FUNCTIONAL ROLE OF TNF-ALPHA CYTOKINES IN BONE REPAIR

描述(改编自《调查者摘要》)：术后骨修复 损伤或手术是一种特殊类型的伤口修复反应，其中骨骼 是为了支持机械载荷而重新生成的。而当 骨修复的过程通常被认为是生物上最优的， 在估计发生的620万个骨折中，有5%到10%是愈合的 在美国，每年都会出现延迟或受损的情况。因此，为了减少 与骨折相关的发病率，并提供更好的控制 与其他重建矫形手术相关的愈合反应， 需要对骨愈合的生物学有更好的理解。数不胜数 研究的重点是细胞因子作为骨骼修复的媒介。细胞因子 可分为三个亚家族：半胱氨酸结生长因子、螺旋 细胞因子和肿瘤坏死因子。肿瘤坏死因子家族 细胞因子已被证明在骨的调节中是必不可少的 改建。我们已经证明，转基因小鼠在P55和P55两个基因上都存在缺陷 和p75肿瘤坏死因子-α受体显示骨修复延迟，缺乏 膜内骨形成，但促进软骨内骨形成和 软骨内软骨摘除失败。的中心假说 这一建议是，肿瘤坏死因子-α提供关键的调节信号，控制 钙化软骨的吸收及其对骨密度的影响 软骨内骨组织修复过程中的成骨作用。这样做的目的是 建议是确定细胞和分子机制，通过 肿瘤坏死因子-α在骨修复中介导这些功能。目标1解决两个问题 相互关联的目标。第一个是定义关键的生物过程和 在骨折过程中，如果两种受体都不存在，细胞功能就会改变 修理。骨骼细胞分化和成熟的速度和数量， 细胞增殖率和凋亡率，组织吸收过程， 组织血管化的过程将在细胞和 体内的分子水平。目标1的第二个目标是定义功能 单个肿瘤坏死因子-α受体(p55或p75)在骨修复中的作用 在转基因小鼠中评估这些受体已经修复的骨折 单独消融。目标2有两个目标。第一个是定义分子 肿瘤坏死因子-α介导肥大软骨细胞凋亡的机制。这个 第二个目标是确定肿瘤坏死因子-α的分子机制 发挥中枢旁分泌/自分泌因子的作用，调节 间充质细胞向成骨或软骨方向分化的研究进展 细胞。

DESCRIPTION (Adapted from the Investigator's Abstract): Bone repair after injury or surgery is a specialized type of wound repair response in which bone is regenerated for the purpose of supporting mechanical loads. While the process of bone repair is usually considered to be biologically optimal, the healing of five to ten percent of the estimated 6.2 million fractures occurring annually in the United States is delayed or impaired. Thus, to reduce the morbidity associated with fractures, and to provide better control over the healing responses associated with other reconstructive orthopedic procedures, an improved understanding of the biology of bone healing is required. Numerous studies have focused on cytokines as mediators of skeletal repair. Cytokines can be grouped into three subfamilies: cysteine-knot growth factors, helical cytokines and tumor necrosis factors. The tumor necrosis factors (TNF) family of cytokines has been shown to be essential in the mediation of bone remodeling. We have demonstrated that transgenic mice deficient in both the p55 and p75 TNF-alpha receptors show delayed bone repair, an absence of intramembranous bone formation but enhanced endochondral bone formation and a failure in the removal of endochondral cartilage. The central hypothesis of this proposal is that TNF-alpha provides key regulatory signals that control the resorption of calcified cartilage and regulates the progression of osteogenesis during of endochondral skeletal tissue repair. The goal of this proposal is to determine the cellular and molecular mechanisms by which TNF-alpha mediates these functions in bone repair. Aim 1 addresses two interrelated goals. The first is to define how key biological processes and cellular functions are altered in the absence of both receptors during fracture repair. Rates and amounts of skeletal cell differentiation and maturation, rates of cellular proliferation and apoptosis, processes of tissue resorption, and processes of tissue vascularization will be assessed at cellular and molecular levels in vivo. The second goal of Aim 1 is to define the functional roles of the individual TNF-alpha receptors (p55 or p75) during bone repair, by assessing fracture repair in transgenic mice in which these receptors have been separately ablated. Aim 2 has two goals. The first is to define the molecular mechanisms by which TNF-alpha mediates hypertrophic chondrocyte apoptosis. The second goal is to determine the molecular mechanisms by which TNF-alpha functions as a central paracrine/autocrine factor that is regulating the progression of mesenchymal cell differentiation into osteogenic or chondrogenic cells.