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.
Thesaurus Terms: biotherapeutic agent, bone fracture, bone regeneration, cell growth regulation, developmental genetics, drug screening /evaluation, lovastatin, nonhuman therapy evaluation, osteogenesis, skeletal disorder chemotherapy biomechanics, bone morphogenetic protein, cell differentiation, cell proliferation, oral administration, physical property biotechnology, histology, laboratory rat, morphometry, radiography
