Li Xeufeng, Ionescu Andreia M, Schwarz Edward M, Zhang Xinping, Drissi Hicham, Puzas J Edward, Rosier Randy N, Zuscik Michael J, O'Keefe Regis J
Center for Musculoskeletal Research, Department of Orthopaedics, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, NY 14642, USA.
J Orthop Res. 2003 Sep;21(5):908-13. doi: 10.1016/S0736-0266(03)00008-1.
BMPs regulate cartilage differentiation and have been approved for clinical use as stimulators of bone repair. BMP signaling is complex and there are multiple potential points of regulation, including modulation of Smad signaling, which is inhibited by both Smad6 and Smad7. In the current manuscript we assessed the expression and biological function of Smad6 during chondrocyte differentiation. We found that the induction of chondrocyte differentiation by BMP-2 in chicken sternal embryonic chondrocytes was accompanied by a marked increase in Smad6 mRNA and protein levels. A morpholino antisense oligonucleotide complementary to Smad6 reduced the expression of Smad6 protein and enhanced the stimulatory effect of BMP-2 on both colX and alkaline phosphatase activity. In contrast, over-expression of Smad6 blocked BMP-2 mediated induction of the type X collagen promoter, b2-640 Luc. Therefore, expression studies as well as gain and loss of function experiments suggest that Smad6 participates in an important negative feedback loop whereby BMP-2 mediated effects on chondrocyte differentiation are reduced by induction of Smad6. Additional studies are required to determine the extent to which this pathway participates in pathologic processes involving cartilage.
骨形态发生蛋白（BMPs）调节软骨分化，已被批准作为骨修复刺激剂用于临床。BMP信号传导复杂，存在多个潜在调节点，包括对Smad信号传导的调节，而Smad信号传导受到Smad6和Smad7的抑制。在本手稿中，我们评估了Smad6在软骨细胞分化过程中的表达及生物学功能。我们发现，在鸡胸骨胚胎软骨细胞中，BMP-2诱导软骨细胞分化伴随着Smad6 mRNA和蛋白水平的显著增加。与Smad6互补的吗啉代反义寡核苷酸降低了Smad6蛋白的表达，并增强了BMP-2对X型胶原和碱性磷酸酶活性的刺激作用。相反，Smad6的过表达阻断了BMP-2介导的X型胶原启动子b2-640 Luc的诱导。因此，表达研究以及功能获得和丧失实验表明，Smad6参与了一个重要的负反馈环，通过诱导Smad6来降低BMP-2对软骨细胞分化的介导作用。需要进一步研究来确定该途径参与涉及软骨的病理过程的程度。
