van den Bosch Martijn H, Blom Arjen B, Sloetjes Annet W, Koenders Marije I, van de Loo Fons A, van den Berg Wim B, van Lent Peter L, van der Kraan Peter M
Department of Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.
Department of Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.
Am J Pathol. 2015 Jul;185(7):1970-80. doi: 10.1016/j.ajpath.2015.03.013. Epub 2015 May 12.
Proteins from the Wnt signaling pathway are very important for joint development. Curiously, osteoarthritis (OA) is thought to be a recapitulation of developmental processes. Various members of the Wnt signaling pathway are overexpressed in the synovium during experimental OA. Here, we investigated the potency of specific Wnt proteins, when expressed in the synovium, to induce OA pathology. We overexpressed Wnt5a, Wnt8a, Wnt16, and WISP1 in the synovium using adenoviral vectors. We determined whether overexpression resulted in OA pathology by histology, and we measured whether Wnt signaling led to increased protease activity in the joint. Synovial overexpression of Wnt8a and Wnt16 led to canonical Wnt signaling in the cartilage, whereas overexpression of Wnt5a did not. Canonical Wnt signaling increased protease activity and induced cartilage damage shortly after overexpression. Specific blocking of the canonical Wnt signaling pathway with Dickkopf-1 reduced the Wnt-signaling-induced cartilage damage. By contrast, the noncanonical signaling Wnt5a did not cause cartilage lesions. Overexpression of WISP1, a downstream protein of canonical Wnt signaling, resulted in increased cartilage damage. In conclusion, our data show that canonical Wnts and WISP1, which we found overexpressed in the synovium during experimental OA, may conduce to OA pathology.
Wnt信号通路中的蛋白质对关节发育非常重要。奇怪的是，骨关节炎（OA）被认为是发育过程的重演。在实验性骨关节炎期间，Wnt信号通路的各种成员在滑膜中过度表达。在此，我们研究了特定Wnt蛋白在滑膜中表达时诱导骨关节炎病理的能力。我们使用腺病毒载体在滑膜中过度表达Wnt5a、Wnt8a、Wnt16和WISP1。我们通过组织学确定过度表达是否导致骨关节炎病理，并且我们测量了Wnt信号是否导致关节中蛋白酶活性增加。Wnt8a和Wnt16在滑膜中的过度表达导致软骨中的经典Wnt信号传导，而Wnt5a的过度表达则没有。经典Wnt信号传导在过度表达后不久增加了蛋白酶活性并诱导了软骨损伤。用Dickkopf-1特异性阻断经典Wnt信号通路可减少Wnt信号传导诱导的软骨损伤。相比之下，非经典信号传导的Wnt5a不会导致软骨病变。经典Wnt信号传导的下游蛋白WISP1的过度表达导致软骨损伤增加。总之，我们的数据表明，我们发现在实验性骨关节炎期间滑膜中过度表达的经典Wnts和WISP1可能导致骨关节炎病理。
