Exosomes are a type of extracellular vesicle released by the fusion of multivesicular bodies with the cell membrane. [Meletios Verra / iStock / Getty Images Plus]
Osteoarthritis (OA) is one of the leading forms of arthritis today, affecting over 32.5 million adults in the US and 300 million worldwide, causing significant complications that reduce the quality of life for many afflicted with the condition. Defined by the degradation of the protective cartilage between bone joints, osteoarthritis is caused by a number of different reasons, but most forms of the condition involve an imbalance between the factors contributing to the formation and maintenance of the articular cartilage, as well as the factors that result in the degeneration of the cartilage. The fundamental causes of such imbalance that have been found include aging, trauma, mechanical loading, and genetic and metabolic disorders.
Osteoarthritis is so devastating due to its degenerative nature; it continues to damage the joints over time, which may lead to symptoms of greater severity such as muscle weakness, bone spurs, or joint weakness. Recent research has pointed to the idea that OA involves the inflammation of all tissue surrounding the synovial joint, not only affecting the articular cartilage but also other portions like the underlying bone or the synovium. This has the potential to cause greater problems by accelerating the progression of the condition itself. By affecting multiple parts surrounding the joint, OA can lead to sequences that continue to exacerbate the condition in a loop.
Conventional treatments for OA that are currently in use are lacking in their capacity to stem the progression of the disease or more importantly, to cure and regenerate the cartilage. However, one of the prospective solutions that are being researched is the use of mesenchymal stem cell (MSC)-derived exosomes.
Current treatments are only symptomatic relying on the use of pharmacological methods and viscosupplements. Because these treatments are palliative and not curative, other therapeutic strategies have requested to be developed. Modern medicine is exploring the regenerative potential of cellular therapy to address the currently unmet medical needs of various degenerative conditions such as OA. Cellular therapy has been extensively invested in exploring a new paradigm for the treatment of many degenerative conditions including degenerative disc disease (DDD) and osteoarthritis of the joints, among many other conditions. Stem cells have the potential to differentiate into various different kinds of adult cells, making them a solution of great potential and versatility to many diseases today. In recent years, several research groups have shown mesenchymal stem/stromal cell (MSC)-based therapies have a positive impact on the outcome of OA. In pre-clinical models, intra-articular injection of MSCs, either from bone marrow or adipose tissue could protect cartilage from degeneration and at least delay OA progression. However, many issues need to be solved in order to make them a viable application. One large problem with using stem cells is the risk of the cells triggering an immune response where they are recognized as a pathogen and killed through methods like inflammation, which can have additional negative consequences. The immune response can be controlled using immunosuppressive drugs, but this is not ideal as such drugs have various side effects, including greater risk of infection, strong toxicity, etc. According to recent research results, most therapeutic effects of stem cell based therapies on OA are attributed to the secretion of mediators with anti-inflammatory and chondroprotective functions. Those mediators are conveyed within extracellular vesicles (EVs) released by MSCs. Several research teams have shown that exosomes isolated from adult mesenchymal stem cells and human embryonic MSCs successfully decreased OA symptoms in vivo. Currently, there are over 500 clinical trials registered on ClinicalTrials.gov, exploring the safety and efficacy of adult stem cells, e.g., pluripotent stem cells, umbilical cord-derived stem cells, placental stem cells, and mesenchymal stem cells, to treat OA. MSCs are described to exert their therapeutic effects by homing to the injured site when injected locally to the joint for a short period of time and then disappearing and are believed to be secreting a myriad of growth factors and cytokines to initiate the repair process.
Among one of the most common mediators of intercellular communication between joint cells are exosomes, which have been studied in the past decade as a potential solution for OA. Exosomes are a type of extracellular vesicle released by the fusion of multivesicular bodies with the cell membrane. They transport key components that serve to mediate or induce various processes in nearby cells, including mRNA, DNA, enzymes, lipids, and more. These components have the potential to be used to treat various conditions by promoting processes that may reverse or control the progression of the condition.
Exosomes are involved in many physiological functions and processes, both normal and pathological. Several studies have shown the potential of exosomes as biomarkers in cancer, as the level of exosomes within circulating blood correlates with prognosis. Furthermore, miRNAs loaded into exosomes have been suggested as diagnostic and prognostic indicators for many different cancer diseases, such as ovarian cancer, lung cancer, colon cancer, prostate cancer, and breast cancer. In addition to miRNAs, exosomal lncRNAs from cancer patients have been defined as novel tumor biomarkers.
