Dysregulation of the Wnt Signaling Pathway and Synovial Stem Cell Dysfunction in Osteoarthritis Development
Dysregulation of the Wnt Signaling Pathway and Synovial Stem Cell Dysfunction in Osteoarthritis Development
复制标题
骨关节炎发展中 Wnt 信号通路的失调和滑膜干细胞功能障碍。
DOI：
10.1089/scd.2019.0260
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发表时间：
2020-02-19
影响因子：
4
通讯作者：
Wu, Song
中科院分区：
文献类型：
--
作者：
Huang, Junjie;Chen, Chuanshun;Wu, Song
在骨关节炎（OA）的关节中发现了干细胞功能障碍和衰竭。然而，OA微环境中损害干细胞功能的确切因素以及干细胞功能障碍在OA发展中的作用尚未完全阐明。在这项研究中，我们评估了OA患者滑膜间充质干细胞（SMSCs）的功能状态，并探讨了OA-SMSCs对大鼠模型软骨降解的影响。然后，我们在OA患者滑膜中筛选了138个Wnt信号相关基因，重点关注5个WNT配体对SMSC功能的影响。OA滑膜组织轻度增生，增生的滑膜组织中可见大量的CD 90 +/CD 105+干细胞。OA-SMSCs显示出细胞衰老表型，增殖和软骨形成能力降低，伴随着迁移、促炎和基质降解活性增强。关节内移植OA-SMSCs后关节软骨的降解和破坏明显加重。在138个Wnt信号转导基因中，有86个基因在OA滑膜中的表达持续改变，其中DVL 2、WNT 10A和DKK 3的表达增加最明显。总之，我们发现OA滑膜中经典Wnt/β-catenin通路被抑制，而非经典PCP和Wnt/Ca 2+通路被激活。在体外实验中，WNT 10A对SMSCs有明显的抗衰老作用。WNT 5 B显著抑制SMSCs的软骨分化，WNT 10A和WNT 5A增加SMSCs中炎性细胞因子的表达。在大鼠模型中，WNT 5A显著加重关节退行性变，而WNT 10A对软骨完整性具有轻度保护作用。总之，OA滑膜中的干细胞功能异常并促进OA的发展，而Wnt信号通路的失调揭示了对SMSC功能和软骨降解的综合影响。
Stem cell dysfunction and failure have been found in joints afflicted by osteoarthritis (OA). However, the exact factors in the OA microenvironment that impair stem cell functions and the role of stem cell dysfunction in OA development have not been fully clarified. In this study, we evaluated the functional status of synovial mesenchymal stem cells (SMSCs) from OA patients and explored the influence of OA-SMSCs on cartilage degradation in a rat model. We then screened 138 Wnt signaling-related genes in the synovium of OA patients, focusing on the effects of 5 WNT ligands on SMSC functions. The OA synovium showed mild hyperplasia, and we found a large number of CD90+/CD105+ stem cells in synovial hyperplasia. The OA-SMSCs revealed a cellular senescence phenotype, with decreased proliferation and chondrogenic capacity, accompanied by enhanced migration, proinflammatory and matrix degradation activities. The intra-articular transplantation of these OA-SMSCs significantly aggravated the degradation and destruction of the articular cartilage. Of 138 Wnt signaling genes, the expression of 86 genes was consistently altered in the OA synovium, among which the increased expression of DVL2, WNT10A and DKK3 was the most marked. In general, we found that canonical Wnt/β-catenin pathways were inhibited in the OA synovium, whereas noncanonical PCP and Wnt/Ca2+ pathways were activated. In vitro, WNT10A had an obvious antisenescence effect on SMSCs. WNT5B significantly inhibited the chondrogenic differentiation of SMSCs, and WNT10A and WNT5A increased the expression of inflammatory cytokines in SMSCs. In a rat model, WNT5A significantly aggravated joint degeneration, whereas WNT10A had a mild protective effect on cartilage integrity. In conclusion, stem cells in the OA synovium were functionally abnormal and promoted the development of OA, while dysregulation of the Wnt signaling pathway revealed a comprehensive influence on SMSC functions and cartilage degradation.