Shenzhen Key Laboratory of Anti-aging and Regenerative Medicine, Department of Medical Cell Biology and Genetics, Health Sciences Center, Shenzhen University, Shenzhen, China.
Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen, 518060, China; Department of Orthopaedic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Biochem Biophys Res Commun. 2021 Sep 17;570:199-205. doi: 10.1016/j.bbrc.2021.07.044. Epub 2021 Jul 20.
Osteoarthritis (OA) is the most common joint disease worldwide; however, disease-modifying treatments are lacking because of the complicated pathological mechanisms. As a breakthrough, aberrant activation of transforming growth factor-β 1 (TGF-β1)in subchondral bone has been confirmed as an essential pathomechanism for OA progression, and has become a potential therapeutic target. In addition to R&D on neutralizing antibodies, small-molecule antagonists and chemical medicines, native antagonists of TGF-β1 could be exploited as another promising approach. Noggin (NOG) is an antagonist of bone morphogenetic proteins (BMPs) and was reported to effectively attenuate OA by protecting cartilage and preventing pathological subchondral bone remodeling. However, the underlying mechanisms have not been fully clarified. We first detected the distribution of NOG in knee joints of an OA mouse model, which showed upregulation at early stage of OA but downregulation later in the subchondral bone and no significant change in the articular cartilage. Furthermore, the interaction between NOG and TGF-β1 was verified, which in turn suppressed the downstream SMAD2/3 activity of TGF-β1. Moreover, the proliferation and chondrogenesis of mesenchymal stem cells (MSCs) were not significantly influenced by NOG. Taken together, the results showed that NOG antagonized TGF-β1 but did not repress MSC proliferation and chondrogenesis; thus, it seems promising for OA treatment.
骨关节炎（OA）是全球最常见的关节疾病；然而，由于复杂的病理机制，缺乏疾病修饰治疗方法。作为一个突破，软骨下骨中转化生长因子-β1（TGF-β1）的异常激活已被证实是 OA 进展的一个重要病理机制，并已成为一个潜在的治疗靶点。除了中和抗体、小分子拮抗剂和化学药物的研发外，TGF-β1 的天然拮抗剂也可以作为另一种有前途的方法加以利用。Noggin（NOG）是骨形态发生蛋白（BMPs）的拮抗剂，据报道，通过保护软骨和防止病理性软骨下骨重塑，NOG 可有效减轻 OA。然而，其潜在的机制尚未完全阐明。我们首先检测了 OA 小鼠模型膝关节中 NOG 的分布，结果显示在 OA 的早期阶段NOG 上调，但在软骨下骨中 later 下调，而在关节软骨中没有明显变化。此外，还验证了 NOG 与 TGF-β1 之间的相互作用，进而抑制了 TGF-β1 的下游 SMAD2/3 活性。此外，NOG 对间充质干细胞（MSCs）的增殖和软骨形成没有明显影响。总之，结果表明，NOG 拮抗 TGF-β1，但不抑制 MSC 的增殖和软骨形成；因此，它似乎有望用于 OA 的治疗。