Exosomes as a therapeutic tool could have applications for the treatment of many disorders characterized by chronic tissue damage. The advantages of small size, low immunogenicity, and the lack of issues such as low cell survival and unpredictable abnormal differentiation and tumor formation associated with direct cell transplantation make exosomes a solution of great promise .
Exosomes have been shown to be a potential form of treatment for cartilage destruction. Contemporary research has shown that exosomes benefit the regeneration process of damaged cartilage greatly, with various markers of cartilage quality corroborating their benefit. While numerous mechanisms are a part of exosomes’ beneficial effect on the cartilage regeneration, a major mechanism involves the delivery of miRNA that induce chondrocyte proliferation and inhibit inflammatory response and apoptosis.
However, there is yet to be more research done before exosomes can be fully approved for human usage. For one thing, previous experiments have all been performed using non-human subjects such as mice or rats, and as such the effect of exosome treatment on human cartilage is yet to be fully evaluated. It is a feasible possibility that there are certain differences that could severely hinder the efficacy of exosome treatment on the human cartilage.
In addition, more research is needed to determine what kinds of stem cells are optimum for different situations of OA. The exosomes secreted by different types of stem cells differ in small and large ways, and this can be a crucial element in deciding what stem cells are optimal for providing exosomes for treatment. Their general efficacy in treating cartilage damage, the mechanisms by which they achieve this, and logistical challenges are among some elements that must be taken into consideration for different situations related to OA.
Yet another aspect of exosome treatment that lacks research is the exact molecular mechanism in how exosomes aid in cartilage regeneration. While certain components of exosomes such as miRNA and lncRNA have been identified as playing a role in aiding cartilage regeneration, research for specific mechanisms as to how they achieve this is insufficient. There are many different ways cartilage regeneration can be promoted, and as of now what components make use of what ways, and what pathways they use to do this are mostly undiscovered. Clarifying these aspects would help optimum application of exosome treatment in the future by providing knowledge on how they should be applied, in what situations they are effective, and what kind of precautions should be taken in their use.
Q&A Section
Jiwon: Earlier on in your article, you mentioned that osteoarthritis is one of the leading forms of arthritis, and that there have been recent studies working on mitigating its negative impacts by researching intercellular communication among joint cells. Does this research strictly pertain to OA—that is, are the same results applicable to other types of arthritis?
It is characteristic of arthritis in general; however, each arthritis has different kinds of intercellular communication going on, and OA is unique in its involvement of specific bone cells like osteoclasts/blasts
Xavier: Who exactly is conducting this research on exosomes? What do you think is their ultimate goal (however many years into the future) with regards to this specific field?
The ultimate goal for these researchers would be to find a fully functional solution to reversing the effects of OA in an non-invasive manner (emphasis on reverse, not just hold)
Eric: Are there any limitations on obtaining stem cells (as most stem-cell based treatments are stuck on actually scaling the production/extraction of stem cells)?
Unlike “pure” stem cells from embryos, mesenchymal stem cells are more of an intermediate stage and can self replicate in different populations rapidly, making them more viable for mass production
John: Why is OA so pervasive? Can we reduce its pervasiveness using medical means?
It affects nearly all aspects of the bone joint, which can lead to widespread loops that continue to exacerbate the condition
Wooseok: Is the stem cell treatment better / safer compared to the existing modern prosthetic body parts? Why or why not?
While it is still in its infancy, this method allows us to fix the limbs without being invasive/sacrificing whole organs
Works Cited
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Cosenza, S., Ruiz, M., Toupet, K., Jorgensen, C., & Noël, D. (2017). Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis. Scientific Reports, 7(1). doi:10.1038/s41598-017-15376-8
Dubey, N. K., Mishra, V. K., Dubey, R., Syed-Abdul, S., Wang, J. R., Wang, P. D., & Deng, W. (2018). Combating Osteoarthritis through Stem Cell Therapies by Rejuvenating Cartilage: A Review. Stem Cells International, 2018, 1-13. doi:10.1155/2018/5421019
Edgar, J. R. (2016). Q&A: What are exosomes, exactly? BMC Biology, 14(1). doi:10.1186/s12915-016-0268-z
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Huang, T., & Deng, C. (2019). Current Progresses of Exosomes as Cancer Diagnostic and Prognostic Biomarkers. International Journal of Biological Sciences, 15(1), 1-11. doi:10.7150/ijbs.27796
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