Osteogenesis imperfecta (OI), an autosomal dominant disorder caused by a mutation in one of the two genes that encode type I collagen (COL1AI or COL1A2), is the most common hereditary bone disease. OI is characterized by mild to severe reduction in the quantity of bone matrix that leads to repeated fractures and bone deformity. In the United States, the incidence of OI is estimated to be 1 per 20,000 live births. A present there is no cure for OI. Treatment is aimed at increasing overall bone strength to prevent fracture. Long-term treatment with the drugs has its own side effects; therefore several strategies are being tested experimentally in OI to enhance bone remodeling, one of them being the use of stem cells. We have shown that hematopoietic stem cell (HSC) transplantation can ameliorate the bone defects seen in oim mice. We also demonstrated that HSCs gives rise to osteoblasts and osteocytes during normal bone turnover as well as non- stabilized fracture repair. Our preliminary data from oim mice transplanted with a clonal population derived from a single enhanced green fluorescent protein (EGFP+) HSC demonstrates a significant improvement in the trabecular and the cortical parameters in engrafted mice. We also show that HSC transplantation leads to the formation of functional osteoblasts that deposited collagen and formed bone in vivo. These studies and our data suggest that osteoblasts can be derived from a novel source, i.e. HSCs. Thus, this proposal is to test the hypothesis that HSCs can give rise to osteoblasts in OI and understanding the molecular factors that promote its mobilization as well as osteogenesis could have therapeutic value in OI.
Aim 1 is to establish that HSCs can give rise to osteoblasts employing transplantation studies with HSCs derived from mice having visual markers under the control of a bone directed collagen type I promoter, which allows for specific identification of cells at various stages of osteoblast lineage. Utilizing the mice expressing GFP in the hematopoietic cells and Red Fluorescent Protein (RFP) in the non-hematopoietic tissues we will do lineage tracing from the HSCs. The goals of Aim 2 are to characterize the factors modifying bone reconstitution by HSCs in OI and define the molecular mechanisms regulating HSC differentiation to osteoblasts. Effect of factors on mobilization of HSCs and their differentiation to osteoblasts will be studied both in vitro and in vivo. Findings from this study ill be significant in that they can be applied to long-term studies to enhance and accelerate bone healing in OI. This will open many new avenues of therapy for a number of bone diseases and injuries through the use and modulation of HSCs.
Previous studies show HSCs can ameliorate bone defect in oim. This proposal tests the hypothesis that HSCs can differentiate into osteoblasts and aims to identify factors modifying their mobilization and differentiation. Findings will be significant as they open new avenues of therapy through the use and modulation of HSCs.