Mutations in Osteoprotegerin Cause Calcium Pyrophosphate Deposition Disease
护骨素突变导致焦磷酸钙沉积病
基本信息
- 批准号:10436891
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-01-01 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAffinityAmericanAmino AcidsArthritisBehaviorBindingBiological MarkersBone DensityCalcium PyrophosphateCalcium pyrophosphate deposition diseaseCell membraneCell surfaceCharacteristicsChondrocytesChromatographyClinicalCodeCrystal FormationCrystallizationDataDimerizationDiseaseDisease ClusteringsElderlyGoalsHeparin BindingHeparitin SulfateICD-9IGF1 geneIn VitroMeasuresMembraneMolecular AbnormalityMolecular Sieve ChromatographyMutationNF-kappa BOsteoblastsOsteoclastsOsteopeniaPainPathway interactionsPatientsPatternPharmaceutical PreparationsPhenotypeProteinsPublishingRecombinantsReportingRisk FactorsRoentgen RaysRoleStructureSurface Plasmon ResonanceTNF-related apoptosis-inducing ligandTNFRSF11B geneTNFSF10 geneTRANCE proteinTerminator CodonTissuesTransforming Growth Factor betaTumor necrosis factor receptor 11bVeteransWorkarticular cartilagedimerdisease phenotypeearly onseteffective therapygain of functiongain of function mutationin vivo Modelinnovationjoint destructionjoint injurykindredloss of functionmilitary veterannew therapeutic targetnovel therapeuticsolder patientosteoclastogenesisprematurepreventreceptorreceptor bindingstemsubchondral bone
项目摘要
Calcium pyrophosphate deposition disease (CPDD) is a common type of arthritis defined by the
presence of calcium pyrophosphate (CPP) crystals in articular cartilage. It is particularly
common in the US Veteran population as risk factors for CPDD including advanced age and
prior joint trauma are highly prevalent in American Veterans. We recently published a study of
US veterans using ICD-9 codes to identify 29,000 American Veterans with the disease in a
single 5-year period. While CPDD affects elderly patients in a sporadic fashion, it also occurs
prematurely in familial patterns. Studies of familial forms of this disease present exciting
opportunities to identify novel therapeutic targets for this currently untreatable arthritis. We
recently confirmed that a mutation in the stop codon of TNFRSF11B causes early onset CPDD.
TNFRSF11B codes for osteoprotegerin (OPG). The OPG mutation causing CPDD (mtOPG)
results in an additional 19 amino acids added to the protein's C terminus near the heparin
binding domain. OPG is decoy receptor for receptor activator of nuclear factor kappa B ligand
(RANKL). RANKL promotes osteoclast formation, and because OPG blocks its function,
reduction of OPG activity results in increased osteoclastogenesis. The phenotype of affected
patients with this mutation includes exuberant CPP crystal formation, mild osteopenia and
severe joint degeneration, a phenotype consistent with a loss of function of OPG. Indeed,
preliminary data demonstrate that recombinant mtOPG displays inefficient inhibition of
membrane-bound RANKL resulting in excess osteoclastogenesis in vitro. Interestingly,
osteoclast conditioned media potently stimulates biomarkers of CPP crystal formation in
chondrocytes. The purpose of this work is to investigate the conceptually innovative
hypothesis that mtOPG produces CPDD by increasing osteoclastogenesis in
subchondral bone. In specific aim 1, using in vitro and in vivo models, we will show that
compared to wild type OPG (wtOPG), mtOPG ineffectively binds to the osteoblast cell
membrane. resulting in excess un-opposed membrane-bound RANKL and increased osteoclast
formation. Overabundant osteoclasts in subchondral bone produce joint damage and release
CPP crystal-promoting factors into articular cartilage. In the second aim, structural studies using
chromatography, surface plasmon resonance and small angle x-ray scattering, will demonstrate
reduced affinity of mtOPG to bind heparan sulfate and decreased dimerization. The scientific
premise of this work stems from careful observations of the phenotype of patients with the OPG
mutation and is supported by preliminary in vitro functional studies of mtOPG. These studies are
the first to identify the OPG/RANKL/RANK pathway in CPDD and to implicate subchondral bone
as a target tissue in this disease. The shared clinical features of patients with CCAL1 and those
with sporadic CPDD as well as the existence of available drugs which target this pathway make
this work particularly exciting.
焦磷酸钙沉积病(CPDD)是一种常见的关节炎类型
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Ann K Rosenthal其他文献
Calcium pyrophosphate deposition is associated with an increased risk for nephrolithiasis: A cohort study
焦磷酸钙沉积与肾结石风险增加相关:一项队列研究
- DOI:
10.1016/j.semarthrit.2025.152641 - 发表时间:
2025-04-01 - 期刊:
- 影响因子:4.400
- 作者:
Mahum Mirza;Alison Fernandes;Katherine Sherman;Ann K Rosenthal - 通讯作者:
Ann K Rosenthal
Ann K Rosenthal的其他文献
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{{ truncateString('Ann K Rosenthal', 18)}}的其他基金
Mutations in Osteoprotegerin Cause Calcium Pyrophosphate Deposition Disease
护骨素突变导致焦磷酸钙沉积病
- 批准号:
10159843 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Mutations in Osteoprotegerin Cause Calcium Pyrophosphate Deposition Disease
护骨素突变导致焦磷酸钙沉积病
- 批准号:
10863809 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Novel roles for articular cartilage vesicles in osteoarthritis
关节软骨囊泡在骨关节炎中的新作用
- 批准号:
8198369 - 财政年份:2010
- 资助金额:
-- - 项目类别:
Novel roles for articular cartilage vesicles in osteoarthritis
关节软骨囊泡在骨关节炎中的新作用
- 批准号:
8043903 - 财政年份:2010
- 资助金额:
-- - 项目类别:
Novel roles for articular cartilage vesicles in osteoarthritis
关节软骨囊泡在骨关节炎中的新作用
- 批准号:
8391602 - 财政年份:2010
- 资助金额:
-- - 项目类别:
Novel roles for articular cartilage vesicles in osteoarthritis
关节软骨囊泡在骨关节炎中的新作用
- 批准号:
8597380 - 财政年份:2010
- 资助金额:
-- - 项目类别:
TRANSGLUTAMINASE PROMOTES CPPD DISEASE IN AGING JOINTS
转谷氨酰胺酶促进老化关节中的 CPPD 疾病
- 批准号:
2561477 - 财政年份:1998
- 资助金额:
-- - 项目类别:
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