Bone morphogenetic proteins
Bone morphogenetic proteins
复制标题
DOI：
10.1080/08977190412331279890
复制
发表时间：
2004-12-01
期刊：
影响因子：
1.8
通讯作者：
Mundy, GR
中科院分区：
文献类型：
--
作者：
Chen, D;Zhao, M;Mundy, GR
骨形态发生蛋白（BMP）是属于转化生长因子β（TGF β）超家族的多功能生长因子。近年来，骨形成蛋白在胚胎发育和出生后及成年动物细胞功能中的作用得到了广泛的研究。信号转导研究表明，Smad 1，5和8是BMP受体的直接下游分子，在BMP信号转导中起着核心作用。来自转基因和基因敲除小鼠以及来自在BMP和相关基因中天然发生突变的动物和人类的研究表明，BMP信号传导在心脏、神经和软骨发育中起关键作用。BMP在出生后骨形成中也起重要作用。BMP活性在不同的分子水平上受到调节。临床前和临床研究表明，BMP-2可用于各种治疗干预，如骨缺损、骨不连骨折、脊柱融合、骨质疏松症和根管手术。需要特异性BMP配体、BMP受体亚型或特异性信号分子的组织特异性敲除，以进一步确定BMP配体、受体或信号分子在特定组织中的特异性作用。BMP的活性在20世纪60年代首次被鉴定（Urist，MR.（1965）“Bone fort-nation by autoinduction”，Science 150，893-899），但是负责骨诱导的蛋白质直到20世纪80年代后期牛BMP-3（成骨蛋白）的纯化和测序以及人BMP-2和4的克隆之前仍然是未知的（Wozney，J.M.等人（1988）“Novel regulators of bone formation：molecular clones and activities”，Science 242，1528-1534; Luyten，F.P.等人（1989）“Purification and partial amino acid sequence of osteogenin，a protein initiating bone differentiation”，J.Biol.Chem.264，13377-13380; Wozney，J.M.（1992）“骨形态发生蛋白家族和成骨作用”，Mol. Reprod. Dev. 32，160-167）。迄今为止，已经鉴定和表征了大约20个BMP家族成员。BMP信号通过丝氨酸/苏氨酸激酶受体，由I型和II型亚型组成。已经显示三种I型受体结合BMP配体，IA和IB型BMP受体（BMPR-IA或ALK-3和BMPR-IB或ALK-6）和IA型激活素受体（ActR-IA或ALK-2）（Koenig，B.B.等人（1994）“Characterization and cloning of a receptor for BMP-2 and BMP-4 from NIH 3T3 cells”，Mol. Cell.等（1994）“Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4”，J Biol.Chem.269，16985-16988; Macias-Silva，M.等人（1998）“Specific activation of Smad1 signaling pathways by the BMP7 type I receptor，ALK2”，J.Biol.Chem.273，25628-25636）。还鉴定了BMP的三种II型受体，它们是II型BMP受体（BMPR-H）以及II型和IIB型激活素受体（ActR-II和ActR-IIB）（Yamashita，H.等人（1995）“Osteogenic protein-1 binds to activin type II receptor and induces certain activin-like effects”，J Cell. 130，217-226; Rosenzweig，B.L.等人（1995）“Cloning and characterization of a human type II receptor for bone morphogenetic proteins”，Proc. Natl Acad Sci. USA 92，7632-7636; Kawabata，M.等人（1995）“Cloning of a novel type II serine/threonine kinase receptor through interaction with the type I transforming growth factor-beta receptor”，J.Biol.Chem.270，5625-5630）。BMPR-IA、IB和H对BMP具有特异性，而ActR-IA、II和IIB也是激活素的信号传导受体。这些受体在各种组织中差异表达。I型和II型BMP受体都是信号转导不可或缺的。在配体结合后，它们形成由两对I型和II型受体复合物组成的异四聚体活化的受体复合物（Moustakas，A.和C. H. Heldi（2002）“From mono- to oligo-Smads：the heart of the matter in TGFbeta signal transduction”Genes Dev. 16，67-871）。I型BMP受体底物包括蛋白质家族，Smad蛋白，其在将BMP信号从受体传递到细胞核中的靶基因中起核心作用。Smad 1、5和8被BMP受体以配体依赖性方式磷酸化（Hoodless，P.A.等人（1996）“MADRl，a MAD-related protein that functions in BMP2 signaling pathways”，Cell 85，489-500; Chen Y等人（1997）“Smad8 mediates the signaling of the receptor serine kinase”，Proc. Natl Acad. Sci：USA 94，12938-12943; Nishimura R.等人（1998）“Smad 5和DPC 4是介导多能间充质前体细胞系C2 C12的BMP-2诱导的成骨细胞分化的关键分子”，J. Biol. Chem. 273，1872-1879）。从受体释放后，磷酸化的Smad蛋白与相关蛋白Smad 4结合，作为共享伴侣。这种复杂的translo 1）.近年来，对BMP配体、受体和信号分子的体内功能的认识取得了重大进展。
Bone morphogenetic proteins (BMPs) are multi-functional growth factors that belong to the transforming growth factor beta (TGFbeta) superfamily. The roles of BMPs in embryonic development and cellular functions in postnatal and adult animals have been extensively studied in recent years. Signal transduction studies have revealed that Smad1, 5 and 8 are the immediate downstream molecules of BMP receptors and play a central role in BMP signal transduction. Studies from transgenic and knockout mice and from animals and humans with naturally occurring mutations in BMPs and related genes have shown that BMP signaling plays critical roles in heart, neural and cartilage development. BMPs also play an important role in postnatal bone formation. BMP activities are regulated at different molecular levels. Preclinical and clinical studies have shown that BMP-2 can be utilized in various therapeutic interventions such as bone defects, non-union fractures, spinal fusion, osteoporosis and root canal surgery. Tissue-specific knockout of a specific BMP ligand, a subtype of BMP receptors or a specific signaling