骨形态发生蛋白诱骨发生过程中TGF-β1和bFGF的表达

目的 :研究转化生长因子 -β1(TGF β1)和碱性成纤维细胞生长因子 (bFGF)在骨形态发生蛋白 (BMP)诱骨发生过程中的表达情况。方法 :应用免疫组化方法检测TGF β1、bFGF和增殖细胞核抗原 (PCNA)在BMP植入小鼠股部肌肉后不同天数的表达情况。结果 :术后早期聚集的大量间充质细胞只表达PCNA ,而不表达TGF β1和bFGF ,但随着间充质细胞分化为前软骨细胞并不断成熟 ,两因子的表达水平迅速提高。TGF β1在成熟软骨细胞中的表达最活跃 ,之后开始下降 ,而bFGF在成熟软骨细胞进入钙化期后仍为高表达。成骨细胞中TGF β1和bFGF的表达均不活跃。结论 :TGF β1和bFGF在BMP诱骨发生的软骨细胞阶段有强烈表达 ,在间充质细胞和成骨细胞中不表达或低表达     

骨形态发生蛋白2/7异源二聚体的研究进展

骨形态发生蛋白2/7（BMP2/7）异源二聚体,较其同源二聚体具有更强的诱导成骨潜能,是目前组织工程骨研究的重要分支之一。本文介绍了异源二聚体BMP2/7诱导成骨的相关实验,比较其与同源二聚体生物活性的差异,并对相关机制进行综述。     

骨形态发生蛋白的临床应用方法研究进展

骨形态发生蛋白(BMP)是转化生长因子(TGF-β)大家族中的一员,其在骨发生、骨诱导、骨修复和骨量保持方面发挥着重要而关键的作用。BMP表达水平的高低直接影响间充质骨祖细胞分化和骨量产生水平。研究发现内源性与外源性BMP均能发挥促进成骨作用,所以BMP被很快引入修复骨缺损、促进骨折愈合、椎体融合、假体固定等领域,并已有成熟产品问世。本文就目前BMP临床应用的主要手段(包括局部植入BMP缓释载体、闭合局部注入及体内导入BMP基因治疗)与临床研究现状进行了综述。     

成纤维细胞生长因子增强骨形态发生蛋白在小鼠体内骨诱导作用

在啮类动物体内植入骨形态发生蛋白后，引起细胞内一系列生化和形态学变化，在植入物内和其周转形成新骨。这过程受多因素影响。本实验将重组人成纤维细胞生长因子与部分纯化的ＢＭＰ悬液混合后注入小鼠肌肉，观察成骨反应。单独注射牛骨ＢＭＰ组和ｂＦＧＦ组为对照。     

Smads在骨形态发生蛋白诱导成骨中的作用

Smads蛋白是骨形态发生蛋白细胞内信号传导中起重要作用的转录因子,在骨形态发生蛋白诱导骨形成中发挥着关键作用.骨形态发生蛋白可以激活多种Smads蛋白并使其转移至细胞核,通过直接与特定DNA序列相结合、与核调节因子形成复合体、募集转录共活化或共抑制因子等3种方式调节目的基因的转录,最终诱导骨形成.该文就Smads蛋白的定义与分类、Smads信号转导通路及其在骨形态发生蛋白诱导成骨中的作用机制、BMP/Smads信号调节通路与其他通路之间的关系等相关研究作一综述.     

骨发生相关因子基因转导在骨组织工程中的研究进展

自1965年Urist报道用脱钙骨基质植入肌肉诱导基质细胞分化形成新骨以来，骨组织工程得到迅速发展，组织工程组织的构建设计也日趋成熟，支架材料与种子细胞加生长因子被认为是组织工程中的3大经典要素组合，是骨组织工程的研究热点之一。但生长因子单纯同支架材料与种子细胞复合修复组织缺损存在易受血液稀释、酶解，释放时间及浓度不易控制等缺陷。     

血管内皮生长因子在骨形态发生蛋白-2诱导成骨过程中的表达

目的探讨血管内皮生长因子（VEGF）在骨形态发生蛋白-2（BMP-2）诱导成骨过程中的表达。方法采用昆明鼠20只，外科手术建立股部肌袋诱导成骨模型，以左侧为实验组，右侧为对照组。实验组肌袋内植入以明胶和羟基磷灰石复合物为载体的重组人骨形态发生蛋白（rh-BMP）-20．25mg；对照组仅植入空白载体。分别于术后3、7、14和21d取材，采用免疫组织化学和Western blot法检测VEGF的表达情况。结果术后3d可见大量问充质细胞聚集，胞质出现VEGF的表达（Western blot IA=4221．323±178．672），但随着间充质细胞分化为前软骨细胞并不断成熟，VEGF在间充质细胞内的表达逐渐消失，而在成软骨细胞和软骨细胞内的表达水平迅速提高（Western blot IA=7139．558±289．347），VEGF在成熟软骨细胞中的表达最为活跃（Western blot IA=15849．848±137．462），至到新骨形成，在成骨细胞和骨细胞中仍可检测到VEGF的强烈表达（Westernbid IA=9463．268±548．453）；而对照组则未检测到VEGF的表达。结论VEGF的表达贯穿BMP-2诱导成骨的全过程，并在成熟软骨细胞和成骨细胞呈现强烈表达；BMP-2具有促进VEGF合成与分泌的作用．rhBMP-2对成骨细胞VEGF表达的促进作用。     

