FGF2 Isoforms in Bone and Phosphate Homeostasis
FGF2 Isoforms in Bone and Phosphate Homeostasis
批准号:
10320412
负责人:
Marja Marie Hurley
金额:
$34.74万
依托单位国家:
美国
项目类别:
财政年份:
2013
资助国家:
美国
项目状态:
已结题
起止时间:
2013-09-17 至 2023-12-31
关键词:
AblationAdultAgeAreaArthritisBlocking AntibodiesCartilageCell LineCell LineageChondrocytesComplementary DNADataDegenerative polyarthritisDevelopmentDiseaseFGF2 geneFGFR1 geneFGFR3 geneFamilial hypophosphatemic bone diseaseFibroblast Growth FactorFibroblast Growth Factor ReceptorsGene ProteinsGenesGenetic TranscriptionHealth Care CostsHealthcare SystemsHistologicHistologyHomeostasisHomologous GeneHumanHypertrophyImageIn VitroIndividualJointsKnee jointMAP Kinase GeneMitogen-Activated Protein Kinase InhibitorModelingMolecularMolecular WeightMonitorMorbidity - disease rateMusOperative Surgical ProceduresOsteoblastsOsteocytesPathogenesisPeriodicityPhenocopyPhenotypeProcessProtein IsoformsPublishingRNA InterferenceReportingResistanceRoleSignal PathwaySignal TransductionStructureTestingTherapeuticTimeUp-RegulationWNT Signaling PathwayWorkagedantibody inhibitorbonein vivoinhibitorinnovationinorganic phosphatelubricinmicroCTneutralizing antibodynew therapeutic targetnoveloverexpressionpre-clinicalpreventprotein biomarkersradiological imagingvector
中文摘要
项目总结:
英文摘要
Project Summary:
The long-term objective of this project is to determine how the high molecular weight isoforms of Fibroblast
growth factor 2 (HMWFGF2) contribute to osteoarthropathy. Osteoarthritis (OA) is the most common form of
arthritis and has a major negative impact on human health and cost to the health care system. Degenerative
osteoarthropathy, a form of OA is prevalent in young individuals with X-linked hypophosphatemia (XLH) and
common to all older XLH individuals and is a major cause of morbidity in these subjects. HMWTg mice
phenocopy the Hyp mouse homolog of XLH that develops severe OA. We also previously published that
HMWFGF2 isoforms are overexpressed in osteoblasts and osteocytes of Hyp mice. Of relevance we recently
published that similar to Hyp mice, HMWTg mice develop progressively severe OA with age. In contrast mice
overexpressing low molecular weight FGF2 isoform (LMWTg) in osteoblast lineage cells do not develop OA.
Our preliminary data also show that mice in which the FGF2HMW isoforms are selectively ablated do not
develop OA compared with aged WT littermates. Of mechanistic relevance our preliminary studies show
upregulation of FGF23/FGFR1/MAPK and BMP/Smad1/5/8 in HMWTg knee joints but not LMWTg joints. We
therefore wish to explore the potential role of FGF23 in HMWTg induced OA since we published that HMW but
not LMW FGF2 transcriptionally regulates FGF23. Furthermore, FGF23 in OA is an understudied area thus
studies of FGF2 isoforms modulating FGF23 in OA could also impact the field. We provide novel preliminary
data that in vivo administration of FGF23 neutralizing antibody ameliorates the OA phenotype in HMWTg mice.
These findings support our overall hypothesis that HMWFGF2 isoforms contribute to OA via
FGF23/FGFR1/MAPK signaling. We also wish to investigate the mechanism of joint homeostasis in LMWTg
and HMWKO mice since LMWFGF2 appears to protect the joint from OA development. Our aims are: Aim
1a:Define the role of FGF23/FGFReceptor signaling in HMWFGF2 induces osteoarthropathy. Aim 1b:
Determine the functional effects of overexpressing of low molecular weight FGF2 or selective ablation of
HMWFGF2 isoforms to confer resistance against osteoarthropathy progression in mice. Aim 2: Define the
mechanism(s) by which HMWFGF2 induces osteoarthropathy. Our preliminary in vitro studies suggest
differential activation of FGF23/FGF receptors and downstream signaling pathways for the catabolic effects of
HMWFGF2 versus anabolic effect of LMWFGF2 in joint homeostasis. Murine chondrogenic cell line ATDC5
transduced with FGF2HMW and FGF2LMW cDNAs and primary murine articular chondrocytes obtained from
Vector, HMWTg and LMWTg mice will be used to interrogate intracellular signaling pathways that are unique
for HMW or LMW in developing or preventing development of OA. Since the role of FGF2 in OA is
controversial with studies supporting both catabolic and anabolic effects of FGF2 and since the potential role of
FGF2 isoforms in OA has not been investigated, our studies could significantly impact the field.
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FGF2 crosstalk with Wnt signaling in mediating the anabolic action of PTH on bone formation.
FGF2 与 Wnt 信号传导串扰介导 PTH 对骨形成的合成代谢作用。
DOI:
10.1016/j.bonr.2018.09.003
发表时间:
2018
期刊:
Bone reports
影响因子:
2.5
作者:
[Xiao,Liping, Fei,Yurong, Hurley,MarjaM]
通讯作者:
Hurley,MarjaM
Fibroblast Growth Factor 2 High Molecular Weight Isoforms in Dentoalveolar Mineralization.
