Regulatory Mechanisms in Load-Induced Bone Formation

 描述(由申请人提供)： 为了治疗骨骼损伤和疾病，迫切需要开发新的方法来加速成骨。作战部队和年迈的退伍军人都遭受着严重的骨科创伤。遭受冲击伤的年轻士兵由于大量骨骼和软组织丢失而需要困难的肢体重建，而患有与年龄相关的骨丢失的资深退伍军人则因骨质疏松性骨折而丧失能力，骨质疏松性骨折通常与成骨能力减弱、愈合延迟和骨不连有关。在急性创伤和与年龄相关的骨折修复中，挑战都集中在一个关键缺陷上：由于干细胞库耗尽，造骨能力减弱。自体骨移植是补充年轻健康患者干细胞库的“黄金标准”，但在极端组织丢失的情况下和老年患者中，可能是不可预测的。这就是我们的动机所在：动员和招募患者自己的干细胞到损伤部位，然后及时激活这些细胞产生骨。我们的研究重点是可溶性干细胞募集因子SDF-1，以及它作为旁分泌信号在机械负荷和损伤反应中调节骨骼动态平衡和再生的作用。这项工作的总体目标是利用功能丧失模型和外源性SDF-1治疗来确定SDF-1信号在成骨和再生过程中的作用。我们的中心假设是，在负荷和损伤诱导的成骨过程中，SDF-1作为祖细胞募集和成骨分化的旁分泌介质。我们进一步假设SDF-1治疗可以加速老年小鼠的骨修复，这是一种再生能力减弱的模型，可能是通过增强细胞募集来实现的。根据我们的假设，我们提出了以下具体目标：(1)确定成骨细胞和骨细胞表达的SDF-1对骨骼动态平衡和负荷诱导成骨的影响；(2)确定成骨细胞和骨细胞表达的SDF-1对骨再生的影响；以及(3)证明局部应用SDF-1可以促进老年小鼠的骨再生，这是一种次优愈合模型。如果我们的假设是正确的，我们的研究将提供令人信服的证据，证明SDF-1在骨骼中以旁分泌的方式发挥作用，这一发现将显著促进我们对骨骼动态平衡的理解，并作为开发治疗方案的基础，以治疗退伍军人中毁灭性的骨科损伤和疾病。

 DESCRIPTION (provided by applicant): There is an urgent need to develop novel approaches to accelerate osteogenesis for the treatment of skeletal injury and disease. Combat troops and aging Veterans alike suffer from devastating orthopaedic injuries. While the young soldier suffering from a blast injury requires difficult limb reconstruction due to massive bone and soft tissue loss, the senior Veteran suffering from age-related bone loss is incapacitated by osteoporotic fractures, which are often associated with diminished osteogenic capacity, delayed healing, and non-union. Challenges in both acute trauma- and age-related fracture repairs converge on one critical deficiency: diminished ability to make bone due to a depleted stem cell pool. Autologous bone grafting, the "gold standard" for replenishing the stem cell pool in young healthy patients, can be unpredictable in cases of extreme tissue loss and in older patients. This is where our motivation lies: to mobilize and recruit a patient's own stem cells to the site of injury, and then activate these cells to produce bone in a timely manner. Our studies focus on a soluble stem cell recruitment factor, SDF-1, and its role as a paracrine signal regulating bone homeostasis and regeneration in response to mechanical loading and injury. The overall objective of this work is to determine the role of SDF-1 signaling during osteogenesis and regeneration using both loss-of-function models and exogenous SDF-1 treatment. Our central hypothesis is that SDF-1 acts as a paracrine mediator of progenitor recruitment and osteogenic differentiation in load- and injury-induced osteogenesis. We further hypothesize that SDF-1 treatment can accelerate bone repair in aged mice, a model of diminished regenerative capacity, possibly by enhancing cellular recruitment. To our hypotheses, we propose the following Specific Aims: (1) Determine the influence of osteoblast- and osteocyte-expressed SDF-1 on skeletal homeostasis and load-induced osteogenesis; (2) Determine the influence of osteoblast- and osteocyte-expressed SDF-1 on bone regeneration; and (3) Demonstrate that locally delivered SDF-1 can augment bone regeneration in aged mice, a model of suboptimal healing. If our hypotheses are correct, our studies will provide convincing evidence that SDF-1 works in a paracrine fashion in bone, a finding that would significantly advance our understanding of skeletal homeostasis and serve as a basis for developing therapeutic protocols to treat devastating orthopaedic injuries and disease in our Veterans.