Yu Xiaodan, Kawakami Hiroko, Tahara Naoyuki, Olmer Merissa, Hayashi Shinichi, Akiyama Ryutaro, Bagchi Anindya, Lotz Martin, Kawakami Yasuhiko
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, 55455.
Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota.
J Orthop Res. 2017 Aug;35(8):1671-1682. doi: 10.1002/jor.23463. Epub 2016 Nov 8.
Increasing evidence supports the idea that bone morphogenetic proteins (BMPs) regulate cartilage maintenance in the adult skeleton. The aim of this study is to obtain insight into the regulation of BMP activities in the adult skeletal system. We analyzed expression of Noggin and Gremlin1, BMP antagonists that are known to regulate embryonic skeletal development, in the adult skeletal system by Noggin-LacZ and Gremlin1-LacZ knockin reporter mouse lines. Both reporters are expressed in the adult skeleton in a largely overlapping manner with some distinct patterns. Both are detected in the articular cartilage, pubic symphysis, facet joint in the vertebrae, and intervertebral disk, suggesting that they regulate BMP activities in these tissues. In a surgically induced knee osteoarthritis model in mice, expression of Noggin mRNA was lost from the articular cartilage, which correlated with loss of BMP2/4 and pSMAD1/5/8, an indicator of active BMP signaling. Both reporters are also expressed in the sterna and rib cartilage, suggesting an extensive role of BMP antagonism in adult cartilage tissue. Moreover, Noggin-LacZ was detected in sutures in the skull and broadly in the nasal cartilage, while Gremlin1-LacZ exhibits a weaker and more restricted expression domain in the nasal cartilage. These results suggest broad regulation of BMP activities by Noggin and Gremlin1 in cartilage tissues in the adult skeleton, and that BMP signaling and its antagonism by NOGGIN play a role in osteoarthritis development. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1671-1682, 2017.
越来越多的证据支持骨形态发生蛋白（BMPs）调节成年骨骼中软骨维持的观点。本研究的目的是深入了解成年骨骼系统中BMP活性的调节机制。我们通过Noggin-LacZ和Gremlin1-LacZ基因敲入报告基因小鼠品系，分析了已知调节胚胎骨骼发育的BMP拮抗剂Noggin和Gremlin1在成年骨骼系统中的表达情况。两种报告基因在成年骨骼中的表达在很大程度上相互重叠，但也有一些不同的模式。在关节软骨、耻骨联合、椎骨小关节和椎间盘均检测到二者的表达，提示它们在这些组织中调节BMP活性。在小鼠手术诱导的膝骨关节炎模型中，关节软骨中Noggin mRNA的表达消失，这与BMP2/4和pSMAD1/5/8的缺失相关，pSMAD1/5/8是BMP信号激活的一个指标。两种报告基因在胸骨和肋软骨中也有表达，提示BMP拮抗作用在成年软骨组织中具有广泛作用。此外，在颅骨缝线和广泛的鼻软骨中检测到Noggin-LacZ，而Gremlin1-LacZ在鼻软骨中的表达较弱且范围较窄。这些结果提示Noggin和Gremlin1在成年骨骼软骨组织中对BMP活性具有广泛调节作用，且BMP信号及其被Noggin的拮抗作用在骨关节炎发展中发挥作用。© 2016骨科研究学会。由Wiley Periodicals, Inc.出版。《骨科研究杂志》35:1671 - 1682, 2017。
