membrane (exocytic MVBs) for the release of ILVs into the extracellular space where it is called an exosome. Exosome secretion can be accelerated by various chemical, mechanical and environmental stimuli such as irradiation, low oxygen, and low PH. The exosomes secreted from primary cells will display various membrane components as their cells of origin. Following the release of exosomes, they may dock over the plasma membrane of recipient target cells. Furthermore, membrane-bound vesicles may either fuse with the plasma membrane directly or be endocytosed in the target cells. Upon endocytosis, exosomes may fuse with the delimiting membrane of an endocytic compartment and release its cargo contents, regulate the target cell gene expression, and finally cause cell commitment, differentiation, and activity.

Figure 2. Bone marrow-MSC derived exosomes enhance bone regeneration by orchestrating a coordinated regulation of osteogenesis, angiogenesis, and osteoclastogenesis

In the bone microenvironment, bone marrow-MSCs actively secrete exosomes, which are taken up by the surrounding cells including osteoblasts, osteoclasts, and endothelial cells. These activities result in a complex interplay of bone homeostasis by accelerating osteogenesis, osteoclastogenesis, and angiogenesis of which may promote vascularized bone development and regeneration.