First Department of Pathology, Wakayama Medical University School of Medicine, 811-1 Kimiidera, Wakayama 641-0012, Japan.
Exp Mol Pathol. 2011 Feb;90(1):107-15. doi: 10.1016/j.yexmp.2010.10.011. Epub 2010 Oct 28.
Smad3 is an intracellular signaling molecule in the transforming growth factor β (TGF-β) pathway that serves as a regulator of chondrogenesis and osteogenesis. To investigate the role of the TGF-β/Smad3 signaling in the process of fracture healing, an open fracture was introduced in mouse tibiae, and the histology of the healing process was compared between wild-type (WT) and Smad3-null (KO) mice. In KO mice, the bone union formed more rapidly with less formation of cartilage in the callus and eventually the fracture was repaired more rapidly than in WT mice. Alkaline phosphatase staining showed that osteoblastic differentiation in the fracture callus was promoted in KO mice. Additionally, TRAP staining and the TUNEL assay revealed that the induction of osteoclasts and apoptotic cells was significantly promoted in the healing callus of KO mice. Sox9 expression clearly decreased at both mRNA and protein levels in the early stage of fracture in KO mice. In contrast, the expression of genes for osteogenesis and osteoclast formation increased from day 5 until day 14 post-fracture in KO mice compared to WT mice. From these results, we concluded that the loss of TGF-β/Smad3 signaling promoted callus formation by promoting osteogenesis and suppressing chondrogenesis, which resulted in faster fracture healing.
Smad3 是转化生长因子 β（TGF-β）通路中的一种细胞内信号分子，作为软骨生成和骨生成的调节剂。为了研究 TGF-β/Smad3 信号在骨折愈合过程中的作用，在小鼠胫骨中引入开放性骨折，并比较野生型（WT）和 Smad3 缺失型（KO）小鼠的愈合过程的组织学。在 KO 小鼠中，骨结合形成得更快，骨痂中软骨形成较少，最终骨折修复速度比 WT 小鼠更快。碱性磷酸酶染色显示 KO 小鼠骨折骨痂中的成骨细胞分化得到促进。此外，TRAP 染色和 TUNEL 检测显示，KO 小鼠愈合骨痂中的破骨细胞和凋亡细胞的诱导明显增强。在 KO 小鼠的骨折早期，Sox9 的表达在 mRNA 和蛋白水平上均明显降低。相比之下，与 WT 小鼠相比，KO 小鼠的成骨基因和破骨细胞形成基因的表达从骨折后第 5 天增加到第 14 天。从这些结果可以得出结论，TGF-β/Smad3 信号的缺失通过促进成骨和抑制软骨生成来促进骨痂形成，从而导致更快的骨折愈合。
