Pharmacologically Enhanced Fracture Repair by Statins

描述（由申请人提供）：我们的长期目标是通过增强骨微环境中局部生长因子的产生来开发骨病理学的先进疗法。该提案的具体目标是确定全身递送的洛伐他汀的疗效，以提高美国每年发生的680万例骨骼骨折的愈合率。对于绝大多数人来说，几个世纪以来，治疗方式基本上没有改变。然而，对于骨科对策的需求显著增加，所述骨科对策比目前可用于解决由老龄化人口特有的进行性骨骼退化驱动的骨科疾病的爆发的那些更有效。 他汀类药物显著增加啮齿类动物骨形成率的观察结果引起了人们的极大兴趣。这些天然产物抑制酶HMG辅酶A还原酶，这是肝胆固醇生物合成的限速步骤。因此，它们可以降低血清胆固醇和随后的心脏病发作风险，因此是最广泛的处方药之一。他汀类药物增加BMP-2基因的转录，从而诱导延长的生物学效应。在骨器官培养物中暴露于他汀类药物6小时，即使在14天后也会对骨形成产生明显影响，在大鼠体内，给予他汀类药物5天与35天后骨形成率增加150%相关。Skogiund等人最近证明，他汀类药物治疗的骨折显示骨痂横截面积显著增加，机械强度增加。这些结果令人震惊，并表明BMP-2的初始诱导引发了一系列事件，这些事件对骨形成的后续影响负责。 目前没有可获得或可接受的刺激大量新骨形成的试剂。因此，他汀类药物代表了一种全新的治疗骨折的治疗方法，与现有的治疗方式相比具有实质性的临床优势。鉴于他汀类药物刺激骨形成的独特效力，本研究的目的是证明口服给药的洛伐他汀在临床前骨干骨折模型中促进骨痂形成和进展的疗效。目标1：利用增殖细胞核抗原单克隆抗体分析洛伐他汀对愈伤组织增殖细胞组成梯度的影响。目的2：应用组织病理学和定量组织形态计量学技术评价洛伐他汀对骨痂形成、成熟和骨折愈合的影响。目的3：评价洛伐他汀对骨痂机械强度和完整性的影响。 全身递送他汀类药物作为加速骨折修复的有效治疗剂代表了一种革命性的新方法，以实现比当前治疗方式显著增强的疗效和易用性。

DESCRIPTION (provided by applicant): Our long-term objective is to develop advanced therapies for pathologies of bone by enhancing growth factor production locally in the bone microenvironment. The specific goal of this proposal is to establish the efficacy of systemically delivered Iovastatin to enhance the rate of healing of the 6.8 million skeletal fractures that occur each year in the United States. For the vast majority, treatment modalities have remained essentially unchanged for centuries. Yet, there is significantly increasing demand for orthopedic countermeasures that are more effective than those currently available to address the explosion of orthopedic maladies driven by the progressive skeletal deterioration endemic to an aging population. The observation that statins dramatically increase bone formation rates in rodents has garnered substantial interest. These natural products inhibit the enzyme HMG Co-A reductase, the rate-limiting step in hepatic cholesterol biosynthesis. As a consequence, they reduce serum cholesterol and the subsequent risk of heart attack and are therefore among the most widely prescribed drugs. Statins increase transcription of the BMP-2 gene, which induces prolonged biological effects. A 6 hour exposure to a statin in bone organ cultures leads to effects on bone formation apparent even after 14 days and in vivo in rats, statin administration for 5 days is associated with a 150% increase in bone formation rates 35 days later. Skogiund et al. have recently demonstrated that statin treated fractures show significantly increased callus transverse areas and increased mechanical strength. These results are astounding and suggest that an initial induction of BMP-2 triggers a cascade of events responsible for the subsequent effects on bone formation. There are no currently available or acceptable agents that stimulate formation of substantial amounts of new bone. As such, statins represent an entirely novel therapeutic approach for the treatment of skeletal fractures, having the potential of substantive clinical advantages over existent treatment modalities. Given the unique potency of statins to stimulate bone formation, the goal of this proposed study is to demonstrate efficacy of orally delivered Iovastatin to enhance callus formation and progression in a preclinical middiaphyseal fracture model. Aim 1: Analyze the effect of iovastatin on the gradient of proliferating cell organization in the developing callus utilizing monoclonal antibodies against proliferating cell nuclear antigen. Aim 2" Evaluate the effect of Iovastatin on callus formation, maturation, and fracture healing using histopathologic and quantitative histomorphometric techniques. Aim 3: Evaluate the effect of iovastatin on callus mechanical strength and integrity. The systemic delivery of statins as effective therapeutic agents for accelerated fracture repair represents a revolutionarily new approach to achieve substantially enhanced efficacy and ease of use over current treatment modalities.