Osteoarthritis (OA) is a common degenerative disease that can lead to persistent pain and motion restriction. In the last decade, stem cells, particularly mesenchymal stem cells (MSCs), have been explored as a potential alternative OA therapy due to their regenerative capacity. Furthermore, it has been shown that trophic factors enveloped in extracellular vesicles (EVs), including exosomes, are a crucial aspect of MSC-based treatment for OA. Evidently, EVs derived from different MSC sources might rescue the OA phenotype by targeting many biological processes associated with cartilage extracellular matrix (ECM) degradation and exerting protective effects on different joint cell types. Despite this advancement, different studies employing EV treatment for OA have revealed reverse outcomes depending on the EV cargo, cell source, and pathological condition. Hence, in this review, we aim to summarize and discuss the possible effects of MSC-derived EVs based on recent findings at different stages of OA development, including effects on cartilage ECM, chondrocyte biology, osteocytes and bone homeostasis, inflammation, and pain management. Additionally, we discuss further strategies and technical advances for manipulating EVs to specifically target OA to bring the therapy closer to clinical use.
In recent years, extracellular vesicles (EVs) secreted by mesenchymal stem cells (MSCs) have emerged as a potential cell-free therapy against osteoarthritis (OA). Thus, we investigated the therapeutic effects of EVs released by cytokine-primed umbilical cord-derived MSCs (UCMSCs) on osteoarthritic chondrocyte physiology. Priming UCMSCs individually with transforming growth factor beta (TGFβ), interferon alpha (IFNα), or tumor necrosis factor alpha (TNFα) significantly reduced the sorting of miR-181b-3p but not miR-320a-3p; two negative regulators of chondrocyte regeneration, into EVs. However, the EV treatment did not show any significant effect on chondrocyte proliferation. Meanwhile, EVs from both non-priming and cytokine-primed UCMSCs induced migration at later time points of measurement. Moreover, TGFβ-primed UCMSCs secreted EVs that could upregulate the expression of chondrogenesis markers (COL2 and ACAN) and downregulate fibrotic markers (COL1 and RUNX2) in chondrocytes. Hence, priming UCMSCs with cytokines can deliver selective therapeutic effects of EV treatment in OA and chondrocyte-related disorders.
Herein, we detail several specific challenges that hinder the effective synthesis of glutamyl hydrazide containing peptides, and we describe a synthetic strategy to work around these challenges. Glutamyl hydrazide is an unnatural amino acid residue that bears an acyl hydrazide functional group on its side chain. This family of compounds has the potential to provide potent and selective inhibitor molecules for several families of enzymes. During peptide synthesis, however, these side chains—even in protected form—can derail the synthesis by initiating undesired side reactions. Avoiding these side reactions is critical for enabling effective access to this family of compounds.
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