Fracture injuries represent a significant clinical burden, with up to 6.2 million fractures occurring annually in the United States alone, of which 10% are complicated by non-unions. Current methods for treatment of non- unions with bone grafts have been fraught with multiple shortcomings, leading to an urgent and unmet need for alternative approaches. Adult bone marrow (BM) contains multipotent mesenchymal stromal cells (MSC) that have all the properties to become a novel therapeutic approach to treat non-unions. MSC have ample regenerative abilities via their multilineage, end-stage mesenchymal cell type differentiation potential (autocrine effect) and through secretion of bioactive molecules that regulate the regenerative microenvironment of an injured tissue (autocrine effect). During the first cycle of this grant, our laboratory has reported in several published investigations the in vivo dynamics of MSC after transplant, their engraftment within a specific fracture callus endosteal niche where they express bone morphogenic protein-2 (BMP-2) and their beneficial effects on fracture tissue healing and strength. We have also found that transplanted MSC expressing insulin- like growth factor-I (IGF-I) differentiate into bone cells within the fracture callus and promote fracture healing by inducing more new bone formation than MSC alone. The central hypothesis of this proposal is that MSC improve the fracture repair process by promoting a regenerative microenvironment through autocrine and paracrine actions. Specifically, we propose the following:
Specific Aims1, to determine whether MSC improve the fracture repair process through induction of BMP-2 expression;
Specific Aim 2, to determine whether MSC programmed to express IGF-I improve fracture healing by promoting bone formation through autocrine and paracrine mechanisms. Our results will open novel perspectives that will allow the full appreciation of the regenerative capacities of MSC and therefore set new research directions in the field of regenerative medicine. A comprehensive approach that combines in vivo and in vitro studies on genetically engineered mice, mouse models for non-unions and novel methods to assess fracture healing will be applied to accomplish the proposed aims. Studies would have major biomedical relevance and implications, as they lead to a better understanding of the mechanisms through which MSC promote fracture repair that will set the foundation for the development of novel MSC-based therapies to promote fracture healing in patients with non-unions.

Public Health Relevance

Non-union fractures remain a challenging clinical problem that affect approximately 600,000 people every year in the United States. Because our elderly population is becoming larger, an increased incidence of non- unions as consequence of poor healing and age-related worsening of osteoporosis is expected. Adult bone marrow contains multipotent mesenchymal stromal cells (MSC) that have all the properties to become a novel therapeutic approach to treat non-unions. The overall goal of this proposal is to understand the mechanisms through which MSC exert their beneficial effects in fracture repair. Unraveling how MSC are capable to respond to the fracture regenerative clue and to provide the adequate environment for tissue regeneration will provide critical insights to develop novel MSC-based therapies to treat patients with non-unions

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Skeletal Biology Structure and Regeneration Study Section (SBSR)
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Malozowski, Saul N
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Myers, Timothy J; Longobardi, Lara; Willcockson, Helen et al. (2015) BMP2 Regulation of CXCL12 Cellular, Temporal, and Spatial Expression is Essential During Fracture Repair. J Bone Miner Res 30:2014-27
Contaldo, Clara; Myers, Timothy J; Zucchini, Cinzia et al. (2014) Expression levels of insulin receptor substrate-1 modulate the osteoblastic differentiation of mesenchymal stem cells and osteosarcoma cells. Growth Factors 32:41-52
Myers, Timothy J; Yan, Yun; Granero-Molto, Froilan et al. (2012) Systemically delivered insulin-like growth factor-I enhances mesenchymal stem cell-dependent fracture healing. Growth Factors 30:230-41
Weis, Jared A; Granero-Moltó, Froilán; Myers, Timothy J et al. (2012) Comparison of microCT and an inverse finite element approach for biomechanical analysis: results in a mesenchymal stem cell therapeutic system for fracture healing. J Biomech 45:2164-70
Granero-Molto, Froilan; Myers, Timothy J; Weis, Jared A et al. (2011) Mesenchymal stem cells expressing insulin-like growth factor-I (MSCIGF) promote fracture healing and restore new bone formation in Irs1 knockout mice: analyses of MSCIGF autocrine and paracrine regenerative effects. Stem Cells 29:1537-48
Myers, Timothy J; Granero-Molto, Froilan; Longobardi, Lara et al. (2010) Mesenchymal stem cells at the intersection of cell and gene therapy. Expert Opin Biol Ther 10:1663-79
Weis, Jared A; Miga, Michael I; Granero-Molto, Froilan et al. (2010) A finite element inverse analysis to assess functional improvement during the fracture healing process. J Biomech 43:557-62
Granero-Molto, Froilan; Weis, Jared A; Miga, Michael I et al. (2009) Regenerative effects of transplanted mesenchymal stem cells in fracture healing. Stem Cells 27:1887-98
Longobardi, Lara; Granero-Molto, Froilan; O'Rear, Lynda et al. (2009) Subcellular localization of IRS-1 in IGF-I-mediated chondrogenic proliferation, differentiation and hypertrophy of bone marrow mesenchymal stem cells. Growth Factors 27:309-20
Granero-Molto, Froilan; Weis, Jared A; Longobardi, Lara et al. (2008) Role of mesenchymal stem cells in regenerative medicine: application to bone and cartilage repair. Expert Opin Biol Ther 8:255-68

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