Mesenchymal stem cell-derived exosomes: a new therapeutic approach to osteoarthritis?

Abstract

Degenerative disorders of joints, especially osteoarthritis (OA), result in persistent pain and disability and high costs to society. Nevertheless, the molecular mechanisms of OA have not yet been fully explained. OA is characterized by destruction of cartilage and loss of extracellular matrix (ECM). It is generally agreed that there is an association between pro-inflammatory cytokines and the development of OA. There is increased expression of matrix metalloproteinase (MMP) and "a disintegrin and metalloproteinase with thrombospondin motifs" (ADAMTS). Mesenchymal stem cells (MSCs) have been explored as a new treatment for OA during the last decade. It has been suggested that paracrine secretion of trophic factors, in which exosomes have a crucial role, contributes to the mechanism of MSC-based treatment of OA. The paracrine secretion of exosomes may play a role in the repair of joint tissue as well as MSC-based treatments for other disorders. Exosomes isolated from various stem cells may contribute to tissue regeneration in the heart, limbs, skin, and other tissues. Recent studies have indicated that exosomes (or similar particles) derived from MSCs may suppress OA development. Herein, for first time, we summarize the recent findings of studies on various exosomes derived from MSCs and their effectiveness in the treatment of OA. Moreover, we highlight the likely mechanisms of actions of exosomes in OA.

Keywords: Cartilage degradation; Chondrocytes; Exosomes; Inflammation; Mesenchymal stem cells; Osteoarthritis; Paracrine mediators.

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