The multifaceted roles of extracellular vesicles in osteonecrosis of the femoral head

Abstract

Osteonecrosis of the femoral head (ONFH) is a severe disease characterized by bone tissue necrosis due to vascular impairment, often leading to joint collapse and requiring surgical intervention. Extracellular vesicles (EVs) serve as crucial mediators of intercellular communication, influencing osteogenesis, angiogenesis, and immune regulation. This review summarizes the dual role of EVs in both the pathogenesis of ONFH and post-necrosis bone repair, highlighting the impact of various EV-mediated signaling pathways on bone regeneration and the potential crosstalk among these pathways. Additionally, EVs hold promise as diagnostic biomarkers or contrast agents to complement conventional imaging techniques for ONFH detection. By elucidating the role of EVs in osteonecrosis and addressing the current challenges, we aspire to establish a foundation for the timely identification and treatment of ONFH. The translational potential of this article: This review comprehensively discusses the role of EVs in ONFH, providing innovative and promising insights for its diagnosis and treatment, which also establishes a theoretical foundation for the future clinical application of EVs in ONFH.

Keywords: Extracellular vesicles; Mesenchymal stem cells; MicroRNA; Osteonecrosis of the femoral head; Pathogenesis.

Graphical abstract

Fig. 1

The biogenesis of extracellular vesicles and the differences between their subtypes. Cells first produce endosomes through endocytosis. These endosomes exchange materials with other cellular organelles and load nucleic acids, proteins, and lipids from the cytoplasm into their lumen. Subsequently, the endosomal membrane invaginates to form small vesicles within the endosome. Eventually, these small vesicles are released when multivesicular bodies fuse with the plasma membrane, a process that results in the secretion of exosomes. In contrast, microvesicles are produced by ectocytosis, where vesicles are shed directly from the plasma membrane. Apoptotic bodies, on the other hand, are formed through a budding mechanism during the process of apoptosis. The red asterisks in the figure represent the characteristics of this type of EVs.

Fig. 2

Mechanisms of ONFH facilitated by extracellular vesicles. Exosomes absence of CD41 impede the proliferation and viability of osteoblasts, whereas particular RNAs, including miR-3133, miR-4693-3p, miR-4693-5p, miR-141-3p, and miR-182-5p, enhance the proliferation of osteoclasts and diminish the population of osteoblasts. The imbalance in the number of osteoblasts and osteoclasts leads to bone loss. Microparticles secreted by abnormally proliferating adipocytes can also enhance the adipogenic differentiation of BMMSCs, leading to the accumulation of fat around blood vessels and promoting the production of vasoconstrictor substances, which results in the femoral head's blood supply being decreased. In addition, extracellular vesicles can also promote blood clotting and inhibit the fibrinolytic system, leading.

Fig. 3

Extracellular vesicles from different cell sources promote the repair of femoral head necrosis through distinct signaling pathways. EVs derived from various cell sources, whether natural or engineered, can act upon mesenchymal stem cells, vascular endothelial cells, and macrophages. They promote the proliferation and differentiation of osteoblasts and vascular endothelial cells through distinct signaling pathways such as Wnt, MAPK, and PI3K. Additionally, these EVs can inhibit apoptosis, enhance bone formation and angiogenesis, and create an immunomodulatory microenvironment conducive to bone regeneration, thereby facilitating bone repair.

Fig. 4

The signaling pathways involved in the repair process of osteonecrosis mediated by extracellular vesicles. EVs derived from different cell sources or engineered EVs (such as those pretreated with LiCl or hypoxia, or loaded with functional substances) can activate Wnt, PI3K/AKT, NF-κB, and MAPK pathways to promote osteogenesis, angiogenesis, or the production of anti-apoptotic factors. The different signaling pathways can interact through their downstream products, and the cargo within EVs can directly inhibit various products in these pathways, thereby promoting bone and vascular regeneration.