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Role of FGF23 in Bone, Kidney, Blood, Crosstalk in Sickle Cell Disease Mice

FGF23 在镰状细胞病小鼠骨、肾、血液和串扰中的作用

基本信息

批准号：
10437233
负责人：
Marja Marie Hurley
金额：
$ 54.85万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10437233
关键词：
Adult Affect Age Anemia Anemia due to Chronic Disorder Apoptosis BFU-E Biochemical Blocking Antibodies Blood Bone Density Bone Diseases Bone Infarction Bone Marrow Bone Marrow Involvement Cell Cycle Chronic Data Diphosphates Dual-Energy X-Ray Absorptiometry Erythrocytes Erythroid Erythroid Cells Erythroid Progenitor Cells Erythropoiesis Erythropoietin Etiology FDA approved Familial hypophosphatemic bone disease Fibroblast Growth Factor Receptors Future Gender General Population Hematopoietic stem cells Hemoglobinopathies Hip region structure Histologic Homeostasis Hormonal Hormones Human Hypophosphatemia Immunoglobulin G Impairment In Vitro Inorganic Phosphate Transporter Ischemia Kidney Kidney Failure Mechanics Menopausal Status Messenger RNA Mitogen-Activated Protein Kinases Molecular Molecular Analysis Mus Necrosis Osteoblasts Osteomalacia Osteoporosis Pathogenesis Pathology Patients Phenotype Physiologic calcification Process Production Proteins RNA analysis Reporting Risk Factors Role Secondary to Serum Serum Markers Sickle Cell Sickle Cell Anemia Signal Pathway Signal Transduction Sodium Stromal Cells Testing Therapeutic Urine Vitamin D Deficiency base bone bone loss bone marrow hyperplasia bone strength bone turnover effective therapy fibroblast growth factor 23 improved in vivo inorganic phosphate iron deficiency microCT mineralization mouse model neutralizing antibody novel osteoblast differentiation prevent progenitor response sodium-phosphate cotransporter proteins targeted treatment wasting

项目摘要

Summary Sickle cell disease (SCD) is a hemoglobinopathy associated with severe bone abnormalities including osteoporosis. Eighty percent of SCD adults have low bone mineral density (BMD) that is independent of risk factors such as age, gender, and menopausal status, suggesting the etiology of osteoporosis in SCD differs from the general population. Proposed contributing factors to bone loss in SCD include marrow hyperplasia secondary to chronic anemia, inflammation, ischemia, and vitamin D deficiency. However, the mechanisms of bone loss in SCD subjects has not been fully investigated, and there are no targeted therapies. Hormonal fibroblast growth factor 23 (FGF23), which controls phosphate homeostasis and has direct and indirect effects on bone mineralization, is reported to be increased in human anemia. Based on our exciting preliminary data showing that increased serum FGF23 and hypophosphatemia in humanized Townes SCD mice, which are anemic but not in renal failure, and that in vitro and in vivo FGF23 blockade partially rescues impaired mineralization and improved reduced BMD in SCD mice, we posit that cross-talk involving bone marrow erythropoiesis, kidney, and bone contributes to osteoporosis in SCD mice. Specifically, we posit that 1) sickling of red blood cells and the resulting anemia causes increased erythropoietin production by the kidney, which increases bone FGF23 production that impairs phosphate reabsorption; and 2) anemia-induced FGF23 results in impaired osteoblast differentiation, mineralization, and bone strength in SCD mice due to hypophosphatemia and pyrophosphate abnormalities via impaired sodium phosphate transporters PIT1 and PIT2 signaling in bone. Furthermore, increased FGF23 reduces PIT1 signaling that can interfere with erythrocyte differentiation, further perpetuating the anemic state. To test our hypotheses, we propose the following Specific Aims: Aim 1: Examine the molecular mechanisms by which FGF23 contributes to phosphate wasting in SCD Mice; Aim 2: Assess the molecular mechanism by which FGF23 contributes to impaired bone mineralization in SCD mice; and Aim 3: Determine whether FGF23 neutralizing antibody modulates the anemia phenotype of SCD mice. Our proposed studies may identify FGF23 as a novel contributor to the pathogenesis of bone loss and anemia in SCD mice. Since the FGF23Ab is now FDA approved for the treatment of X-linked hypophosphatemia, it may also be a useful therapy to prevent bone loss and improve anemia in human SCD in the future.

总结