骨形态发生蛋白研究新进展

自１９６５年Ｕｒｉｓｔ首先证实脱钙骨基质具有诱导成骨能力后,人们在纯化脱钙骨移植物活性成分的过程中发现了骨形态发生蛋白（ｂｏｎｅｍｏｒｐｈｏｇｅｎｅｔｉｃｐｒｏｔｅｉｎ,ＢＭＰ）家族。在过去的１０年间,随着基因工程技术的广泛应用,ＢＭＰ在胚胎发育、机体疾病、创伤愈合等方面的作用日益受到关注。本文重点对其分子生物学特性及在矫形外科中的应用新进展作一综述。１　ＢＭＰ及其受体（ＢＭＰＲ）的分子生物学随着重组ＤＮＡ技术的运用,目前已有１６种不同的ＢＭＰｃＤＮＡ被克隆（见表１）,除ＢＭＰ－１外均属于转化…     

骨形态发生蛋白在骨折愈合中的作用

骨折愈合是一个复杂的组织学变化过程,涉及一系列不同的细胞活动,自1965年Urist提出骨诱导学说,并相继提纯骨形态发生蛋白(BMP)以来,对骨的再生修复均有了进一步的认识,并已开始将BMP初步应用于临床实践治疗骨不连接及骨缺损。对内源性BMP在骨折修复中的作用机制尚不清楚。本文应用骨形态发生蛋白单克隆抗体检测骨折愈合过程中外骨痂内BMP的分布及细胞定位,探讨BMP在闭合性骨折愈合外骨痂形成中的作用,以期对闭合性骨折之愈合获得进一步的认识。     

The family of bone morphogenetic proteins

The family of bone morphogenetic proteins. Bone morphogenetic proteins (BMPs) are secreted signaling molecules belonging to the transforming growth factor-beta (TGF-beta) superfamily of growth factors. The first BMPs were originally identified by their ability to induce ectopic bone formation when implanted under the skin of rodents. In this ectopic overexpression assay, there was a recapitulation of all the events occurring during skeletogenesis. This latter aspect indicated that these molecules could play important roles during development. More than 30 BMPs have been identified to date. The study of their expression pattern as well as the analysis of spontaneously mutated or genetically depleted mice have demonstrated a much broader range of function. These activities are mainly localized at sites of epithelial-mesenchymal interactions, including but not restricted to the skeleton. This review presents our current knowledge about the functions of BMPs during skeleton development as well as in many other biologic processes.     

成体干细胞在骨组织工程中的应用

种子细胞的来源、分离纯化、规模化扩增和保持体内成骨活性等是制约骨组织工程研究与应用发展的重要瓶颈问题之一.干细胞研究的进展和突破给骨组织工程种子细胞的选择带来了新希望.该文在论述骨组织工程对种子细胞要求的基础之上,对成体干细胞与胚胎干细胞进行比较,并对研究较多的骨髓间充质干细胞、脂肪干细胞、外周血干细胞及新近提取的胎盘来源干细胞的生物学特性、成骨能力、临床应用及其在骨组织工程中的应用前景进行阐述与讨论,以最终实现根据临床实际需要而选择合适的种子细胞的目标.     

Development and application of bone morphogenetic proteins for the enhancement of bone healing

Abstract Bone morphogenetic proteins are multifunctional cytokines and members of the transforming growth factor- superfamily. They include the only signaling molecules that can singly induce de novo bone formation at orthotopic and heterotopic sites. Their osteoinductive potency and ability to enhance or accelerate bone healing has been demonstrated in animal models of human orthopedic injuries and diseases, and in human clinical orthopedic patients. Recombinant human bone morphogenetic proteins 2 and 7 have recently received the approval of regulatory agencies for the clinical treatment of selected human acute long bone fractures and nonunions, as well as lumbar fusion. It is likely that additional indications will be approved as supportive data for the proteins efficacy in the treatment of specific orthopedic conditions are generated. In addition to the type I collagen presently being used clinically as a locally implantable delivery vehicle for bone morphogenetic proteins, mineral, synthetic polymer, and extracellular matrix components continue to be tested as alternative matrices. Other means of bone morphogenetic protein delivery undergoing preliminary evaluation include gene transfer therapy and systemic administration.     

