Regulatory Mechanisms in Load-Induced Bone Formation

 描述（由申请人提供）： 目前迫切需要开发新的方法来加速骨生成以治疗骨骼损伤和疾病。战斗部队和年老的退伍军人都遭受毁灭性的骨科损伤。年轻士兵遭受爆炸伤后，由于大量骨和软组织损失，需要进行困难的肢体重建，而老年老兵遭受与年龄相关的骨损失，由于骨质疏松性骨折而丧失能力，这通常与成骨能力降低、愈合延迟和骨不连有关。急性创伤和年龄相关骨折修复的挑战都集中在一个关键的缺陷上：由于干细胞库耗尽而导致的造骨能力下降。自体骨移植是补充年轻健康患者干细胞库的“金标准”，在极端组织损失和老年患者中可能是不可预测的。这就是我们的动机所在：动员和招募患者自身的干细胞到受伤部位，然后及时激活这些细胞以产生骨骼。我们的研究集中在可溶性干细胞募集因子SDF-1及其作为旁分泌信号调节骨稳态和再生的作用，以响应机械负荷和损伤。这项工作的总体目标是确定SDF-1信号传导在骨生成和再生过程中的作用，使用功能丧失模型和外源性SDF-1治疗。我们的中心假设是，SDF-1作为一个旁分泌介质的祖细胞招聘和成骨分化的负荷和损伤诱导的成骨。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。对于我们的假设，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对骨骼稳态和负荷诱导的骨生成的影响;（2）确定成骨细胞和骨细胞表达的SDF-1对骨再生的影响;（3）证明局部递送的SDF-1可以增强老年小鼠（一种次优愈合模型）的骨再生。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在骨骼中以旁分泌方式起作用，这一发现将大大促进我们对骨骼稳态的理解，并作为制定治疗方案的基础，以治疗我们退伍军人的毁灭性骨科损伤和疾病。

 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.