Kenneth Sims IV

Introduction.  Osteoarthritis (OA) is a “wear-and-tear” disease in which synovial joints, such as the knee or shoulder, degenerate over time. This disease can cause significant pain and immobility, and there is a need for therapy beyond symptomatic management.  Within the OA joint, chondrocytes lose the ability to maintain homeostasis between matrix synthesis and degradation.  At the molecular level, catabolic enzymes such as matrix metalloprotease-13 (MMP-13) show increased expression.¹ Numerous studies have shown that WNT5A protein promotes OA through various signal cascades that enhance chondrocyte hypertrophy², mineralization² , and catabolism.³  Studies have also shown that stem cells may show therapeutic efficacy in treating OA^4,5; specifically, mesenchymal stem cell (MSC)-derived exosomes have demonstrated the ability to mitigate the OA environment in both in vitro and in vivo mouse studies.  It is postulated that exosomal miRNA may play a role in this mechanism. The broad purpose of this mechanistic study is to develop a potential OA therapy that mitigates underlying OA pathology.  This study specifically investigates the mechanism by which MSC-derived exosomes impact on chondrogenesis and cartilage degradation via miR-92a-3-mediated inhibition of WNT5A in chondrocytes.⁶  Methods.  In this study, exosomal miR-92a-3p expression was assessed in vitro in normal and OA primary human chondrocytes (PHC).⁶  The chondrocytes were treated with miR-92a-3p derived from exosomes of MSC origin or its anti-sense inhibitor.  The mechanistic relationship between miR-92a-3p and WNT5A was experimentally determined using small interfering RNAs (siRNA) and a luciferase reporter assay.⁶  Results.  The results showed that exosomal miR-92a-3p expression was significantly reduced in OA chondrocyte-secreted exosomes compared to exosomes from healthy cartilage.⁶  The luciferase reporter assay revealed that miR-92-3p suppressed the 3’-UTR of WNT5A mRNA in MSCs and PHCs.⁶ In the mouse model, the MSC exosome with miR-92a-3p inhibited cartilage degradation.⁶   Conclusions.  The results suggest that miR-92a-3p can regulate cartilage homeostasis by promoting chondrogenesis and by downregulating OA pathogenesis through post-transcriptional modification of WNT5A mRNA.⁶  Thus, inhibiting WNT5A with exosomal miR-92a-3p may provide a useful mechanism for treating OA by targeting its underlying causes rather than just the symptoms.

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2. Diederichs, S., Tonnier, V., März, M. et al. Regulation of WNT5A and WNT11 during MSC in vitro chondrogenesis: WNT inhibition lowers BMP and hedgehog activity, and reduces hypertrophy. (2019) Cell. Mol. Life Sci. 76, 3875–3889.
3. Huang, G., Chubinskaya, S., Liao, W., & Loeser, R. (2017). Wnt5a induces catabolic signaling and matrix metalloproteinase production in human articular chondrocytes. Osteoarthritis and Cartilage, 25(9), 1505–1515.
4. Zhang, S., Chuah, S. J., Lai, R. C., Hui, J. H. P., Lim, S. K., & Toh, W. S. (2018). MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials, 156, 16–27.
5. Mianehsaz, E., Mirzaei, H. R., Mahjoubin-Tehran, M., Rezaee, A., Sahebnasagh, R., Pourhanifeh, M. H., Mirzaei, H., & Hamblin, M. R. (2019). Mesenchymal stem cell-derived exosomes: a new therapeutic approach to osteoarthritis? Stem cell research & therapy, 10(1), 340.
6. Mao, G., Zhang, Z., Hu, S., Zhang, Z., Chang, Z., Huang, Z., Liao, W., & Kang, Y. (2018). Exosomes derived from miR-92a-3p-overexpressing human mesenchymal stem cells enhance chondrogenesis and suppress cartilage degradation via targeting WNT5A. Stem cell research & therapy, 9(1), 247.