molecule is required to further determine the specific role of a BMP ligand, receptor or signaling molecule in a particular tissue.BMPs are members of the TGFbeta superfamily. The activity of BMPs was first identified in the 1960s (Urist, MR. (1965) "Bone fort-nation by autoinduction", Science 150, 893-899), but the proteins responsible for bone induction remained unknown until the purification and sequence of bovine BMP-3 (osteogenin) and cloning of human BMP-2 and 4 in the late 1980s (Wozney, J.M. et al. (1988) "Novel regulators of bone formation: molecular clones and activities", Science 242, 1528-1534; Luyten, F.P. et al. (1989) "Purification and partial amino acid sequence of osteogenin, a protein initiating bone differentiation", J. Biol. Chem. 264, 13377-13380; Wozney, J.M. (1992) "The bone morphogenetic protein family and osteogenesis", Mol. Reprod. Dev. 32, 160-167). To date, around 20 BMP family members have been identified and characterized. BMPs signal through serine/threonine kinase receptors, composed of type I and II subtypes. Three type I receptors have been shown to bind BMP ligands, type IA and IB BMP receptors (BMPR-IA or ALK-3 and BMPR-IB or ALK-6) and type IA activin receptor (ActR-IA or ALK-2) (Koenig, B.B. et al. (1994) "Characterization and cloning of a receptor for BMP-2 and BMP-4 from NIH 3T3 cells", Mol. Cell. Biol. 14, 5961-5974; ten Dijke, P. et al. (1994) "Identification of type I receptors for osteogenic protein-l and bone morphogenetic protein-4", J Biol. Chem. 269, 16985-16988; Macias-Silva, M. et al. (1998) "Specific activation of Smad1 signaling pathways by the BMP7 type I receptor, ALK2", J. Biol. Chem. 273, 25628-25636). Three type II receptors for BMPs have also been identified and they are type II BMP receptor (BMPR-H) and type II and IIB activin receptors (ActR-II and ActR-IIB) (Yamashita, H. et al. (1995) "Osteogenic protein-1 binds to activin type II receptors and induces certain activin-like effects", J Cell. Biol. 130, 217-226; Rosenzweig, B.L. et al. (1995) "Cloning and characterization of a human type II receptor for bone morphogenetic proteins", Proc. Natl Acad Sci. USA 92, 7632-7636; Kawabata, M. et al. (1995) "Cloning of a novel type II serine/threonine kinase receptor through interaction with the type I transforming growth factor-beta receptor", J. Biol. Chem. 270, 5625-5630). Whereas BMPR-IA, IB and H are specific to BMPs, ActR-IA, II and IIB are also signaling receptors for activins. These receptors are expressed differentially in various tissues. Type I and II BMP receptors are both indispensable for signal transduction. After ligand binding they form a heterotetrameric-activated receptor complex consisting of two pairs of a type I and II receptor complex (Moustakas, A. and C.H. Heldi (2002) "From mono- to oligo-Smads: the heart of the matter in TGFbeta signal transduction" Genes Dev. 16, 67-871). The type I BMP receptor substrates include a protein family, the Smad proteins, that play a central role in relaying the BMP signal from the receptor to target genes in the nucleus. Smad 1, 5 and 8 are phosphorylated by BMP receptors in a ligand-dependent manner (Hoodless, P.A. et al. (1996) "MADR1, a MAD-related protein that functions in BMP2 signaling pathways", Cell 85, 489-500; Chen Y et al. (1997) "Smad8 mediates the signaling of the receptor serine kinase", Proc. Natl Acad. Sci: USA 94, 12938-12943; Nishimura R. et al. (1998) "Smad5 and DPC4 are key molecules in mediating BMP-2-induced osteoblastic differentiation of the pluripotent mesenchymal precursor cell line C2C12", J. Biol. Chem. 273, 1872-1879). After release from the receptor, the phosphorylated Smad proteins associate with the related protein Smad4, which acts as a shared partner. This complex translo1). A significant advancement about the understanding of in vivo functions of BMP ligands, receptors and signaling molecules has been achieved in recent years.