Bone morphogenetic proteins in bone tumors

Bone morphogenetic proteins (BMPs), inducers of ectopic bone formation in vivo, are present in a number of osteosarcomas. BMPs are responsible for reactive bone formation, including periosteal reactions by normal osteoblasts, rather than production of tumorous osteoid by tumor cells. Osteosarcomas producing BMPs contain less-differentiated mesenchymal cells, resulting in a poorer prognosis for those patients. BMPs are also expressed in malignant fibrous histiocytomas (MFHs) of bone and dedifferentiated chondrosarcomas exhibiting undifferentiated features. However, BMPs in MFH do not show any osteoinductive activity in vivo, suggesting that those BMPs may be inactive forms and have additional functions unrelated to bone formation. Among benign bone tumors, BMPs are expressed in osteoid osteomas or osteoblastomas and effect reactive bone formation such as a surrounding sclerosis. BMPs and a BMP receptor (BMPRIB) are also detected in the cartilage cap in osteochondroma, suggesting that BMP signaling via BMPRIB might be involved in the pathogenesis of osteochondroma. Clinically, BMPs have utility as diagnostic and prognostic markers for characterizing the stage of differentiation of mesenchymal cells and mesenchymal tumors, and they may be of value in predicting the prognosis of sarcoma patients. This article reviews the accumulated information on BMPs in bone tumors, including the most recent findings, and discusses the biological and clinical significance of BMPs in bone tumors.Presented at the 36th Annual Musculoskeletal Tumor Meeting of the Japanese Orthopaedic Association, Kobe, Japan, July 2003     

Recent advances toward the clinical application of bone morphogenetic proteins in bone and cartilage repair

Inefficient healing of bony and cartilaginous defects is a common situation encountered by orthopedic surgeons. Enhancing the regenerative potential of bone and articular cartilage has the potential for profound applications in treatment of nonunions, large segmental bone and cartilage defects, and arthritis. The bone morphogenetic proteins (BMPs) encode a highly conserved class of signaling factors that possess the ability to induce ectopic cartilage and bone formation in vivo. Bone morphogenetic protein family members are expressed during limb development, endochondral ossification, and early fracture and cartilage repair. Loss-of-function and gain-of-function studies have demonstrated the necessity and sufficiency of these genes, respectively, in regulating both cartilage and bone development. Several recent animal studies have demonstrated the potential of BMPs to enhance spinal fusion, repair critical-size defects, accelerate union, and heal articular cartilage lesions. A limited number of clinical trials using BMPs in human beings have been reported, and these agents are currently available for clinical use within and outside the United States. Current challenges to be met are the development of efficient delivery systems to present BMP proteins or genes to target sites and to enhance their duration and function at these locations.     

Use of bone morphogenetic proteins in traumatology

An estimated 5–10% of all fractures show impaired healing, leading to delayed union, or non-union. Chemical, or physical methods to accelerate bone healing are of great interest to the orthopaedic and trauma community. Research over the last 20 years has established that successful fracture healing is steered by specific growth factors. Of these, the bone morphogenetic proteins (BMPs) are probably the most important. The signalling pathway of these proteins is tightly regulated, overseeing a finely orchestrated cascade of events that occur after a fracture. The promising results of BMPs in preclinical studies have recently cleared the way for their use in specific fractures, or non-unions in clinical practice. The purpose of this work is to give a brief overview of BMPs and to review the clinical data currently available on the use of BMPs in fracture healing.     

The role of human bone morphogenetic proteins in spinal fusion

The attainment of a stable arthrodesis is critical to the successful management of some types of spinal disorders. Autologous iliac-crest bone graft has been the most commonly utilized substance associated with predictable healing in spinal fusion applications. Although alternative graft substances exist, these have not been shown to be as uniformly effective in achieving spinal fusion. Because of the morbidity associated with bone autograft harvest, there is increasing interest in alternative graft substances and especially in the osteoinductive abilities of bone morphogenetic proteins (BMPs). Several animal models have demonstrated that BMP-containing allograft or synthetic carrier medium is as effective as or superior to autograft bone in promoting spinal fusion. Furthermore, the limited number of human trials utilizing BMPs to treat nonunions in the appendicular skeleton indicate that the results found in animal models will be reproducible in the clinical setting.     

大鼠颅骨缺损模型在骨组织工程中的应用

目前，颅、颌面骨缺损的修复对于整形外科和口腔颌面外科的治疗仍是挑战。用于修复骨缺损的骨移植材料若想应用于临床，必须要具备可充分提高体内骨愈合能力的组织学证据，而通过不同方法将不同的骨移植材料进行动物实验不失为一种行之有效的检测方法。但如果在实验动物模型的选择上缺乏一致性，则很难客观地比较各种移植物之间的修复效果，只有采用标准动物模型才能有效地对其效果进行评估。