Fig. 1

Exosome biogenesis and its relationship with osteoarthritis. A clathrin-dependent pathway or a clathrin-independent pathway initially mediates endocytosis, at a lipid raft. The endocytic vesicles contain signaling proteins, growth factor receptors, oncoproteins, combined with normal membrane proteins, including tetraspanins (e.g., CD9, CD63, and CD81), MHC I and II, and adhesion molecules (e.g., cadherins, integrins). Exosome biogenesis occurs via the endosomal network in the endosomal sorting complexes needed for ESCRT-independent or ESCRT-dependent pathways. Inward budding of MVB produces intra-luminal vesicles (exosomes). Several cytoplasmic molecules (e.g., heat shock proteins, ubiquitin-related proteins, mRNAs, microRNAs [miRNAs], cytoskeleton proteins) and nuclear molecules (e.g., long-noncoding RNAs [lncRNAs], transcriptional factors, DNAs) can be loaded into MVB by stage-specific pathways, some of which are osteoarthritis type-specific. Moreover, plasma membrane fusion of multi-vesicular bodies leads to release of exosomes by exocytosis. Numerous Rab GTPases (such as Rab11/35, Rab7, and Rab27) are present in secreted exosomes. Eventually, MSC-derived exosomes are transported to the osteoarthritis micro-environment where they modulate osteoarthritis. ESCRT, endosomal sorting complexes required for transport; MHC, major histocompatibility complex; MSCs, mesenchymal stem cells; MVB, multi-vesicular bodies; rER, rough endoplasmic reticulum; sER, smooth endoplasmic reticulum; Rab, Ras-associated binding