Phlpp phosphatases in osteoarthritis
Phlpp phosphatases in osteoarthritis
批准号:
10707868
负责人:
Jennifer J Westendorf
金额:
$39.75万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-09-21 至 2027-08-31
关键词:
AdultAffectAfferent NeuronsAgeAge MonthsAgingAnimal ModelArthralgiaArticulationAtomic Force MicroscopyBehaviorBehavior TherapyBiological AssayBiomechanicsBone SpurCartilageCell ProliferationCellsChondrocytesCompensationCoupledDataDegenerative polyarthritisDeteriorationDevelopmentDiseaseDisease ProgressionEconomic BurdenElasticityEnzymesGenesGoalsHistologyHistopathologyHumanIn VitroInjuryIntra-Articular InjectionsJointsKnock-outKnockout MiceMeasuresMedial meniscus structureMeniscus structure of jointMessenger RNAMolecularMotionMusNatural regenerationNeuritesNeuronal PlasticityNeuronsNeurotransmittersOperative Surgical ProceduresPainPainlessPathogenesisPathologicPathologyPeriosteumPharmaceutical PreparationsPhenotypePhosphoric Monoester HydrolasesProductionProliferatingPropertyReporterRisk FactorsRoleSalineSurfaceSynovial MembraneSynovitisTamoxifenTestingThickTissuesWeight-Bearing stateWorkaggrecanallodyniaarticular cartilageburden of illnesscartilage degradationcartilage regenerationcartilage repaircell typechronic painful conditiondisabilityimproved mobilityin vivoinhibitorinnovationinsightinterestjoint injuryligament injurymultidisciplinarynerve supplyneurofilamentnovel therapeuticsosteoarthritis painoverexpressionpain behaviorpain reliefpalliativepreservationpreventregenerativesmall molecule inhibitorsubchondral bonetissue regenerationtissue repairtranscriptomics
中文摘要
摘要
骨关节炎(OA)是一种慢性疼痛的疾病,也是世界各地导致残疾的主要原因。办公自动化是
以关节软骨恶化和其他关节病变为特征,包括半月板和韧带
损伤、滑膜炎、骨刺和关节疼痛。目前批准的治疗方法都不能改变疾病
通过减缓关节软骨退化或修复对关节组织的损伤而进展。我们确认了Phlpp
磷酸酶作为软骨再生和关节疼痛的可修改靶点。PHLPP1和Phlpp2是
在人骨性关节炎软骨中异常表达。PHLPP1基因敲除(KO)小鼠受到软骨保护
手术后的退化和疼痛相关行为(痛觉过敏和活动减少)会破坏关节的稳定
内侧半月板(DMM),但PHLPP1条件性缺失的小鼠仅表达聚集蛋白(AGC)
细胞(PHLPP1 CKOAgc)只能防止软骨退化,而不能减少流动性。这些结果
提示PHLPP1在软骨细胞中的内在作用,以及PHLPP1/2在其他组织或细胞中的作用
在关节内。有趣的是,PHLPP1和Phlpp2的小分子抑制剂进一步减缓了软骨的生长
在PHLPP1 CKOAgc小鼠体内降解,并增加行动能力。PHLPP1/2抑制剂也刺激软骨细胞
抑制神经突起的生长和感觉神经元基因的表达
体外和体内。总之,这些数据表明PHLPP1/2在多种细胞类型/组织中的活性
关节参与了骨性关节炎的发病,而Phlpp2可能通过以下途径影响骨性关节炎的表型
通过调节关节神经支配和疼痛相关来补偿软骨和/或PHLPP1缺陷
行为。这个项目的总体目标是定义PHLPP1和Phlpp2如何调节软骨数量
和质量(即僵硬)以及PHLPP1/2失活如何促进损伤诱导的神经支配。具体的
目的:1)阐明PHLPP1和Phlpp2在关节损伤后关节软骨细胞中的作用;2)
确定PHLPP1和Phlpp2如何影响关节软骨的生物力学和结构特性
损伤后和整个衰老过程中的其他关节组织,以及3)确定感觉神经元中PHLPP1/2的活性
以及与骨性关节炎相关的疼痛行为。这些研究将提供关于两国之间关系的新信息
关节损伤,关节神经支配和疼痛。这样的洞察力将使急需的疾病的发展-
修改治疗骨性关节炎的药物。
英文摘要
ABSTRACT
Osteoarthritis (OA) is a chronically painful condition and a leading cause of disability around the world. OA is
characterized by articular cartilage deterioration and other joint pathologies including meniscus and ligament
damage, synovitis, bone spurs and joint pain. None of the currently approved treatments alter disease
progression by slowing articular cartilage degradation or repairing damage to joint tissues. We identified Phlpp
phosphatases as modifiable targets for cartilage regeneration and joint pain. Phlpp1 and Phlpp2 are
abnormally expressed in human OA cartilage. Phlpp1 knockout (KO) mice are protected from cartilage
degradation and pain-related behaviors (allodynia and reduced mobility) after surgery that destabilizes the
medial meniscus (DMM), but mice where Phlpp1 is conditionally depleted in just aggrecan (Agc)-expressing
cells (Phlpp1 CKOAgc) are only protected from cartilage degradation, not reduced mobility. These results
indicate an intrinsic role for Phlpp1 in chondrocytes, as well as a role for Phlpp1/2 in other tissues or cells
within articulating joints. Of interest, small molecule inhibitors of Phlpp1 and Phlpp2 further slow cartilage
degradation in Phlpp1 CKOAgc mice and increase mobility. Phlpp1/2 inhibitors also stimulate chondrocyte
proliferation and matrix production and prevent neurite outgrowth and expression of sensory neuron genes in
vitro and in vivo. Together these data indicate that Phlpp1/2 activity in multiple cell types/tissues within
