Department of Orthopedics, The Ninth Affiliated Hospital of Guangxi Medical University, Beihai, Guangxi, China; Department of Orthopedics, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, Zhejiang, China.
Department of Neurosurgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
Biomed Pharmacother. 2020 Nov;131:110650. doi: 10.1016/j.biopha.2020.110650. Epub 2020 Sep 1.
Osteoarthritis (OA) is a common degenerative disease with a series of changes occurring in aging cartilage, such as increased oxidative stress, decreased markers of healthy cartilage and alterations in the autophagy pathway. And increasing evidence indicates that osteoarthritis affects the whole joint, including both cartilage and subchondral bone. The agents that can effectively suppress chondrocyte degradation and subchondral bone deterioration are crucial for the prevention and treatment of OA. Ruboxistaurin (RU), an orally active protein kinase C inhibitor, can reduce macrophage adhesion to endothelial cells and relieve the local inflammation when applicating in diabetes and kinds of aging-related vasculopathy, which were realized by its effects on decreasing inflammatory cytokines' expression and increasing cell anti-oxidative stress ability. However, whether ruboxistaurin protects against OA remains unknown. In this study, we investigated the therapeutic effects of ruboxistaurin in an anterior cruciate ligament transection (ACLT)-induced OA model by preventing the bone mass loss of subchondral bone. We found that ruboxistaurin can effectively alleviate ACLT-induced osteoarthritis, as demonstrated by the phenomenon of correcting pathological bone loss caused by osteoclasts overactivated in the early stage of osteoarthritis and protecting against articular cartilage degeneration. Moreover, we found that ruboxistaurin inhibited osteoclast formation and resorption activity by suppressing the expressions of osteoclast-related genes and (PKCδ/MAPKs) signaling cascade. Taken together, these results show that ruboxistaurin may be a potential therapeutic agent for rescuing abnormal subchondral bone deterioration and cartilage degradation in OA and reverses the vicious cycle related to osteoarthritis.
骨关节炎（OA）是一种常见的退行性疾病，在衰老的软骨中会发生一系列变化，如氧化应激增加、健康软骨标志物减少以及自噬途径改变。越来越多的证据表明，骨关节炎会影响整个关节，包括软骨和软骨下骨。能够有效抑制软骨细胞降解和软骨下骨恶化的药物对于 OA 的预防和治疗至关重要。罗苏司他丁（RU）是一种具有活性的蛋白激酶 C 抑制剂，在糖尿病和各种与衰老相关的血管病变中应用时，可减少巨噬细胞黏附在内皮细胞上并缓解局部炎症，这是通过降低炎症细胞因子的表达和增加细胞抗氧化应激能力来实现的。然而，罗苏司他丁是否能预防 OA 尚不清楚。在这项研究中，我们通过防止软骨下骨骨量丢失，研究了罗苏司他丁在前交叉韧带切断（ACLT）诱导的 OA 模型中的治疗效果。我们发现，罗苏司他丁可以有效缓解 ACLT 诱导的骨关节炎，这表现在纠正由破骨细胞过度激活引起的早期骨关节炎病理性骨丢失和保护关节软骨退化方面。此外，我们发现罗苏司他丁通过抑制破骨细胞相关基因的表达和（PKCδ/MAPKs）信号级联来抑制破骨细胞的形成和吸收活性。综上所述，这些结果表明，罗苏司他丁可能是一种潜在的治疗药物，可用于挽救 OA 中异常的软骨下骨恶化和软骨降解，并逆转与骨关节炎相关的恶性循环。
