Impact of TPO Treatment on Bone Healing and Angiogenesis in Type 2 Diabetes

TPO 治疗对 2 型糖尿病骨愈合和血管生成的影响

• 批准号: 9492356
• 负责人: Melissa A Kacena
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9492356
• 关键词: Adjuvant; Adverse effects; Affect; American; Angiogenic Factor; Autologous Transplantation; Binding; Biological; Biomechanics; Blood Cells; Blood Circulation; Blood Platelets; Blood Vessels; Blood capillaries; Bone Morphogenetic Proteins; Bone Regeneration; Bone Resorption; Bone Transplantation; Bone callus; Caring; Cell physiology; Cells; Chronic; Comprehensive Health Care; Data; Day Care; Defect; Diabetes Mellitus; Diabetic mouse; Diet; Disease; Endothelial Cells; Equilibrium; FDA approved; Family suidae; Fat-Restricted Diet; Femur; Fracture; Fracture Healing; Frequencies; Functional disorder; Generations; Glucose Intolerance; Goals; Gold; Growth Factor; Harvest; Healthcare Systems; Hematological Disease; Hematopoietic; High Fat Diet; Hip region structure; Histologic; Hyperglycemia; Hyperinsulinism; Impairment; In Vitro; Individual; Intervention; Knock-out; Link; Literature; MPL gene; Malignant Neoplasms; Measures; Mediating; Megakaryocytes; Mesenchymal; Microcirculation; Minerals; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Orthopedics; Osteoblasts; Osteoclasts; Osteogenesis; Outcome; Overweight; Pain; Pathway interactions; Patients; Performance; Persons; Pharmacy facility; Physiological; Platelet Count measurement; Population; Property; Rattus; Regulatory Pathway; Research Personnel; Risk; Risk Factors; Role; Safety; Saline; Series; Site; Source; Surgeon; Techniques; Testing; Therapeutic Effect; Thrombopoietin; Time; Torque; Torsion; Treatment Efficacy; Veterans; Work; Wound Healing; angiogenesis; base; bone; bone healing; bone morphogenetic protein 2; cost; diabetes control; diabetic; diabetic patient; experimental group; healing; hospital bed; improved; microCT; mimetics; mouse model; non-diabetic; novel therapeutics; regenerative; scaffold; statistics; vasculogenesis

Currently, 1 in 4 veterans receiving VA care is diabetic, and over 70% are overweight or obese and at risk of developing diabetes. Diabetes is a risk factor for impaired fracture healing and numerous studies have demonstrated increased frequency of non-union, partial union, or delayed union in diabetic patients as compared to non-diabetic patients. Diabetic patients have impaired microcirculation which is partially responsible for these fracture complications. In the case of non-union, additional interventions are required such as bone grafting techniques. The gold standard for grafting to achieve bone union is the use of autograft from the patient's hip, which may not always achieve healing. Additionally, the harvest of bone often leaves patients with a painful donor site that may not resolve. Therefore, orthopaedic surgeons desire a biologic enhancement for bone healing that does not require the harvesting of iliac crest bone. Local placement of bone morphogenetic proteins (BMPs) is the only FDA approved biological option capable of healing non-unions. BMPs, although potent in promoting bone regeneration, have been associated with several side effects, including a link with cancer. Therefore, there is a great need for new therapies that heal bone with improved safety profiles. Recently, we found that thrombopoietin [TPO, a megakaryocyte (MK) growth factor] could heal critical-sized bone defects in mice, rats and pigs, as well as, if not better than, BMP-2. The long-term goal of this work is to determine whether thrombopoietic agents could serve as novel therapies for bone healing. Our studies as well as the literature show that TPO increases pathways associated with angiogenesis, increases hematopoietic cell populations, including osteoclasts (OCs) and MKs, and increases osteoblasts (OBs) and bone formation, the latter is indirectly through MK-mediated OB proliferation. Based on these ideas, we hypothesize that TPO accelerates bone healing in type 2 diabetes (T2D) by stimulating angiogenesis which has the direct benefit of delivering mesenchymal and hematopoietic cells that mediate wound healing. In Aim 1, we will assess the therapeutic effects of TPO on bone healing in diet-induced obesity with hyperglycemia, hyperinsulinemia, and glucose intolerance (T2D). Mice on a C57BL/6 background will be fed a low fat diet (LFD) or a high fat diet (HFD), will undergo a segmental bone defect surgery, will be treated with saline (negative control), BMP-2 (positive control), or TPO (experimental group), and bone healing assessed. In Aim 2, we will demonstrate the role of TPO in stimulating angiogenesis/vasculogenesis. This will be accomplished by characterizing angiogenesis/vasculogenesis in mice from Aim 1, as well as in mice in which the TPO receptor has been selectively knocked out of endothelial cells (ECs). We will also conduct a series of in vitro studies to assess the impact of TPO treatment as well as secreted factors from MKs on EC function to begin dissecting the mechanisms responsible. Successful accomplishment of these Aims will demonstrate the utility of using TPO for improving bone healing in diabetic patients. This project has high translational potential as thrombopoietic agents are currently FDA approved for treatment of low platelet numbers. Therefore, the regulatory pathway for obtaining FDA approval for a new indication, fracture healing, is easier than it would be for a compound or biologic which has never been used in patients. Finally, demonstrating the mechanism by which TPO stimulates angiogenesis will be important for determining whether other downstream targets should also be evaluated for therapeutic efficacy.

目前，四分之一接受退伍军人事务部护理的退伍军人患有糖尿病，超过70%的人超重或肥胖