Guping Mao1,2, Yiyang Xu1,2,3, Dianbo Long1,2, Hong Sun4, Hongyi Li1,2, Ruobin Xin1,2, Ziji Zhang5,6, Zhiwen Li7,8, Zhi Yang9,10, Yan Kang11,12. 1. Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, #58 Zhongshan 2nd Road, Guangzhou, 510080, Guangdong, China. 2. Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, China. 3. Department of Orthopedics, Fujian Provincial Hospital/Shengli Clinical Medical College, Fujian Medical University, Fuzhou, 350003, Fujian, China. 4. Department of Orthopaedics, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, Guizhou, China. 5. Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, #58 Zhongshan 2nd Road, Guangzhou, 510080, Guangdong, China. zhangziji@mail.sysu.edu.cn. 6. Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, China. zhangziji@mail.sysu.edu.cn. 7. Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, #58 Zhongshan 2nd Road, Guangzhou, 510080, Guangdong, China. lizhiw28@mail2.sysu.edu.cn. 8. Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, China. lizhiw28@mail2.sysu.edu.cn. 9. Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, #58 Zhongshan 2nd Road, Guangzhou, 510080, Guangdong, China. yangzh95@sysu.edu.cn. 10. Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, China. yangzh95@sysu.edu.cn. 11. Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, #58 Zhongshan 2nd Road, Guangzhou, 510080, Guangdong, China. kangyan@mail.sysu.edu.cn. 12. Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, China. kangyan@mail.sysu.edu.cn.
Abstract
OBJECTIVES: Aberrations in exosomal circular RNA (circRNA) expression have been identified in various human diseases. In this study, we investigated whether exosomal circRNAs could act as competing endogenous RNAs (ceRNAs) to regulate the pathological process of osteoarthritis (OA). This study aimed to elucidate the specific MSC-derived exosomal circRNAs responsible for MSC-mediated chondrogenic differentiation using human bone marrow-derived MSCs (hMSCs) and a destabilization of the medial meniscus (DMM) mouse model of OA. METHODS: Exosomal circRNA deep sequencing was performed to evaluate the expression of circRNAs in human bone marrow-derived MSCs (hMSCs) induced to undergo chondrogenesis from day 0 to day 21. The regulatory and functional roles of exosomal circRNA_0001236 were examined on day 21 after inducing chondrogenesis in hMSCs and were validated in vitro and in vivo. The downstream target of circRNA_0001236 was also explored in vitro and in vivo using bioinformatics analyses. A luciferase reporter assay was used to evaluate the interaction between circRNA_0001236 and miR-3677-3p as well as the target gene sex-determining region Y-box 9 (Sox9). The function and mechanism of exosomal circRNA_0001236 in OA were explored in the DMM mouse model. RESULTS: Upregulation of exosomal circRNA_0001236 enhanced the expression of Col2a1 and Sox9 but inhibited that of MMP13 in hMSCs induced to undergo chondrogenesis. Moreover, circRNA_0001236 acted as an miR-3677-3p sponge and functioned in human chondrocytes via targeting miR-3677-3p and Sox9. Intra-articular injection of exosomal circRNA_0001236 attenuated OA in the DMM mouse model. CONCLUSIONS: Our results reveal an important role for a novel exosomal circRNA_0001236 in chondrogenic differentiation. Overexpression of exosomal circRNA_0001236 promoted cartilage-specific gene and protein expression through the miR-3677-3p/Sox9 axis. Thus, circRNA_0001236-overexpressing exosomes may alleviate cartilage degradation, suppressing OA progression and enhancing cartilage repair. Our findings provide a potentially effective therapeutic strategy for treating OA.
OBJECTIVES: Aberrations in exosomal circular RNA (circRNA) expression have been identified in various human diseases. In this study, we investigated whether exosomal circRNAs could act as competing endogenous RNAs (ceRNAs) to regulate the pathological process of osteoarthritis (OA). This study aimed to elucidate the specific MSC-derived exosomal circRNAs responsible for MSC-mediated chondrogenic differentiation using human bone marrow-derived MSCs (hMSCs) and a destabilization of the medial meniscus (DMM) mouse model of OA. METHODS: Exosomal circRNA deep sequencing was performed to evaluate the expression of circRNAs in human bone marrow-derived MSCs (hMSCs) induced to undergo chondrogenesis from day 0 to day 21. The regulatory and functional roles of exosomal circRNA_0001236 were examined on day 21 after inducing chondrogenesis in hMSCs and were validated in vitro and in vivo. The downstream target of circRNA_0001236 was also explored in vitro and in vivo using bioinformatics analyses. A luciferase reporter assay was used to evaluate the interaction between circRNA_0001236 and miR-3677-3p as well as the target gene sex-determining region Y-box 9 (Sox9). The function and mechanism of exosomal circRNA_0001236 in OA were explored in the DMMmouse model. RESULTS: Upregulation of exosomal circRNA_0001236 enhanced the expression of Col2a1 and Sox9 but inhibited that of MMP13 in hMSCs induced to undergo chondrogenesis. Moreover, circRNA_0001236 acted as an miR-3677-3p sponge and functioned in human chondrocytes via targeting miR-3677-3p and Sox9. Intra-articular injection of exosomal circRNA_0001236 attenuated OA in the DMMmouse model. CONCLUSIONS: Our results reveal an important role for a novel exosomal circRNA_0001236 in chondrogenic differentiation. Overexpression of exosomal circRNA_0001236 promoted cartilage-specific gene and protein expression through the miR-3677-3p/Sox9 axis. Thus, circRNA_0001236-overexpressing exosomes may alleviate cartilage degradation, suppressing OA progression and enhancing cartilage repair. Our findings provide a potentially effective therapeutic strategy for treating OA.
Authors: Johanne Martel-Pelletier; Andrew J Barr; Flavia M Cicuttini; Philip G Conaghan; Cyrus Cooper; Mary B Goldring; Steven R Goldring; Graeme Jones; Andrew J Teichtahl; Jean-Pierre Pelletier Journal: Nat Rev Dis Primers Date: 2016-10-13 Impact factor: 52.329