Extracellular Vesicles in Joint Disease and Therapy

Abstract

The use of extracellular vesicles (EVs) as a potential therapy is currently explored for different disease areas. When it comes to the treatment of joint diseases this approach is still in its infancy. As in joint diseases both inflammation and the associated articular tissue destruction are important factors, both the immune-suppressive and the regenerative properties of EVs are potentially advantageous characteristics for future therapy. There is, however, only limited knowledge on the basic features, such as numerical profile and function, of EVs in joint articular tissues in general and their linking medium, the synovial fluid, in particular. Further insight is urgently needed in order to appreciate the full potential of EVs and to exploit these in EV-mediated therapies. Physiologic joint homeostasis is a prerequisite for proper functioning of joints and we postulate that EVs play a key role in the regulation of joint homeostasis and hence can have an important function in re-establishing disturbed joint homeostasis, and, in parallel, in the regeneration of articular tissues. In this mini-review EVs in the joint are explained from a historical perspective in both health and disease, including the potential niche for EVs in articular tissue regeneration. Furthermore, the translational potential of equine models for human joint biology is discussed. Finally, the use of MSC-derived EVs that is recently gaining ground is highlighted and recommendations are given for further EV research in this field.

Keywords: cartilage; extracellular vesicle; immune suppression; inflammation; joint; joint homeostasis; regeneration; therapy.

Figure 1

Major routes of EV biogenesis and communication with the target cell.

Figure 2

Matrix vesicles start cartilage calcification during endochondral ossification. Vesicles originating from maturing (hypertrophic) chondrocytes and osteoblasts accumulate calcium and phosphate ions in their lumen for the formation of hydroxyapatite (HA) crystals. Deposition of HA crystals in the extracellular matrix (ECM), together with calcification promoting proteins, leads to complete transformation of cartilage into bone. It is hypothesized that other factors found in matrix vesicles, such as BMPs, VEGF, and MMPs, could be involved in chondrocyte and osteoblast differentiation, neovascularisation and ECM degradation, respectively (34, 35). The electrophoretic profile of matrix vesicles is characterized by mineralisation promoting enzymes (TNAP, ATPases, etc.) that hydrolyze adenosine triphosphate (ATP) and nucleoside triphosphate (NTP) into inorganic pyrophosphate (PP_i) and PP_i into inorganic phosphate (P_i), thereby increasing concentrations of P_i and decreasing concentrations of PP_i in the vesicle lumen and its surrounding matrix (36, 37). Keeping PP_i concentrations low at sites of active mineralisation is critical, since PP_i is the most important physiologic suppressor of hydroxyapatite crystal deposition (38). To further increase the pool of P_i in the vesicle lumen, the enzyme PHOSPHO1 is suggested to hydrolyse luminal phosphoethanolamine and phosphocholine (derived from membrane phospholipids) in order to produce P_i (37, 39, 40). Active phosphate transporters in the vesicle membrane facilitate further influx of P_i from the ECM (18).