Subchondral mesenchymal stem cells from osteoarthritic knees display high osteogenic differentiation capacity through microRNA-29a regulation of HDAC4
Subchondral mesenchymal stem cells from osteoarthritic knees display high osteogenic differentiation capacity through microRNA-29a regulation of HDAC4
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DOI：
10.1007/s00109-017-1583-8
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发表时间：
2017-12-01
影响因子：
4.7
通讯作者：
Wang, Feng-Sheng
中科院分区：
文献类型：
--
作者：
Lian, Wei-Shiung;Wu, Ren-Wen;Wang, Feng-Sheng
过度矿化导致的软骨下骨退化和骨赘形成是终末期膝骨关节炎（OA）的显着特征。软骨下完整性降低的细胞事件仍然难以捉摸。本研究旨在表征从需要全膝关节置换术的终末期膝关节 OA 患者中分离出的软骨下间充质干细胞 (SMSC)。 SMSC 表达表面抗原 CD29、CD44、CD73、CD90、CD105 和 CD166，但缺乏 CD31、CD45 和 MHCII 表达。细胞培养物表现出更高的增殖能力以及更强的成骨和软骨形成能力，而它们的群体倍增时间和脂肪形成谱系定向低于骨髓间充质干细胞（BMMSC）。与 BMMSC 相比，它们还表现出胚胎干细胞标志物 OCT3/4 和成骨因子 Wnt3a、β-catenin 和 microRNA-29a (miR-29a) 的较高表达，同时关节有害因子 HDAC4、TGF-β 1、IL-1 beta、TNF-α 和 MMP3 的表达较低。 miR-29a 的敲低通过提高 HDAC4 翻译来降低 Wnt3a 表达和 SMSC 的成骨分化，从而直接调节 HDAC4 的 3'-非翻译区。同样，在成骨细胞中过度表达 miR-29a 的转基因小鼠在软骨下区域表现出高骨量。与野生型小鼠相比，转基因小鼠中的 SMSC 显示出更高的成骨分化和更低的 HDAC4 信号传导。综上所述，骨关节炎膝关节中的 SMSC 具有较高的成骨能力。 miR-29a 对 HDAC4 和 Wnt3a 信号传导的调节可归因于成骨的增加。这项研究揭示了 SMSC 的特征，并强调了 SMSC 在加剧终末期膝骨关节炎软骨下完整性方面的贡献。
Subchondral bone deterioration and osteophyte formation attributable to excessive mineralization are prominent features of end-stage knee osteoarthritis (OA). The cellular events underlying subchondral integrity diminishment remained elusive. This study was undertaken to characterize subchondral mesenchymal stem cells (SMSCs) isolated from patients with end-stage knee OA who required total knee arthroplasty. The SMSCs expressed surface antigens CD29, CD44, CD73, CD90, CD105, and CD166 and lacked CD31, CD45, and MHCII expression. The cell cultures exhibited higher proliferation and greater osteogenesis and chondrogenesis potencies, whereas their population-doubling time and adipogenic lineage commitment were lower than those of bone marrow MSCs (BMMSCs). They also displayed higher expressions of embryonic stem cell marker OCT3/4 and osteogenic factors Wnt3a, beta-catenin, and microRNA-29a (miR-29a), concomitant with lower expressions of joint-deleterious factors HDAC4, TGF-beta 1, IL-1 beta, TNF-alpha, and MMP3, in comparison with those of BMMSCs. Knockdown of miR-29a lowered Wnt3a expression and osteogenic differentiation of the SMSCs through elevating HDAC4 translation, which directly regulated the 3'-untranslated region of HDAC4. Likewise, transgenic mice that overexpressed miR-29a in osteoblasts exhibited a high bone mass in the subchondral region. SMSCs in the transgenic mice showed a higher osteogenic differentiation and lower HDAC4 signaling than those in wild-type mice. Taken together, high osteogenesis potency existed in the SMSCs in the osteoarthritic knee. The miR-29a modulation of HDAC4 and Wnt3a signaling was attributable to the increase in osteogenesis. This study shed an emerging light on the characteristics of SMSCs and highlighted the contribution of SMSCs in the exacerbation of subchondral integrity in end-stage knee OA.