It is well known that osteoporosis is disease of increased bone fragility that results from estrogen deficiency and aging. A decrease in the number of mesenchymal stem cells (MSCs) in bone marrow with aging leads to reduced osteogenesis and thus reduces bone formation and increases bone fragility. Bone regeneration by the means of induction of osteogenesis from MSCs offers rational therapeutic implications. This approach is problematic due to the major obstacle of controlling the MSCs'commitment, growth and differentiation into functional osteoblasts on bone surface. The proposed research offers a solution to this issue. Recently our laboratory group used a combinatorial library method to identify a small molecule ligand, LLP2A, that specifically targets integrin 1421. This integrin is expressed in osteoblast progenitors and has the potential to direct the MSCs to the bone surface. We then chemically linked a bisphosphonate (a bone targeting agent) to LLP2A. This new hybrid drug, Bis-LLP2A, was found to concentrate in the bone surface. Based on these observations, we hypothesize that bone marrow progenitor cell (MSC) attachment and osteogenic differentiation would be achieved when they are """"""""guided"""""""" to bone surface that is rich in extra cellular matrix and growth factors that are necessary for osteoblast maturation. We further hypothesize that if MSCs are guided to the bone surface, additional treatment with an anabolic agent, will augment the new bone formation and restore bone mass and bone strength. We have the following two specific aims to test our hypothesis: 1. To determine the specificity and efficacy of Bis-LLP2A for guiding MSCs to bone surface and enhancing bone formation. We will evaluate specificity and toxicity of the Bis-LLP2A to MSCs in vitro and in vivo. In addition, we will evaluate the efficacy of combination low-dose anabolic agents and Bis-LLP2A in the augmentation of bone formation in osteoporotic animals. 2.To determine the bone migration efficacy of Bis-LLP2A in homing of human MSCs in mice with severe osteoporosis. The proposal is high risk in nature but it is a critical """"""""proof-of-concept"""""""" step before we move forward to pursue our ultimate goal, which is to screen highly specific ligand(s) for osteoprogenitors. The major obstacle for MSCs therapeutic application in bone diseases is that MSCs do not home to bone. We believe that our bisphosphonate-ligand conjugates can overcome this obstacle by guiding MSCs to the bone surface, which is the most critical step for MSC therapy in the enhancement of bone formation during bone growth, bone trauma repair and the treatment of osteoporosis.
Osteoporosis is disease characterized by progressive bone loss that predisposes bone to fracture. Mesenchymal stem cells (MSCs) in bone marrow are groups of cells that can differentiate into bone forming cells. However, direct infusions of MSCs failed to yield bone forming response due to the inability of MSCs migrate to the bone surface. We propose a novel method that can guide the MSCs to bone surface, which can provide novel treatment options for bone diseases such as osteoporosis and bone trauma repair.
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