Smads及其相关转录因子与骨形态发生蛋白诱导成骨的信号传导

THE ROLE OF Smads AND RELATED TRANSCRIPTION FACTORS IN THE SIGNAL TRANSDUCTION OF BONE MORPHOGENETIC PROTEIN INDUCING BONE FORMATION

目的 综述有关骨形态发生蛋白 (BMPs)诱导成骨的信号传导机制 ,深入了解 BMPs基础及应用研究的理论依据。 方法 查阅近期相关文献 ,了解 BMPs相关蛋白 (Smads)及其相关转录因子在 BMPs诱导成骨的信号传导中的作用。 结果 BMPs的信号传导过程是 :BMPs首先与 型受体和 型受体结合 , 型受体磷酸化 Smads,Smads进入核内与转录因子相互作用影响相关蛋白的转录。Smads可分为受体调节 Smads(R- Smads:Smad1、2、3、5、8和9)、共同介导者 Smad(Co- Smad:Smad4 )和抑制性 Smads(I- Smads:Smad6、7)。 Smad1、Smad5和 Smad8,可能还有Smad9涉及 BMPs的信号传导。多种激酶如局部粘连激酶 (FAK)、Ras-细胞外信号调节激酶 (ERK)、磷脂酰肌醇 3激酶(PI3K)和 Akt丝 /苏氨酸激酶与 Smads的信号传导有关。与 Smad1和 Smad5相关的转录因子有核心结合蛋白 A1(CB-FA1)、Smad相互作用蛋白 1(SIP1)、鸟氨酸脱羧酶拮抗酶 (OAZ)、激活蛋白 - 1(AP- 1)、蟾蜍腹侧形成同源框蛋白 - 2(Xvent- 2 )、生长抑素 (Ski)、抗增殖蛋白 (Tob)、同源结构域转录因子 - 8(Hoxc- 8)等。CBFA1与转化生长因子 - β和 BMP- 2信号传导有关 ,能与 Smad1、2、3、5相互作用 ,在骨形成中起重要作用。锁骨、颅骨发育不良被认为是

Objective To clarify the mechanisms of the signal transduction of bone morphogenetic proteins (BMPs) inducing bone formation and to provide theoretical basis for basic and applying research of BMPs. Method We looked up the literature of the role of Smads and related transcription factors in the signal transduction of BMPs inducing bone formation. Results The signal transduction processes of BMPs included: ① BMPs combined with type Ⅱ and type Ⅰ receptors; ② the type Ⅰ receptor phosphorylated Smads; and ③ Smads entered the cell nucleus, interacted with transcription factors and influenced the transcription of related proteins. Smads could be divided into receptor regulated Smads (R Smads: Smad1, Smad2, Smad3, Smad5, Smad8 and Smad9), common mediator Smad (co Smad: Smad4) , and inhibitory Smads (I Smads: Smad6 and Smad7). Smad1, Smad5, Smad8, and probable Smad9 were involved in the signal transduction of BMPs. Multiple kinases, such as focal adhesion kinase (FAK), Ras extracellular signal regulated kinase (ERK), phosphatidylinositol 3 kinase (PI3K), and Akt serine/threonine kinase were related to Smads signal transduction. Smad1 and Smad5 related with transcription factors included core binding factor A1 (CBFA1), smad interacting protein 1(SIP1), ornithine decarboxylase antizyme(OAZ), activating protein 1(AP 1), xenopus ventralizing homeobox protein 2(Xvent 2), sandostatin(Ski), antiproliferative proteins(Tob), and homeodomain containing transcriptian factor 8(Hoxc 8), et al. CBFA1 could interact with Smad1, Smad2, Smad3, and Smad5, so it was involved in TGF β and BMP 2 signal transduction, and played an important role in the bone formation. Cleidocranial dysplasia (CCD) was thought to be caused by heterozygous mutations in CBFA1. The CBFA1 knockout mice showed no osteogenesis and had maturational disturbance of chondrocytes. Conclusion Smads and related transcription factors, especially Smad1, Smad5, Smad8 and CBFA1, play an important role in the signal transduction of BMPs inducing bone formation.