Sonic hedgehog regulates osteoblast function by focal adhesion kinase signaling in the process of fracture healing.
Sonic hedgehog regulates osteoblast function by focal adhesion kinase signaling in the process of fracture healing.
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DOI：
10.1371/journal.pone.0076785
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sasaki A
中科院分区：
文献类型：
--
作者：
Horikiri Y;Shimo T;Kurio N;Okui T;Matsumoto K;Iwamoto M;Sasaki A
一些生物学研究表明，Hedgehog信号在成骨细胞的增殖和分化中起重要作用，Sonic Hedgehog(SHH)的表达与磷酸化粘着斑激酶(FAK)Tyr397呈正相关。然而，它们之间的关系以及它们在正常骨折修复过程中的作用尚不清楚。免疫组织化学分析显示，骨折后第5天小鼠肋骨骨折处破骨细胞附近碱性磷酸酶阳性的成骨细胞表达SHH和pFAK Tyr397，碱性磷酸酶阳性的成骨细胞也表达pFAK Tyr397。第14天，SHH和pFAK Tyr397在肥大软骨细胞附近的成骨细胞中可检测到。体外分析表明，SHH上调成骨细胞MC3T3-E1细胞FAK mRNA和pFAK Tyr397的表达，并呈时间依赖性。功能分析显示，编码短发夹状FAK RNAs(ShFAK)的5个慢病毒感染的MC3T3-E1细胞组细胞形态呈圆形，细胞增殖、黏附、迁移和分化能力下降。Shh可促进MC3T3-E1细胞的增殖和分化，但对感染shFAK的细胞无明显影响。Shh还可促进MC3T3-E1和小鼠CD11b+骨髓细胞共培养体系中破骨细胞的形成，但不影响shFAK感染的MC3T3-E1共培养组。这些数据表明，SHH信号在骨折动态重塑部位的成骨细胞中被激活，并通过FAK信号调节其增殖和分化以及破骨细胞的形成。
Several biological studies have indicated that hedgehog signaling plays an important role in osteoblast proliferation and differentiation, and sonic hedgehog (SHH) expression is positively correlated with phosphorylated focal adhesion kinase (FAK) Tyr397. However, the relationship between them and their role in the process of normal fracture repair has not been clarified yet. Immunohistochemical analysis revealed that SHH and pFAK Tyr397 were expressed in bone marrow cells and that pFAK Tyr397 was also detected in ALP-positive osteoblasts near the TRAP-positive osteoclasts in the fracture site in the ribs of mice on day 5 after fracture. SHH and pFAK Tyr397 were detectable in osteoblasts near the hypertrophic chondrocytes on day 14. In vitro analysis showed that SHH up-regulated the expression of FAK mRNA and pFAK Tyr397 time dependently in osteoblastic MC3T3-E1 cells. Functional analysis revealed that 5 lentivirus encoding short hairpin FAK RNAs (shFAK)-infected MC3T3-E1 cell groups displayed a round morphology and decreased proliferation, adhesion, migration, and differentiation. SHH stimulated the proliferation and differentiation of MC3T3-E1 cells, but had no effect on the shFAK-infected cells. SHH also stimulated osteoclast formation in a co-culture system containing MC3T3-E1 and murine CD11b+ bone marrow cells, but did not affect the shFAK-infected MC3T3-E1 co-culture group. These data suggest that SHH signaling was activated in osteoblasts at the dynamic remodeling site of a bone fracture and regulated their proliferation and differentiation, as well as osteoclast formation, via FAK signaling.
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