Chen Rebecca, Mian Michelle, Fu Martin, Zhao Jing Ying, Yang Liang, Li Yefu, Xu Lin
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts.
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts; Faculty of Medicine, Harvard Medical School, Boston, Massachusetts.
Am J Pathol. 2015 Nov;185(11):2875-85. doi: 10.1016/j.ajpath.2015.07.003. Epub 2015 Sep 4.
Transforming growth factor beta 1 (TGF-β1) is implicated in osteoarthritis. We therefore studied the role of TGF-β1 signaling in the development of osteoarthritis in a developmental stage-dependent manner. Three different mouse models were investigated. First, the Tgf-β receptor II (Tgfbr2) was specifically removed from the mature cartilage of joints. Tgfbr2-deficient mice were grown to 12 months of age and were then euthanized for collection of knee and temporomandibular joints. Second, Tgfbr2-deficient mice were subjected to destabilization of the medial meniscus (DMM) surgery. Knee joints were then collected from the mice at 8 and 16 weeks after the surgery. Third, wild-type mice were subjected to DMM at the age of 8 weeks. Immediately after the surgery, these mice were treated with the Tgfbr2 inhibitor losartan for 8 weeks and then euthanized for collection of knee joints. All joints were characterized for evidences of articular cartilage degeneration. Initiation or acceleration of articular cartilage degeneration was not observed by the genetic inactivation of Tgfbr2 in the joints at the age of 12 months. In fact, the removal of Tgfbr2 and treatment with losartan both delayed the progression of articular cartilage degeneration induced by DMM compared with control littermates. Therefore, we conclude that inhibition of Tgf-β1 signaling protects adult knee joints in mice against the development of osteoarthritis.
转化生长因子β1（TGF-β1）与骨关节炎有关。因此，我们以发育阶段依赖性方式研究了TGF-β1信号传导在骨关节炎发展中的作用。研究了三种不同的小鼠模型。首先，从关节的成熟软骨中特异性去除Tgf-β受体II（Tgfbr2）。将Tgfbr2基因敲除小鼠饲养至12个月龄，然后实施安乐死以收集膝关节和颞下颌关节。其次，对Tgfbr2基因敲除小鼠进行内侧半月板不稳定（DMM）手术。然后在手术后8周和16周从这些小鼠收集膝关节。第三，在8周龄时对野生型小鼠进行DMM手术。手术后立即用Tgfbr2抑制剂氯沙坦治疗这些小鼠8周，然后实施安乐死以收集膝关节。对所有关节进行表征以寻找关节软骨退变的证据。在12个月龄时，未观察到关节中Tgfbr2基因失活引发或加速关节软骨退变。事实上，与对照同窝小鼠相比，去除Tgfbr2和用氯沙坦治疗均延迟了DMM诱导的关节软骨退变的进展。因此，我们得出结论，抑制TGF-β1信号传导可保护小鼠成年膝关节免受骨关节炎的发展。
