The Hospital for Rheumatic Diseases, Hanyang University, Seoul, South Korea.
Med Hypotheses. 2012 Dec;79(6):757-60. doi: 10.1016/j.mehy.2012.08.022. Epub 2012 Sep 8.
Inflammatory bone destruction is a prominent feature and a cause of substantial morbidity in several inflammatory diseases, including rheumatoid arthritis (RA), periodontitis, and peri-prosthetic loosening. Osteoclasts are unique, multinucleated giant cells that effectively resorb bone and thus are directly responsible for bone destruction in several inflammatory diseases. PI3K/Akt/mTOR pathway has been well known to play important roles in regulating adaptive and innate immune cell function. In addition to play roles in immune responses, several lines of evidence demonstrate that PI3K/Akt/mTOR pathway is critical for osteoclast differentiation and survival. These results suggest that inhibition of PI3K/Akt/mTOR pathway could protect against bone destruction in inflammatory diseases, including RA. However, the clinical use of mTOR inhibitors may be hampered due to limited clinical efficacy and frequent toxic side effects. In the treatment of RA, combination therapy with various disease-modifying antirheumatic drugs (DMARDs) has been suggested to improve the therapeutic efficacy and limit the side effects. In this report, we show several experimental evidences that vitamin D(3) modulates mTOR pathway, and present a hypothesis that the combination of mTOR inhibitor and vitamin D(3) can effectively inhibit osteoclast differentiation and function in chronic inflammatory condition such as RA, therefore this combination will be a powerful therapeutic regimen in preventing the inflammation-induced bone destruction in RA.
炎症性骨破坏是几种炎症性疾病的一个显著特征和主要发病原因，包括类风湿关节炎（RA）、牙周炎和假体松动。破骨细胞是一种独特的多核巨细胞，能够有效地吸收骨骼，因此直接负责几种炎症性疾病中的骨破坏。PI3K/Akt/mTOR 通路在调节适应性和先天免疫细胞功能方面起着重要作用，这一点已经得到了充分的认识。除了在免疫反应中发挥作用外，有几条证据表明，PI3K/Akt/mTOR 通路对于破骨细胞的分化和存活至关重要。这些结果表明，抑制 PI3K/Akt/mTOR 通路可以预防炎症性疾病中的骨破坏，包括 RA。然而，由于临床疗效有限和频繁的毒性副作用，mTOR 抑制剂的临床应用可能会受到阻碍。在 RA 的治疗中，联合使用各种疾病修饰抗风湿药物（DMARDs）已被建议用于提高治疗效果并限制副作用。在本报告中，我们展示了维生素 D(3) 调节 mTOR 通路的几个实验证据，并提出了一个假设，即 mTOR 抑制剂和维生素 D(3)的联合使用可以有效地抑制慢性炎症状态下（如 RA）的破骨细胞分化和功能，因此这种联合将是预防 RA 中炎症引起的骨破坏的一种强大治疗方案。