成纤维细胞生长因子2在牙道肺泡矿化中高分子量同工型。
DOI:
10.1007/s00223-021-00888-3
发表时间:
2022-01
期刊:
Calcified tissue international
影响因子:
4.2
作者:
[Millington G, Joseph J, Xiao L, Vijaykumar A, Mina M, Hurley MM]
通讯作者:
Hurley MM
DOI:
10.1210/js.2018-00105
发表时间:
2018-07-01
期刊:
Journal of the Endocrine Society
影响因子:
4.1
作者:
[Coffin JD, Homer-Bouthiette C, Hurley MM]
通讯作者:
Hurley MM
DOI:
10.1038/s41598-022-20269-6
发表时间:
2022-09-24
期刊:
SCIENTIFIC REPORTS
影响因子:
4.6
作者:
[Hurley, Marja M, Coffin, J Douglas, Doetschman, Thomas, Valera, Christina, Clarke, Kai, Xiao, Liping]
通讯作者:
Xiao, Liping
Inhibition of FGFR Signaling Partially Rescues Hypophosphatemic Rickets in HMWFGF2 Tg Male Mice.
抑制 FGFR 信号可部分缓解 HMWFGF2 Tg 雄性小鼠的低磷血症性佝偻病。
DOI:
10.1210/en.2016-1617
发表时间:
2017
期刊:
Endocrinology
影响因子:
4.8
作者:
[Xiao,Liping, Du,Erxia, Homer-Bouthiette,Collin, Hurley,MarjaM]
通讯作者:
Hurley,MarjaM
共 6 条
Role of FGF23 in Bone, Kidney, Blood, Crosstalk in Sickle Cell Disease Mice
-
批准号:10437233
-
项目类别:
-
资助金额:$54.85万
-
财政年份:2022
-
负责人:Marja Marie Hurley
-
依托单位:
Role of FGF23 in Bone, Kidney, Blood, Crosstalk in Sickle Cell Disease Mice
-
批准号:10597099
-
项目类别:
-
资助金额:$55.43万
-
财政年份:2022
-
负责人:Marja Marie Hurley
-
依托单位:
FGF2 Isoforms in Bone and Phosphate Homeostasis
-
批准号:10026143
-
项目类别:
-
资助金额:$5.82万
-
财政年份:2013
-
负责人:Marja Marie Hurley
-
依托单位:
FGF2 Isoforms in Bone and Phosphate Homeostasis
-
批准号:8735135
-
项目类别:
-
资助金额:$34.32万
-
财政年份:2013
-
负责人:Marja Marie Hurley
-
依托单位:
FGF2 Isoforms in Bone and Phosphate Homeostasis
-
批准号:8628923
-
项目类别:
-
资助金额:$33.26万
-
财政年份:2013
-
负责人:Marja Marie Hurley
-
依托单位:
The University of Connecticut BRIDGES Network
-
批准号:6828356
-
项目类别:
-
资助金额:$21.54万
-
财政年份:2004
-
负责人:Marja Marie Hurley
-
依托单位:
Action of Anabolic Factors on Bone Formation in Mice
-
批准号:7189060
-
项目类别:
-
资助金额:$20.62万
-
财政年份:2004
-
负责人:Marja Marie Hurley
-
依托单位:
Action of Anabolic Factors on Bone Formation in Mice
-
批准号:7528585
-
项目类别:
-
资助金额:$30.34万
-
财政年份:2004
-
负责人:Marja Marie Hurley
-
依托单位:
Action of Anabolic Factors on Bone Formation in Mice
-
批准号:8278563
-
项目类别:
-
资助金额:$28.87万
-
财政年份:2004
-
负责人:Marja Marie Hurley
-
依托单位:
Action of Anabolic Factors on Bone Formation in Mice
-
批准号:7667977
-
项目类别:
-
资助金额:$30.34万
-
财政年份:2004
-
负责人:Marja Marie Hurley
-
依托单位:
The University of Connecticut BRIDGES Network
-
批准号:6931686
-
项目类别:
-
资助金额:$21.58万
-
财政年份:2004
-
负责人:Marja Marie Hurley
-
依托单位:
Action of Anabolic Factors on Bone Formation in Mice
-
批准号:8073004
-
项目类别:
-
资助金额:$28.87万
-
财政年份:2004
-
负责人:Marja Marie Hurley
-
依托单位:
Action of Anabolic Factors on Bone Formation in Mice
-
批准号:7845633
-
项目类别:
-
资助金额:$30.04万
-
财政年份:2004
-
负责人:Marja Marie Hurley
-
依托单位:
Action of Anbolic Factors on Bone Formation in Mice
-
批准号:6881999
-
项目类别:
-
资助金额:$21.75万
-
财政年份:2004
-
负责人:Marja Marie Hurley
-
依托单位:
Action of Anabolic Factors on Bone Formation in Mice
-
批准号:8712679
-
项目类别:
-
资助金额:$7.16万
-
财政年份:2004
-
负责人:Marja Marie Hurley
-
依托单位:
The University of Connecticut BRIDGES Network
-
批准号:7107116
-
项目类别:
-
资助金额:$5.96万
-
财政年份:2004
-
负责人:Marja Marie Hurley
-
依托单位:
Action of Anbolic Factors on Bone Formation in Mice
-
批准号:7288537
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项目类别:
-
资助金额:$4.95万
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财政年份:2004
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负责人:Marja Marie Hurley
-
依托单位:
Action of Anbolic Factors on Bone Formation in Mice
-
批准号:7035839
-
项目类别:
-
资助金额:$21.24万
-
财政年份:2004
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负责人:Marja Marie Hurley
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依托单位:
Action of Anabolic Factors on Bone Formation in Mice
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批准号:6777845
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项目类别:
-
资助金额:$21.75万
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财政年份:2004
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负责人:Marja Marie Hurley
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依托单位:
BASIC FIBROBLAST GROWTH FACTOR EXPRESSION IN BONE CELLS
-
批准号:6497444
-
项目类别:
-
资助金额:$26.22万
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财政年份:2000
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负责人:Marja Marie Hurley
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依托单位:
海外基金