articulating joints contributes to OA pathogenesis and that Phlpp2 may contribute to OA phenotypes by
compensating for Phlpp1 deficiency in cartilage and/or by regulating joint innervation and pain-related
behaviors. The overall goals of this project are to define how Phlpp1 and Phlpp2 modulate cartilage quantity
and quality (i.e. stiffness) and how Phlpp1/2 inactivation contributes to injury-induced innervation. The specific
aims are to: 1) Elucidate the roles of Phlpp1 and Phlpp2 in articular chondrocytes following a joint injury, 2)
Determine how Phlpp1 and Phlpp2 affect biomechanical and structural properties of articular cartilage and
other joint tissues after injury and throughout aging, and 3) Define activities of Phlpp1/2 in sensory neurons
and OA-associated pain behaviors. These studies will provide new information about the relationship between
joint damage, joint innervation and pain. Such insights will enable the development of much needed disease-
modifying drugs for osteoarthritis.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.3390/s23041835
发表时间:
2023-02-07
期刊:
Sensors (Basel, Switzerland)
影响因子:
--
作者:
[Arnold KM, Sicard D, Tschumperlin DJ, Westendorf JJ]
通讯作者:
Westendorf JJ
Phlpp phosphatases in osteoarthritis
-
批准号:10318360
-
项目类别:
-
资助金额:$39.75万
-
财政年份:2022
-
负责人:Jennifer J Westendorf
-
依托单位:
Girk2/3 channels in cartilage biology and disease
-
批准号:9902333
-
项目类别:
-
资助金额:$17.49万
-
财政年份:2019
-
负责人:Jennifer J Westendorf
-
依托单位:
Girk2/3 channels in cartilage biology and disease
-
批准号:9755834
-
项目类别:
-
资助金额:$20.99万
-
财政年份:2019
-
负责人:Jennifer J Westendorf
-
依托单位:
Protein Phosphatase Phlpp1 in Cartilage Development & Osteoarthritis Progression
-
批准号:9316518
-
项目类别:
-
资助金额:$34.98万
-
财政年份:2014
-
负责人:Jennifer J Westendorf
-
依托单位:
Phlpp protein phosphatases in cartilage development and disease
-
批准号:10021149
-
项目类别:
-
资助金额:$55.18万
-
财政年份:2014
-
负责人:Jennifer J Westendorf
-
依托单位:
Protein Phosphatase Phlpp1 in Cartilage Development & Osteoarthritis Progression
-
批准号:8687230
-
项目类别:
-
资助金额:$34.98万
-
财政年份:2014
-
负责人:Jennifer J Westendorf
-
依托单位:
Runx2 and Axin2 Interactions During Bone Formation
-
批准号:8092653
-
项目类别:
-
资助金额:$37.1万
-
财政年份:2010
-
负责人:Jennifer J Westendorf
-
依托单位:
Runx2 and Axin2 Interactions During Bone Formation
-
批准号:8721570
-
项目类别:
-
资助金额:$9.62万
-
财政年份:2010
-
负责人:Jennifer J Westendorf
-
依托单位:
Runx2 and Axin2 Interactions During Bone Formation
-
批准号:8685767
-
项目类别:
-
资助金额:$47.48万
-
财政年份:2010
-
负责人:Jennifer J Westendorf
-
依托单位:
Runx2 and Axin2 Interactions During Bone Formation
-
批准号:8485581
-
项目类别:
-
资助金额:$36.35万
-
财政年份:2010
-
负责人:Jennifer J Westendorf
-
依托单位:
Runx2 and Axin2 Interactions During Bone Formation
-
批准号:8277079
-
项目类别:
-
资助金额:$37.86万
-
财政年份:2010
-
负责人:Jennifer J Westendorf
-
依托单位:
Musculoskeletal Research Training Program
-
批准号:8261861
-
项目类别:
-
资助金额:$33.91万
-
财政年份:2009
-
负责人:Jennifer J Westendorf
-
依托单位:
Musculoskeletal Research Training Program
-
批准号:7822860
-
项目类别:
-
资助金额:$31.85万
-
财政年份:2009
-
负责人:Jennifer J Westendorf
-
依托单位:
Musculoskeletal Research Training Program
-
批准号:8664128
-
项目类别:
-
资助金额:$26.67万
-
财政年份:2009
-
负责人:Jennifer J Westendorf
-
依托单位:
Musculoskeletal Research Training Program
-
批准号:10403945
-
项目类别:
-
资助金额:$56.63万
-
财政年份:2009
-
负责人:Jennifer J Westendorf
-
依托单位:
Regulation of RUNX-2 Transcriptional Activity
-
批准号:7900638
-
项目类别:
-
资助金额:$7.14万
-
财政年份:2009
-
负责人:Jennifer J Westendorf
-
依托单位:
Musculoskeletal Research Training Program
-
批准号:10615206
-
项目类别:
-
资助金额:$39.02万
-
财政年份:2009
-
负责人:Jennifer J Westendorf
-
依托单位:
Musculoskeletal Research Training Program
-
批准号:7626157
-
项目类别:
-
资助金额:$32.64万
-
财政年份:2009
-
负责人:Jennifer J Westendorf
-
依托单位:
Musculoskeletal Research Training Program
-
批准号:9914218
-
项目类别:
-
资助金额:$47.73万
-
财政年份:2009
-
负责人:Jennifer J Westendorf
-
依托单位:
Musculoskeletal Research Training Program
-
批准号:8465098
-
项目类别:
-
资助金额:$30.49万
-
财政年份:2009
-
负责人:Jennifer J Westendorf
-
依托单位:
海外基金