Department of Prosthodontics, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Haidian District, Beijing, 100081, China.
National Engineering Lab for Digital and Material Technology of Stomatology, Peking University School and Hospital of Stomatology, Beijing, 100081, China.
Stem Cell Res Ther. 2018 Mar 9;9(1):65. doi: 10.1186/s13287-018-0809-1.
Mesenchymal stem cells (MSCs) are a reliable resource for bone regeneration and tissue engineering, but the molecular mechanisms of differentiation remain unclear. The tumor antigen 15-leucine-rich repeat containing membrane protein (LRRC15) is a transmembrane protein demonstrated to play important roles in cancer. However, little is known about its role in osteogenesis. This study was to evaluate the functions of LRRC15 in osteogenic differentiation of MSCs.
Osteogenic-induction treatment and the ovariectomized (OVX) model were performed to investigate the potential relationship between LRRC15 and MSC osteogenesis. A loss-of-function study was used to explore the functions of LRRC15 in osteogenic differentiation of MSCs in vitro and in vivo. NF-κB pathway inhibitor BAY117082, siRNA, nucleocytoplasmic separation, and ChIP assays were performed to clarify the molecular mechanism of LRRC15 in bone regulation.
Our results first demonstrated that LRRC15 expression was upregulated upon osteogenic induction, and the level of LRRC15 was significantly decreased in OVX mice. Both in-vitro and in-vivo experiments detected that LRRC15 was required for osteogenesis of MSCs. Mechanistically, LRRC15 inhibited transcription factor NF-κB signaling by affecting the subcellular localization of p65. Further studies indicated that LRRC15 regulated osteogenic differentiation in a p65-dependent manner.
Taken together, our findings reveal that LRRC15 is an essential regulator for osteogenesis of MSCs through modulating p65 cytoplasmic/nuclear translocation, and give a novel hint for MSC-mediated bone regeneration.
间充质干细胞（MSCs）是骨再生和组织工程的可靠资源，但分化的分子机制仍不清楚。肿瘤抗原 15-亮氨酸丰富重复包含膜蛋白（LRRC15）是一种跨膜蛋白，已被证明在癌症中发挥重要作用。然而，其在成骨中的作用知之甚少。本研究旨在评估 LRRC15 在 MSCs 成骨分化中的功能。
进行成骨诱导治疗和去卵巢（OVX）模型，以研究 LRRC15 与 MSC 成骨之间的潜在关系。采用功能丧失研究，体外和体内探索 LRRC15 在 MSC 成骨分化中的功能。采用 NF-κB 通路抑制剂 BAY117082、siRNA、核质分离和 ChIP 测定，阐明 LRRC15 在骨调节中的分子机制。
我们的研究结果首次表明，LRRC15 在成骨诱导时表达上调，在 OVX 小鼠中 LRRC15 水平显著降低。体内外实验均检测到 LRRC15 是 MSC 成骨所必需的。机制上，LRRC15 通过影响 p65 的亚细胞定位来抑制转录因子 NF-κB 信号。进一步的研究表明，LRRC15 通过依赖 p65 的方式调节成骨分化。
综上所述，我们的研究结果揭示了 LRRC15 通过调节 p65 胞质/核易位，是 MSC 成骨的重要调节因子，为 MSC 介导的骨再生提供了新的线索。
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